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Entry
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- *300005 - METHYL-CpG-BINDING PROTEIN 2; MECP2
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- OMIM
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<div class="container hidden-print">
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<div id="mimAlertBanner">
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</div>
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*300005</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/300005">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000169057;t=ENST00000453960" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=4204" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=300005" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000169057;t=ENST00000453960" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001110792,NM_001316337,NM_001369391,NM_001369392,NM_001369393,NM_001369394,NM_001386137,NM_001386138,NM_001386139,NM_004992,XM_024452383,XM_047442115,XM_047442116,XM_047442117,XM_047442118,XM_047442119,XM_047442120,XM_047442121,XM_047442122" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001110792" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=300005" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=02050&isoform_id=02050_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/MECP2" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/899296,972765,1708973,1752668,1934902,2246416,3002591,4826830,5419677,6959308,15079580,21594353,31874179,45181603,62088508,119593163,119593164,119593165,158259911,160707950,225734655,242350737,242350739,262089225,289719650,294487675,294487881,295651477,300518922,300518924,305861203,306450689,320006183,320006185,332368141,514314670,514314672,514314674,514314676,514314678,514314680,514314682,514314684,514314686,514314688,514314690,514314692,514314694,514314696,514314698,514314700,514314702,514314704,514314706,514314708,514314710,514314712,514314714,514314716,514314718,514314720,514314722,514314724,514314726,514314728,514314730,514314732,514314734,514314736,514314738,514314740,514314742,514314744,514314746,514314748,514314750,514314752,514314754,514314756,514314758,514314760,514314762,514314764,514314766,514314768,514314770,514314772,514314774,514314776,514314778,514314780,514314782,514314784,514314786,514314788,514314790,514314792,514314794,514314796,514314798,514314800,514314802,514314804,514314806,514314808,514314810,514314812,514314814,514314816,514314818,514314820,514314822,514314824,514314826,514314828,514314830,514314832,514314834,514314836,514314838,514314840,514314842,514314844,514314846,514314848,514314850,514314852,514314854,514314856,514314858,514314860,514314862,514314864,514314866,514314868,514314870,514314872,514314874,514314876,514314878,514314880,514314882,514314884,514314886,514314888,514314890,514314892,514314894,514314896,514314898,514314900,514314902,514314904,514314906,514314908,514314910,514314912,514314914,514314916,514314918,514314920,514314922,514314924,514314926,514314928,514314930,514314932,514314934,514314936,514314938,514314940,514314942,514314944,514314946,514314948,514314950,514314952,514314954,514314956,514314958,514314960,514314962,514314964,514314966,514314968,514314970,514314972,514314974,514314976,514314978,514314980,514314982,514314984,514314986,514314988,514314990,514314992,514314994,514314996,514314998,514315000,514315002,514315004,514315006,514315008,514315010,514315012,514315014,514315016,514315018,514315020,514315022,514315024,514315026,514315028,514315030,514315032,514315034,514315036,514315038,514315040,514315042,514315044,514315046,514315048,514315050,514315052,514315054,514315056,514315058,514315060,514315062,514315064,514315066,514315068,514315070,514315072,514315074,514315076,514315078,514315080,514315082,514315084,514315086,514315088,514315090,514315092,514315094,514315096,514315098,514315100,514315102,514315104,514315106,514315108,514315110,514315112,514315114,514315116,514315118,514315120,514315122,514315124,514315126,514315128,514315130,514315132,514315134,514315137,514315139,514315141,514315143,514315145,514315147,514315149,514315151,514315153,514315155,514315157,514315159,514315161,514315163,514315165,514315167,514315169,514315171,514315173,514315175,514315177,514315179,514315181,514315183,514315185,514315187,514315189,514315191,514315193,514315195,514315197,514315199,514315201,514315203,514315205,514315207,514315209,514315211,514315213,514315215,514315217,514315219,514315221,514315223,514315225,514315227,514315229,514315231,514315233,514315235,514315237,514315239,514315241,514315243,514315245,514315247,514315249,514315251,514315253,514315255,514315257,514315259,514315261,514315263,514315265,514315267,514315269,514315271,514315273,514315275,514315277,514315279,514315281,514315283,514315285,514315287,514315289,514315291,514315293,514315295,514315297,514315299,514315301,514315303,514315305,514315307,684774532,938320031,957949722,957949725,957949728,957949731,957949734,957949737,957949740,1370516199,1609037527,1609038312,1609039335,1609043903,1887789650,1887789719,1887789737,2217392285,2217392287,2217392323,2217392325,2217392327,2217392329,2217392331,2217392333,2462629520,2462629522,2462629524,2462629526,2462629528,2462629530,2462629532,2462629534,2462629536" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/P51608" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=4204" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000169057;t=ENST00000453960" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=MECP2" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=MECP2" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+4204" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/MECP2" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:4204" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/4204" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chrX&hgg_gene=ENST00000453960.7&hgg_start=154021573&hgg_end=154097717&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:6990" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:6990" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=300005[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=300005[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/MECP2/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000169057" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=MECP2" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=MECP2" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=MECP2" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://mecp2.chw.edu.au/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">RettBASE</a></div><div style="margin-left: 0.5em;"><a href="http://www.LOVD.nl/MECP2" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">MECP2 database at LOVD</a></div><div style="margin-left: 0.5em;"><a href="https://research.cchmc.org/LOVD2/home.php?select_db=MECP2" title="CCHMC Molecular Genetics Laboratory Mutation Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">CCHMC Molecular Genetics L…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=MECP2&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA30729" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:6990" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:99918" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/MECP2#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:99918" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/4204/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA002406/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=4204" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-7190" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:300005" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=MECP2&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 68618008, 702356009, 702816000, 718393002, 771303004<br />
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<strong>ICD10CM:</strong> F84.2<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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300005
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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METHYL-CpG-BINDING PROTEIN 2; MECP2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=MECP2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MECP2</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/X/851?start=-3&limit=10&highlight=851">Xq28</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:154021573-154097717&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">X:154,021,573-154,097,717</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=300496,300673,300055,300260,312750,312750,312750" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
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|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
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</th>
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|
<th>
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|
Inheritance
|
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</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
|
</thead>
|
|
<tbody>
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|
|
|
<tr>
|
|
<td rowspan="7">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/X/851?start=-3&limit=10&highlight=851">
|
|
Xq28
|
|
</a>
|
|
</span>
|
|
</td>
|
|
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<td>
|
|
<span class="mim-font">
|
|
{Autism susceptibility, X-linked 3}
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/300496"> 300496 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked">XL</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
|
</td>
|
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</tr>
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Encephalopathy, neonatal severe
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/300673"> 300673 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Intellectual developmental disorder, X-linked syndromic 13
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/300055"> 300055 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Intellectual developmental disorder, X-linked syndromic, Lubs type
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/300260"> 300260 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Rett syndrome
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/312750"> 312750 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked dominant">XLD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Rett syndrome, atypical
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/312750"> 312750 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked dominant">XLD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Rett syndrome, preserved speech variant
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/312750"> 312750 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked dominant">XLD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
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|
|
</tbody>
|
|
</table>
|
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/300005" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/300005" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
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<p />
|
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</div>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
|
<a id="text" class="mim-anchor"></a>
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<h4>
|
|
|
|
<span class="mim-font">
|
|
<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
|
<strong>TEXT</strong>
|
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</span>
|
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</span>
|
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</h4>
|
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|
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<div>
|
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<a id="description" class="mim-anchor"></a>
|
|
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div id="mimDescriptionFold" class="collapse in ">
|
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<span class="mim-text-font">
|
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<p>MECP2, which binds methylated CpGs, is a chromatin-associated protein that can both activate and repress transcription. It is required for maturation of neurons and is developmentally regulated (summary by <a href="#127" class="mim-tip-reference" title="Swanberg, S. E., Nagarajan, R. P., Peddada, S., Yasui, D. H., LaSalle, J. M. <strong>Reciprocal co-regulation of EGR2 and MECP2 is disrupted in Rett syndrome and autism.</strong> Hum. Molec. Genet. 18: 525-534, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19000991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19000991</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19000991[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn380" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19000991">Swanberg et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19000991" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
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</span>
|
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
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<p><a href="#78" class="mim-tip-reference" title="Lewis, J. D., Meehan, R. R., Henzel, W. J., Maurer-Fogy, I., Jeppesen, P., Klein, F., Bird, A. <strong>Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA.</strong> Cell 69: 905-914, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1606614/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1606614</a>] [<a href="https://doi.org/10.1016/0092-8674(92)90610-o" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1606614">Lewis et al. (1992)</a> identified and cloned Mecp2 from a rat brain cDNA library. The deduced 492-amino acid protein has a molecular mass of 53 kD and is rich in basic amino acids and potential phosphorylation sites. Immunofluorescent staining showed that the distribution of Mecp2 along chromosomes parallels that of methyl-CpG. In the mouse, Mecp2 is concentrated in pericentromeric heterochromatin, which contains about 40% of all genomic 5-methylcytosine. Unlike methyl-CpG-binding protein-1 (MBD1; <a href="/entry/156535">156535</a>), MECP2 is able to bind a single methyl-CpG pair. <a href="#100" class="mim-tip-reference" title="Nan, X., Meehan, R. R., Bird, A. <strong>Dissection of the methyl-CpG binding domain from the chromosomal protein MeCP2.</strong> Nucleic Acids Res. 21: 4886-4892, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8177735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8177735</a>] [<a href="https://doi.org/10.1093/nar/21.21.4886" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8177735">Nan et al. (1993)</a> cloned the rat Mecp2 gene and defined the methyl-CpG-binding domain (MBD). The MBD is 85 amino acids long and binds exclusively to DNA that contains one or more symmetrically methylated CpGs. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8177735+1606614" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a rat MECP2 probe to screen a human skeletal muscle cDNA library, <a href="#36" class="mim-tip-reference" title="D'Esposito, M., Quaderi, N. A., Ciccodicola, A., Bruni, P., Esposito, T., D'Urso, M., Brown, S. D. M. <strong>Isolation, physical mapping, and Northern analysis of the X-linked human gene encoding methyl CpG-binding protein, MECP2.</strong> Mammalian Genome 7: 533-535, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8672133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8672133</a>] [<a href="https://doi.org/10.1007/s003359900157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8672133">D'Esposito et al. (1996)</a> isolated the human homolog, which encodes a deduced 485-amino acid protein. The human and rat proteins share 93% overall sequence identity and 100% identity in the MBD region. Northern blot analysis detected a 1.8-kb transcript in all tissues analyzed, with the highest level of expression in heart and skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8672133" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#92" class="mim-tip-reference" title="Mnatzakanian, G. N., Lohi, H., Munteanu, I., Alfred, S. E., Yamada, T., MacLeod, P. J. M., Jones, J. R., Scherer, S. W., Schanen, N. C., Friez, M. J., Vincent, J. B., Minassian, B. A. <strong>A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome.</strong> Nature Genet. 36: 339-341, 2004. Note: Erratum: Nature Genet. 36: 540 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034579</a>] [<a href="https://doi.org/10.1038/ng1327" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15034579">Mnatzakanian et al. (2004)</a> identified a theretofore unknown isoform of MECP2 that they called MECP2B. They referred to the known isoform as MECP2A, which has a translation start site in exon 2 and uses full-length exons 3 and 4 to yield a 486-residue protein. In contrast, the MECP2B transcript uses exon 1 of MECP2, skips exon 2, and then uses full-length exons 3 and 4 to yield a 498-residue protein. Thus, the 2 isoforms differ at the N terminus. MECP2B is expressed in all tissues, including fetal and adult brain and brain subregions. In adult human brain, MECP2B expression is 10 times higher than that of MECP2A. MECP2A is expressed more abundantly in placenta, liver, and skeletal muscle. The MECP2A and MECP2B (or MECP2-beta) isoforms are also known, respectively, as MeCP2_e2 (encoded by exons 2, 3, and 4) and MeCP2_e1 (encoded by exons 1, 3, and 4) (<a href="#44" class="mim-tip-reference" title="Fichou, Y., Nectoux, J., Bahi-Buisson, N., Rosas-Vargas, H., Girard, B., Chelly, J., Bienvenu, T. <strong>The first missense mutation causing Rett syndrome specifically affecting the MeCP2_e1 isoform.</strong> Neurogenetics 10: 127-133, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19034540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19034540</a>] [<a href="https://doi.org/10.1007/s10048-008-0161-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19034540">Fichou et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15034579+19034540" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In mice, <a href="#64" class="mim-tip-reference" title="Itoh, M., Tahimic, C. G. T., Ide, S., Otsuki, A., Sasaoka, T., Noguchi, S., Oshimura, M., Goto, Y., Kurimasa, A. <strong>Methyl CpG-binding protein isoform MeCP2_e2 is dispensable for Rett syndrome phenotypes but essential for embryo viability and placenta development.</strong> J. Biol. Chem. 287: 13859-13867, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22375006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22375006</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22375006[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M111.309864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22375006">Itoh et al. (2012)</a> demonstrated a role for the Mecp2_e2 isoform in placenta development and embryo viability (see ANIMAL MODEL). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22375006" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#111" class="mim-tip-reference" title="Reichwald, K., Thiesen, J., Wiehe, T., Weitzel, J., Stratling, W. H., Kioschis, P., Poustka, A., Rosenthal, A., Platzer, M. <strong>Comparative sequence analysis of the MECP2-locus in human and mouse reveals new transcribed regions.</strong> Mammalian Genome 11: 182-190, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10723722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10723722</a>] [<a href="https://doi.org/10.1007/s003350010035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10723722">Reichwald et al. (2000)</a> determined that the human MECP2 gene has 4 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10723722" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#109" class="mim-tip-reference" title="Quaderi, N. A., Meehan, R. R., Tate, P. H., Cross, S. H., Bird, A. P., Chatterjee, A., Herman, G. E., Brown, S. D. M. <strong>Genetic and physical mapping of a gene encoding a methyl CpG binding protein, Mecp2, to the mouse X chromosome.</strong> Genomics 22: 648-651, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8001979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8001979</a>] [<a href="https://doi.org/10.1006/geno.1994.1442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8001979">Quaderi et al. (1994)</a> mapped the mouse Mecp2 gene to a 40-kb interval between L1cam and Rsvp in the central span of the mouse X chromosome, close to the microsatellite marker DXMit1. This region is known to be syntenically equivalent to human Xq28, and, with the exception of F8A, locus order is conserved between the 2 species. Therefore, <a href="#36" class="mim-tip-reference" title="D'Esposito, M., Quaderi, N. A., Ciccodicola, A., Bruni, P., Esposito, T., D'Urso, M., Brown, S. D. M. <strong>Isolation, physical mapping, and Northern analysis of the X-linked human gene encoding methyl CpG-binding protein, MECP2.</strong> Mammalian Genome 7: 533-535, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8672133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8672133</a>] [<a href="https://doi.org/10.1007/s003359900157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8672133">D'Esposito et al. (1996)</a> expected the human MECP2 gene to be located between L1CAM (<a href="/entry/308840">308840</a>) and the RCP/GCP color vision loci. A filter containing all YACs localized between these 2 points was hybridized with the rat Mecp2 probe, and 3 overlapping YACs were positive for MECP2, placing MECP2 about 70 kb centromeric to the RCP/GCP color vision cluster. By fluorescence in situ hybridization, <a href="#136" class="mim-tip-reference" title="Vilain, A., Apiou, F., Vogt, N., Dutrillaux, B., Malfoy, B. <strong>Assignment of the gene for methyl-CpG-binding protein 2 (MECP2) to human chromosome band Xq28 by in situ hybridization.</strong> Cytogenet. Cell Genet. 74: 293-294, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8976388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8976388</a>] [<a href="https://doi.org/10.1159/000134438" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8976388">Vilain et al. (1996)</a> confirmed the Xq28 map position of MECP2. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8672133+8976388+8001979" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#106" class="mim-tip-reference" title="Ohki, I., Shimotake, N., Fujita, N., Jee, J.-G., Ikegami, T., Nakao, M., Shirakawa, M. <strong>Solution structure of the methyl-CpG binding domain of human MBD1 in complex with methylated DNA.</strong> Cell 105: 487-497, 2001. Note: Erratum: Cell 105: 815 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11371345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11371345</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00324-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11371345">Ohki et al. (2001)</a> reported the solution structure of the conserved MBD of human MBD1 bound to methylated DNA. DNA binding causes a loop in MBD1 to fold into a major and novel DNA-binding interface. Recognition of the methyl groups and CG sequence at the methylation site is due to 5 highly conserved residues that form a hydrophobic patch. The authors concluded that the structure indicates how the MBD may access nucleosomal DNA without encountering steric interference from core histones. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11371345" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Electron Microscopy</em></strong></p><p>
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<a href="#51" class="mim-tip-reference" title="Georgel, P. T., Horowitz-Scherer, R. A., Adkins, N., Woodcock, C. L., Wade, P. A., Hansen, J. C. <strong>Chromatin compaction by human MeCP2: assembly of novel secondary chromatin structures in the absence of DNA methylation.</strong> J. Biol. Chem. 278: 32181-32188, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12788925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12788925</a>] [<a href="https://doi.org/10.1074/jbc.M305308200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12788925">Georgel et al. (2003)</a> used electron cryomicroscopy and electron microscope tomography to characterize complexes formed between recombinant human MECP2 and 12-mer nucleasomal arrays. At molar ratios near 1 MECP2 per nucleosome, binding of MECP2 converted extended nucleosomal arrays into extensively compacted 60S ellipsoidal structures. At molar ratios at or above 1 MECP2 per nucleosome, the 60S particles assembled into morphologically defined oligomeric suprastructures. The ability of MECP2 to mediate chromatin compaction did not require its MBD. <a href="#51" class="mim-tip-reference" title="Georgel, P. T., Horowitz-Scherer, R. A., Adkins, N., Woodcock, C. L., Wade, P. A., Hansen, J. C. <strong>Chromatin compaction by human MeCP2: assembly of novel secondary chromatin structures in the absence of DNA methylation.</strong> J. Biol. Chem. 278: 32181-32188, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12788925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12788925</a>] [<a href="https://doi.org/10.1074/jbc.M305308200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12788925">Georgel et al. (2003)</a> concluded that MECP2 is a chromatin-condensing protein that mediates assembly of novel secondary chromatin structures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12788925" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Inactivation of X-linked genes is usually associated with methylation of the CpG island at the 5-prime end of the gene. Proteins that recognize and bind to methylated bases in DNA include the methylated DNA-binding protein MECP2. To determine whether this gene is expressed from the inactive X chromosome, <a href="#3" class="mim-tip-reference" title="Adler, D. A., Quaderi, N. A., Brown, S. D. M., Chapman, V. M., Moore, J., Tate, P., Disteche, C. M. <strong>The X-linked methylated DNA binding protein, Mecp2, is subject to X inactivation in the mouse.</strong> Mammalian Genome 6: 491-492, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8589515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8589515</a>] [<a href="https://doi.org/10.1007/BF00356163" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8589515">Adler et al. (1995)</a> used an X/autosome translocation system in the mouse in which expression from the Mecp2 allele on the inactive X chromosome could be assayed. Results from these experiments indicated that Mecp2 is subject to X inactivation in mouse. <a href="#36" class="mim-tip-reference" title="D'Esposito, M., Quaderi, N. A., Ciccodicola, A., Bruni, P., Esposito, T., D'Urso, M., Brown, S. D. M. <strong>Isolation, physical mapping, and Northern analysis of the X-linked human gene encoding methyl CpG-binding protein, MECP2.</strong> Mammalian Genome 7: 533-535, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8672133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8672133</a>] [<a href="https://doi.org/10.1007/s003359900157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8672133">D'Esposito et al. (1996)</a> demonstrated that the MECP2 gene in humans is subject to X inactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8672133+8589515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To find out whether the heterochromatic localization of MECP2 depends on DNA methylation, <a href="#102" class="mim-tip-reference" title="Nan, X., Tate, P., Li, E., Bird, A. <strong>DNA methylation specifies chromosomal localization of MeCP2.</strong> Molec. Cell. Biol. 16: 414-421, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8524323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8524323</a>] [<a href="https://doi.org/10.1128/MCB.16.1.414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8524323">Nan et al. (1996)</a> transiently expressed rat Mecp2-LacZ fusion proteins in cultured cells. Intact protein was targeted to heterochromatin in wildtype cells but was insufficiently localized in mutant cells with low levels of genomic DNA methylation. Deletions within Mecp2 showed that localization to heterochromatin required the 85-amino acid methyl-CpG binding domain but not the remainder of the protein. Thus, Mecp2 is a methyl-CpG-binding protein in vivo and is likely to be a major mediator of downstream consequences of DNA methylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8524323" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>MECP2 is an abundant chromosomal protein that binds specifically to methylated DNA in vitro and depends upon methyl-CpG for its chromosomal distribution in vivo. To assess its functional significance, <a href="#128" class="mim-tip-reference" title="Tate, P., Skarnes, W., Bird, A. <strong>The methyl-CpG binding protein MeCP2 is essential for embryonic development in the mouse.</strong> Nature Genet. 12: 205, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8563762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8563762</a>] [<a href="https://doi.org/10.1038/ng0296-205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8563762">Tate et al. (1996)</a> mutated the X-linked gene in male mouse embryonic stem (ES) cells using a promoterless gene-targeting construct containing a lacZ reporter gene. Mutant ES cells lacking MECP2 grew with the same vigor as the parental line and were capable of considerable differentiation. Chimeric embryos derived from several independent mutant lines, however, exhibited development defects with a severity that was positively correlated with the distribution of mutant cells. The results demonstrated to the authors that MECP2, like DNA methyltransferase (DNMT1; <a href="/entry/126375">126375</a>), is dispensable in stem cells but is essential for embryonic development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8563762" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#98" class="mim-tip-reference" title="Nan, X., Campoy, F. J., Bird, A. <strong>MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin.</strong> Cell 88: 471-481, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9038338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9038338</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81887-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9038338">Nan et al. (1997)</a> found that native and recombinant rat Mecp2 repressed transcription in vitro from methylated promoters but did not repress nonmethylated promoters. Moreover, Mecp2 was able to displace histone H1 (HIF1; <a href="/entry/142709">142709</a>) from preassembled chromatin that contains methyl-CpG. These properties, together with the abundance of Mecp2 and the high frequency of its 2-bp binding site, suggested a role as a global transcriptional repressor in vertebrate genomes. <a href="#101" class="mim-tip-reference" title="Nan, X., Ng, H.-H., Johnson, C. A., Laherty, C. D., Turner, B. M., Eisenman, R. N., Bird, A. <strong>Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex.</strong> Nature 393: 386-389, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9620804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9620804</a>] [<a href="https://doi.org/10.1038/30764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9620804">Nan et al. (1998)</a> studied the mechanism of repression by Mecp2. Mecp2 binds tightly to chromosomes in a methylation-dependent manner. It contains a transcriptional-repression domain (TRD) that can function at a distance in vitro and in vivo. <a href="#101" class="mim-tip-reference" title="Nan, X., Ng, H.-H., Johnson, C. A., Laherty, C. D., Turner, B. M., Eisenman, R. N., Bird, A. <strong>Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex.</strong> Nature 393: 386-389, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9620804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9620804</a>] [<a href="https://doi.org/10.1038/30764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9620804">Nan et al. (1998)</a> showed that a region of Mecp2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases (see HDAC1; <a href="/entry/601241">601241</a>). Transcriptional repression in vivo is relieved by the deacetylase inhibitor trichostatin A, indicating that deacetylation of histones (and/or of other proteins) is an essential component of this repression mechanism. The data suggested that 2 global mechanisms of gene regulation, DNA methylation and histone deacetylation, can be linked by Mecp2. In Xenopus oocytes, DNA methylation dominantly silences transcription through the assembly of a repressive nucleosomal array. <a href="#66" class="mim-tip-reference" title="Jones, P. L., Veenstra, G. J. C., Wade, P. A., Vermaak, D., Kass, S. U., Landsberger, N., Strouboulis, J., Wolffe, A. P. <strong>Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription.</strong> Nature Genet. 19: 187-191, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9620779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9620779</a>] [<a href="https://doi.org/10.1038/561" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9620779">Jones et al. (1998)</a> found that silencing conferred by Mecp2 and methylated DNA can be relieved by inhibition of histone deacetylase, facilitating the remodeling of chromatin and transcriptional activation. These results established a direct causal relationship between DNA methylation-dependent transcriptional silencing and the modification of chromatin. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9038338+9620804+9620779" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#121" class="mim-tip-reference" title="Shahbazian, M. D., Antalffy, B., Armstrong, D. L., Zoghbi, H. Y. <strong>Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation.</strong> Hum. Molec. Genet. 11: 115-124, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11809720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11809720</a>] [<a href="https://doi.org/10.1093/hmg/11.2.115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11809720">Shahbazian et al. (2002)</a> investigated the spatial and temporal distribution of the Mecp2 protein during mouse and human development. By Western blot analysis, they found that Mecp2 in the adult mouse is high in the brain, lung, and spleen, lower in heart and kidney, and barely detectable in liver, stomach, and small intestine. There was no obvious correlation between protein levels and RNA levels, suggesting that translation may be posttranscriptionally regulated by tissue-specific factors. The timing of Mecp2 expression in mouse and human correlated with the maturation of the central nervous system, with the ontogenetically older structures such as the spinal cord and brainstem becoming positive before newer structures such as the hippocampus and cerebral cortex. In the cortex, Mecp2 first appeared in the Cajal-Retzius cells, then in the neurons of the deeper, more mature cortical layers, and finally in the neurons of the more superficial layers. The Mecp2 protein was eventually present in a majority of neurons but was absent from glial cells. <a href="#121" class="mim-tip-reference" title="Shahbazian, M. D., Antalffy, B., Armstrong, D. L., Zoghbi, H. Y. <strong>Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation.</strong> Hum. Molec. Genet. 11: 115-124, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11809720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11809720</a>] [<a href="https://doi.org/10.1093/hmg/11.2.115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11809720">Shahbazian et al. (2002)</a> suggested that Mecp2 may become abundant only once a neuron has reached a certain degree of maturity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11809720" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Chen, W. G., Chang, Q., Lin, Y., Meissner, A., West, A. E., Griffith, E. C., Jaenisch, R., Greenberg, M. E. <strong>Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2.</strong> Science 302: 885-889, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14593183/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14593183</a>] [<a href="https://doi.org/10.1126/science.1086446" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14593183">Chen et al. (2003)</a> found that MECP2 binds selectively to BDNF (<a href="/entry/113505">113505</a>) promoter III and functions to repress expression of the BDNF gene. Membrane depolarization triggers the calcium-dependent phosphorylation and release of MECP2 from BDNF promoter III, thereby facilitating transcription. <a href="#29" class="mim-tip-reference" title="Chen, W. G., Chang, Q., Lin, Y., Meissner, A., West, A. E., Griffith, E. C., Jaenisch, R., Greenberg, M. E. <strong>Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2.</strong> Science 302: 885-889, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14593183/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14593183</a>] [<a href="https://doi.org/10.1126/science.1086446" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14593183">Chen et al. (2003)</a> concluded that MECP2 plays a key role in the control of neuronal activity-dependent gene regulation and that the deregulation of this process may underlie the pathology of Rett syndrome (RTT; <a href="/entry/312750">312750</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14593183" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#84" class="mim-tip-reference" title="Martinowich, K., Hattori, D., Wu, H., Fouse, S., He, F., Hu, Y., Fan, G., Sun, Y. E. <strong>DNA methylation-related chromatin remodeling in activity-dependent Bdnf gene regulation.</strong> Science 302: 890-893, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14593184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14593184</a>] [<a href="https://doi.org/10.1126/science.1090842" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14593184">Martinowich et al. (2003)</a> reported that increased synthesis of BDNF in mouse neurons after depolarization correlates with a decrease in CpG methylation within the regulatory region of the BDNF gene. Moreover, increased BDNF transcription involves dissociation of the MECP2-histone deacetylase-Sin3A (<a href="/entry/607776">607776</a>) repression complex from its promoter. <a href="#84" class="mim-tip-reference" title="Martinowich, K., Hattori, D., Wu, H., Fouse, S., He, F., Hu, Y., Fan, G., Sun, Y. E. <strong>DNA methylation-related chromatin remodeling in activity-dependent Bdnf gene regulation.</strong> Science 302: 890-893, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14593184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14593184</a>] [<a href="https://doi.org/10.1126/science.1090842" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14593184">Martinowich et al. (2003)</a> concluded that DNA methylation-related chromatin remodeling is important for activity-dependent gene regulation that may be critical for neural plasticity. <a href="#84" class="mim-tip-reference" title="Martinowich, K., Hattori, D., Wu, H., Fouse, S., He, F., Hu, Y., Fan, G., Sun, Y. E. <strong>DNA methylation-related chromatin remodeling in activity-dependent Bdnf gene regulation.</strong> Science 302: 890-893, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14593184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14593184</a>] [<a href="https://doi.org/10.1126/science.1090842" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14593184">Martinowich et al. (2003)</a> proposed a model in which DNA methylation and its related chromatin remodeling play critical roles in regulating gene transcription response to neuronal activity. CpG methylation at any critical site may increase the likelihood of MECP2 binding, which can recruit histone deacetylases and the H3-K9 methyltransferase to mediate inactive chromatin remodeling, or may directly induce chromatin compaction to repress gene expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14593184" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In Xenopus embryos, <a href="#125" class="mim-tip-reference" title="Stancheva, I., Collins, A. L., Van den Veyver, I. B., Zoghbi, H., Meehan, R. R. <strong>A mutant form of MeCP2 protein associated with human Rett syndrome cannot be displaced from methylated DNA by notch in Xenopus embryos.</strong> Molec. Cell 12: 425-435, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14536082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14536082</a>] [<a href="https://doi.org/10.1016/s1097-2765(03)00276-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14536082">Stancheva et al. (2003)</a> found that Mecp2 with the R168X (<a href="#0020">300005.0020</a>) truncation was unable to interact with the Smrt (NCOR2; <a href="/entry/600848">600848</a>) complex or fully activate Hairy2a, a a Notch-regulated neuronal repressor, during primary neurogenesis. This disruption of Mecp2 activity resulted in abnormal patterning of primary neurons during neuronal differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14536082" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By expressing rodent cDNAs in human embryonic kidney cells, <a href="#68" class="mim-tip-reference" title="Kimura, H., Shiota, K. <strong>Methyl-CpG-binding protein, MeCP2, is a target molecule for maintenance DNA methyltransferase, Dnmt1.</strong> J. Biol. Chem. 278: 4806-4812, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12473678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12473678</a>] [<a href="https://doi.org/10.1074/jbc.M209923200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12473678">Kimura and Shiota (2003)</a> showed that Dnmt1 interacted directly with Mecp2. Dnmt1 formed complexes with HDACs as well as with Mecp2, but Mecp2-interacting Dnmt1 did not bind Hdac1. Mecp2 could form complexes with hemimethylated and fully methylated DNA. Immunoprecipitated Mecp2 complexes showed DNA methyltransferase activity to hemimethylated DNA. <a href="#68" class="mim-tip-reference" title="Kimura, H., Shiota, K. <strong>Methyl-CpG-binding protein, MeCP2, is a target molecule for maintenance DNA methyltransferase, Dnmt1.</strong> J. Biol. Chem. 278: 4806-4812, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12473678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12473678</a>] [<a href="https://doi.org/10.1074/jbc.M209923200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12473678">Kimura and Shiota (2003)</a> concluded that DNMT1 associates with MECP2 in order to perform maintenance methylation during cell division. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12473678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#58" class="mim-tip-reference" title="Harikrishnan, K. N., Chow, M. Z., Baker, E. K., Pal, S., Bassal, S., Brasacchio, D., Wang, L., Craig, J. M., Jones, P. L., Sif, S., El-Osta, A. <strong>Brahma links the SWI/SNF chromatin-remodeling complex with MeCP2-dependent transcriptional silencing.</strong> Nature Genet. 37: 254-264, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15696166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15696166</a>] [<a href="https://doi.org/10.1038/ng1516" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15696166">Harikrishnan et al. (2005)</a> found that BRM (SMARCA2; <a href="/entry/600014">600014</a>) associated with MECP2 in mouse fibroblasts and human T-lymphoblastic leukemia cells, and the association was functionally linked with repression. Promoter methylation specified the recruitment of MECP2 and BRM, and inhibition of methylation caused their release. The MECP2-BRM corepressor complex was directly recruited to the FMR1 gene, and somatic knockdown in fragile X cells alleviated the repression. <a href="#58" class="mim-tip-reference" title="Harikrishnan, K. N., Chow, M. Z., Baker, E. K., Pal, S., Bassal, S., Brasacchio, D., Wang, L., Craig, J. M., Jones, P. L., Sif, S., El-Osta, A. <strong>Brahma links the SWI/SNF chromatin-remodeling complex with MeCP2-dependent transcriptional silencing.</strong> Nature Genet. 37: 254-264, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15696166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15696166</a>] [<a href="https://doi.org/10.1038/ng1516" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15696166">Harikrishnan et al. (2005)</a> concluded that both MECP2 and components of the SWI/SNF complex are involved in gene repression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15696166" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#71" class="mim-tip-reference" title="Klose, R. J., Sarraf, S. A., Schmiedeberg, L., McDermott, S. M., Stancheva, I., Bird, A. P. <strong>DNA binding selectivity of MeCP2 due to a requirement for A/T sequences adjacent to methyl-CpG.</strong> Molec. Cell 19: 667-678, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16137622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16137622</a>] [<a href="https://doi.org/10.1016/j.molcel.2005.07.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16137622">Klose et al. (2005)</a> found that genomic sites occupied by MECP2 and MBD2 (<a href="/entry/603547">603547</a>) were largely mutually exclusive. MBD2 was able to colonize sites vacated by MECP2 depletion, but the reverse was not true. Artificial selection of MECP2-binding sites in vitro demonstrated that MECP2 required an A/T run of 4 or more base pairs adjacent to the methyl-CpG for efficient DNA binding. <a href="#71" class="mim-tip-reference" title="Klose, R. J., Sarraf, S. A., Schmiedeberg, L., McDermott, S. M., Stancheva, I., Bird, A. P. <strong>DNA binding selectivity of MeCP2 due to a requirement for A/T sequences adjacent to methyl-CpG.</strong> Molec. Cell 19: 667-678, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16137622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16137622</a>] [<a href="https://doi.org/10.1016/j.molcel.2005.07.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16137622">Klose et al. (2005)</a> concluded that methyl-CpG is necessary, but not sufficient, for MECP2 binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16137622" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#99" class="mim-tip-reference" title="Nan, X., Hou, J., Maclean, A., Nasir, J., Lafuente, M. J., Shu, X., Kriaucionis, S., Bird, A. <strong>Interaction between chromatin proteins MECP2 and ATRX is disrupted by mutations that cause inherited mental retardation.</strong> Proc. Nat. Acad. Sci. 104: 2709-2714, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17296936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17296936</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17296936[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0608056104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17296936">Nan et al. (2007)</a> found that MECP2 interacts with ATRX (<a href="/entry/300032">300032</a>), a DNA helicase/ATPase that is mutated in the alpha-thalassemia/mental retardation syndrome (<a href="/entry/301040">301040</a>). Studies in cultured mouse cells showed that MECP2 targeted the C-terminal helicase domain of ATRX to heterochromatic foci. The heterochromatic localization of ATRX was disturbed in neurons from Mecp2-null mice. The findings suggested that disruption of MECP2-ATRX interaction leads to pathologic changes that contribute to mental retardation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17296936" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#120" class="mim-tip-reference" title="Schule, B., Li, H. H., Fisch-Kohl, C., Purmann, C., Francke, U. <strong>DLX5 and DLX6 expression is biallelic and not modulated by MeCP2 deficiency.</strong> Am. J. Hum. Genet. 81: 492-506, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17701895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17701895</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17701895[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/520063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17701895">Schule et al. (2007)</a> found that lymphoblastoid cells and brain cells from RTT patients with MECP2 mutations showed normal imprinting of the imprinted genes PEG3 (<a href="/entry/601483">601483</a>) and PEG10 (<a href="/entry/609810">609810</a>), indicating that the MECP2 protein is not necessary for normal imprinting to occur. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17701895" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In rodent brain tissue, <a href="#39" class="mim-tip-reference" title="Deng, V., Matagne, V., Banine, F., Frerking, M., Ohliger, P., Budden, S., Pevsner, J., Dissen, G. A., Sherman, L. S., Ojeda, S. R. <strong>FXYD1 is an MeCP2 target gene overexpressed in the brains of Rett syndrome patients and Mecp2-null mice.</strong> Hum. Molec. Genet. 16: 640-650, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17309881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17309881</a>] [<a href="https://doi.org/10.1093/hmg/ddm007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17309881">Deng et al. (2007)</a> identified the FXYD1 (<a href="/entry/602359">602359</a>) promoter as an endogenous target of MECP2, which can cause transcriptional regulation of FXYD1. Transgenic Mecp2-null mice had increased Fxyd1 mRNA and protein levels in the frontal cortex, similar to that observed in patients with Rett syndrome. Increased Fxyd1 expression in Mecp2-null mice was associated with decreased Na,K-ATPase activity in the frontal cortex. In cultured mouse neurons, overexpression of Fxyd1 was associated with decreased neuronal dendritic tree and spine formation compared to controls, findings that have been observed in Rett syndrome. Overall, the results suggested that derepression of FXYD1, resulting from inactivation of MECP2, may contribute to the neuropathogenesis of Rett syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17309881" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Chahrour, M., Jung, S. Y., Shaw, C., Zhou, X., Wong, S. T. C., Qin, J., Zoghbi, H. Y. <strong>MeCP2, a key contributor to neurological disease, activates and represses transcription.</strong> Science 320: 1224-1229, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18511691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18511691</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18511691[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1153252" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18511691">Chahrour et al. (2008)</a> examined gene expression patterns in the hypothalamus of mice that either lack or overexpress MECP2. In both models, MECP2 dysfunction induced changes in the expression levels of thousands of genes, but expectedly, the majority of genes (about 85%) appeared to be activated by MECP2. <a href="#24" class="mim-tip-reference" title="Chahrour, M., Jung, S. Y., Shaw, C., Zhou, X., Wong, S. T. C., Qin, J., Zoghbi, H. Y. <strong>MeCP2, a key contributor to neurological disease, activates and represses transcription.</strong> Science 320: 1224-1229, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18511691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18511691</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18511691[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1153252" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18511691">Chahrour et al. (2008)</a> then selected 6 genes, SST (<a href="/entry/182450">182450</a>), OPRK1 (<a href="/entry/165196">165196</a>), MEF2C (<a href="/entry/600662">600662</a>), GAMT (<a href="/entry/601240">601240</a>), GPRIN1 (<a href="/entry/611239">611239</a>), and A2BP1 (<a href="/entry/605104">605104</a>), and confirmed that MECP2 binds to their promoters. Furthermore, <a href="#24" class="mim-tip-reference" title="Chahrour, M., Jung, S. Y., Shaw, C., Zhou, X., Wong, S. T. C., Qin, J., Zoghbi, H. Y. <strong>MeCP2, a key contributor to neurological disease, activates and represses transcription.</strong> Science 320: 1224-1229, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18511691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18511691</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18511691[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1153252" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18511691">Chahrour et al. (2008)</a> showed that MECP2 associates with the transcriptional activator CREB1 (<a href="/entry/123810">123810</a>) at the promoter of an activated target but not a repressed target. <a href="#24" class="mim-tip-reference" title="Chahrour, M., Jung, S. Y., Shaw, C., Zhou, X., Wong, S. T. C., Qin, J., Zoghbi, H. Y. <strong>MeCP2, a key contributor to neurological disease, activates and represses transcription.</strong> Science 320: 1224-1229, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18511691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18511691</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18511691[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1153252" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18511691">Chahrour et al. (2008)</a> concluded that their study suggested that MECP2 regulates the expression of a wide range of genes in the hypothalamus and that it can function as both an activator and a repressor of transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18511691" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#127" class="mim-tip-reference" title="Swanberg, S. E., Nagarajan, R. P., Peddada, S., Yasui, D. H., LaSalle, J. M. <strong>Reciprocal co-regulation of EGR2 and MECP2 is disrupted in Rett syndrome and autism.</strong> Hum. Molec. Genet. 18: 525-534, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19000991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19000991</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19000991[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn380" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19000991">Swanberg et al. (2009)</a> showed by chromatin immunoprecipitation analysis that EGR2 (<a href="/entry/129010">129010</a>) bound to the MECP2 promoter and that MeCP2 bound to the intron 1 enhancer region of EGR2. Reduction in EGR2 and MeCP2 levels in cultured human neuroblastoma cells by RNAi reciprocally reduced expression of both EGR2 and MECP2 and their protein products. Mecp2-deficient mouse cortex samples showed significantly reduced EGR2 by quantitative immunofluorescence. Furthermore, MeCP2 and EGR2 showed coordinately increased levels during postnatal development of both mouse and human cortex. In contrast to age-matched controls, Rett and autism (<a href="/entry/209850">209850</a>) postmortem cortex samples showed significant reduction in EGR2. <a href="#127" class="mim-tip-reference" title="Swanberg, S. E., Nagarajan, R. P., Peddada, S., Yasui, D. H., LaSalle, J. M. <strong>Reciprocal co-regulation of EGR2 and MECP2 is disrupted in Rett syndrome and autism.</strong> Hum. Molec. Genet. 18: 525-534, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19000991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19000991</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19000991[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn380" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19000991">Swanberg et al. (2009)</a> proposed a role of dysregulation of an activity-dependent EGR2/MeCP2 pathway in Rett syndrome and autism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19000991" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Abuhatzira, L., Shemer, R., Razin, A. <strong>MeCP2 involvement in the regulation of neuronal alpha-tubulin production.</strong> Hum. Molec. Genet. 18: 1415-1423, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19174478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19174478</a>] [<a href="https://doi.org/10.1093/hmg/ddp048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19174478">Abuhatzira et al. (2009)</a> conducted expression analysis of cytoskeleton-related genes in brain tissue from RTT and AS patients. Striking examples of genes with reduced expression were TUBA1B (<a href="/entry/602530">602530</a>) and TUBA3 (TUBA1A; <a href="/entry/602529">602529</a>) that encode the ubiquitous alpha-tubulin and the neuronal specific alpha-tubulin, respectively. In accordance with downregulation of these genes, there was a reduction in the level of the corresponding protein product-tyrosinated alpha-tubulin. Low levels of alpha-tubulin and deteriorated cell morphology were also observed in Mecp2(-/y) mouse embryonic fibroblast cells. The effects of MeCP2 deficiency in these cells were completely reversed by introducing and expressing the human MECP2 gene. <a href="#1" class="mim-tip-reference" title="Abuhatzira, L., Shemer, R., Razin, A. <strong>MeCP2 involvement in the regulation of neuronal alpha-tubulin production.</strong> Hum. Molec. Genet. 18: 1415-1423, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19174478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19174478</a>] [<a href="https://doi.org/10.1093/hmg/ddp048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19174478">Abuhatzira et al. (2009)</a> proposed that MECP2 is involved in the regulation of neuronal alpha-tubulin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19174478" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#97" class="mim-tip-reference" title="Muotri, A. R., Marchetto, M. C. N., Coufal, N. G., Oefner, R., Yeo, G., Nakashima, K., Gage, F. H. <strong>L1 retrotransposition in neurons is modulated by MeCP2.</strong> Nature 468: 443-446, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21085180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21085180</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21085180[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21085180">Muotri et al. (2010)</a> showed that L1 neuronal transcription and retrotransposition in rodents are increased in the absence of Mecp2. Using neuronal progenitor cells derived from human induced pluripotent stem cells and human tissues, they revealed that patients with Rett syndrome, carrying MeCP2 mutations, have increased susceptibility for L1 retrotransposition. <a href="#97" class="mim-tip-reference" title="Muotri, A. R., Marchetto, M. C. N., Coufal, N. G., Oefner, R., Yeo, G., Nakashima, K., Gage, F. H. <strong>L1 retrotransposition in neurons is modulated by MeCP2.</strong> Nature 468: 443-446, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21085180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21085180</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21085180[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21085180">Muotri et al. (2010)</a> concluded that L1 retrotransposition can be controlled in a tissue-specific manner and that disease-related genetic mutations can influence the frequency of neuronal L1 retrotransposition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21085180" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#45" class="mim-tip-reference" title="Forlani, G., Giarda, E., Ala, U., Di Cunto, F., Salani, M., Tupler, R., Kilstrup-Nielsen, C., Landsberger, N. <strong>: The MeCP2/YY1 interaction regulates ANT1 expression at 4q35: novel hints for Rett syndrome pathogenesis.</strong> Hum. Molec. Genet. 19: 3114-3123, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20504995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20504995</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20504995[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq214" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20504995">Forlani et al. (2010)</a> demonstrated that MeCP2 interacts in vitro and in vivo with YY1 (<a href="/entry/600013">600013</a>). <a href="#45" class="mim-tip-reference" title="Forlani, G., Giarda, E., Ala, U., Di Cunto, F., Salani, M., Tupler, R., Kilstrup-Nielsen, C., Landsberger, N. <strong>: The MeCP2/YY1 interaction regulates ANT1 expression at 4q35: novel hints for Rett syndrome pathogenesis.</strong> Hum. Molec. Genet. 19: 3114-3123, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20504995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20504995</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20504995[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq214" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20504995">Forlani et al. (2010)</a> showed that MeCP2 cooperates with YY1 in repressing the ANT1 (<a href="/entry/103220">103220</a>) gene, encoding a mitochondrial adenine nucleotide translocase. Importantly, ANT1 mRNA levels are increased in human and mouse cell lines devoid of MeCP2, in Rett patient fibroblast, and in the brain of MeCP2-null mice. <a href="#45" class="mim-tip-reference" title="Forlani, G., Giarda, E., Ala, U., Di Cunto, F., Salani, M., Tupler, R., Kilstrup-Nielsen, C., Landsberger, N. <strong>: The MeCP2/YY1 interaction regulates ANT1 expression at 4q35: novel hints for Rett syndrome pathogenesis.</strong> Hum. Molec. Genet. 19: 3114-3123, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20504995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20504995</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20504995[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq214" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20504995">Forlani et al. (2010)</a> further demonstrated that ANT1 protein levels are upregulated in MeCP2-null mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20504995" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using phosphotryptic mapping, <a href="#43" class="mim-tip-reference" title="Ebert, D. H., Gabel, H. W., Robinson, N. D., Kastan, N. R., Hu, L. S., Cohen, S., Navarro, A. J., Lyst, M. J., Ekiert, R., Bird, A. P., Greenberg, M. E. <strong>Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR.</strong> Nature 499: 341-345, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23770587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23770587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23770587[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature12348" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23770587">Ebert et al. (2013)</a> identified 3 sites (S86, S274, and T308) of activity-dependent MeCP2 phosphorylation. Phosphorylation of these sites is differentially induced by neuronal activity, brain-derived neurotrophic factor (BDNF; <a href="/entry/113505">113505</a>), or agents that elevate the intracellular level of cAMP, indicating that MeCP2 may function as an epigenetic regulator of gene expression that integrates diverse signals from the environment. <a href="#43" class="mim-tip-reference" title="Ebert, D. H., Gabel, H. W., Robinson, N. D., Kastan, N. R., Hu, L. S., Cohen, S., Navarro, A. J., Lyst, M. J., Ekiert, R., Bird, A. P., Greenberg, M. E. <strong>Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR.</strong> Nature 499: 341-345, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23770587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23770587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23770587[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature12348" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23770587">Ebert et al. (2013)</a> showed that the phosphorylation of T308 blocks the interaction of the repressor domain of MeCP2 with the nuclear receptor corepressor (NCoR) complex (see <a href="/entry/600849">600849</a>) and suppresses the ability of MeCP2 to repress transcription. In knockin mice bearing the common human RTT missense mutation R306C (<a href="#0016">300005.0016</a>), neuronal activity failed to induce MeCP2 T308 phosphorylation, suggesting that the loss of T308 phosphorylation might contribute to RTT. Consistent with this possibility, the mutation of MeCP2 T308A in mice led to a decrease in the induction of a subset of activity-regulated genes and to RTT-like symptoms. <a href="#43" class="mim-tip-reference" title="Ebert, D. H., Gabel, H. W., Robinson, N. D., Kastan, N. R., Hu, L. S., Cohen, S., Navarro, A. J., Lyst, M. J., Ekiert, R., Bird, A. P., Greenberg, M. E. <strong>Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR.</strong> Nature 499: 341-345, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23770587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23770587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23770587[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature12348" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23770587">Ebert et al. (2013)</a> concluded that the activity-dependent phosphorylation of MeCP2 at T308 regulates the interaction of MeCP2 with the NCoR complex, and that RTT in humans may be due, in part, to the loss of activity-dependent MeCP2 T308 phosphorylation and a disruption of the phosphorylation-regulated interaction of MeCP2 with the NCoR complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23770587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using mouse and cellular models of Huntington disease (HD; <a href="/entry/143100">143100</a>), <a href="#86" class="mim-tip-reference" title="McFarland, K. N., Huizenga, M. N., Darnell, S. B., Sangrey, G. R., Berezovska, O., Cha, J.-H. J., Outerio, T. F., Sadri-Vakili, G. <strong>MeCP2: a novel huntingtin interactor.</strong> Hum. Molec. Genet. 23: 1036-1044, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24105466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24105466</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24105466[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddt499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24105466">McFarland et al. (2014)</a> showed that mutant Htt (<a href="/entry/613004">613004</a>) protein interacted directly with Mecp2. Htt-Mecp2 interactions were enhanced in the presence of the expanded polyglutamine tract and were stronger in nucleus compared with cytoplasm. Binding of Mecp2 to the promoter of Bdnf increased in the presence of mutant Htt. Decreasing Mecp2 expression through small interfering RNA treatment in cells expressing mutant Htt increased Bdnf levels, suggesting that MECP2 downregulates BDNF expression in HD. <a href="#86" class="mim-tip-reference" title="McFarland, K. N., Huizenga, M. N., Darnell, S. B., Sangrey, G. R., Berezovska, O., Cha, J.-H. J., Outerio, T. F., Sadri-Vakili, G. <strong>MeCP2: a novel huntingtin interactor.</strong> Hum. Molec. Genet. 23: 1036-1044, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24105466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24105466</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24105466[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddt499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24105466">McFarland et al. (2014)</a> proposed that aberrant interactions between HTT and MECP2 contribute to transcriptional dysregulation in HD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24105466" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By expression profiling of discrete neuronal subtypes from Mecp2-knockout mice, <a href="#126" class="mim-tip-reference" title="Sugino, K., Hempel, C. M., Okaty, B. W., Arnson, H. A., Kato, S., Dani, V. S., Nelson, S. B. <strong>Cell-type-specific repression by methyl-CpG-binding protein 2 is biased toward long genes.</strong> J. Neurosci. 34: 12877-12883, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25232122/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25232122</a>] [<a href="https://doi.org/10.1523/JNEUROSCI.2674-14.2014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25232122">Sugino et al. (2014)</a> found that loss of Mecp2 primarily resulted in misregulation of genes involved in neuronal connectivity and communication. Genes upregulated were biased toward longer genes, whereas downregulated genes showed no such bias, suggesting that MECP2 selectively represses long genes. Since genes involved in neuronal connectivity and communication are enriched among longer genes, the authors proposed that their misregulation following loss of MECP2 suggests a possible etiology for altered circuit function in Rett syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25232122" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By identifying a genomewide length-dependent increase in gene expression in Mecp2-mutant mouse models and human RTT brains, <a href="#48" class="mim-tip-reference" title="Gabel, H. W., Kinde, B., Stroud, H., Gilbert, C. S., Harmin, D. A., Kastan, N. R., Hemberg, M., Ebert, D. H., Greenberg, M. E. <strong>Disruption of DNA-methylation-dependent long gene repression in Rett syndrome.</strong> Nature 522: 89-93, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25762136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25762136</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25762136[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature14319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25762136">Gabel et al. (2015)</a> presented evidence that MECP2 represses gene expression by binding to methylated CA sites within long genes, and that in neurons lacking MECP2, decreasing the expression of long genes attenuates RTT-associated cellular deficits. In addition, the authors found that long genes as a population are enriched for neuronal functions and are selectively expressed in the brain. <a href="#48" class="mim-tip-reference" title="Gabel, H. W., Kinde, B., Stroud, H., Gilbert, C. S., Harmin, D. A., Kastan, N. R., Hemberg, M., Ebert, D. H., Greenberg, M. E. <strong>Disruption of DNA-methylation-dependent long gene repression in Rett syndrome.</strong> Nature 522: 89-93, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25762136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25762136</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25762136[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature14319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25762136">Gabel et al. (2015)</a> concluded that these findings suggested that mutations in MECP2 may cause neurologic dysfunction by specifically disrupting long gene expression in the brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25762136" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#130" class="mim-tip-reference" title="Tillotson, R., Selfridge, J., Koerner, M. V., Gadalla, K. K. E., Guy, J., De Sousa, D., Hector, R. D., Cobb, S. R., Bird, A. <strong>Radically truncated MeCP2 rescues Rett syndrome-like neurological defects.</strong> Nature 550: 398-401, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29019980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29019980</a>] [<a href="https://doi.org/10.1038/nature24058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29019980">Tillotson et al. (2017)</a> tested the hypothesis that the single dominant function of MeCP2 is to physically connect DNA with the NCoR/SMRT complex, by removing almost all amino acid sequences except the methyl-CpG binding and NCoR/SMRT interaction domains. <a href="#130" class="mim-tip-reference" title="Tillotson, R., Selfridge, J., Koerner, M. V., Gadalla, K. K. E., Guy, J., De Sousa, D., Hector, R. D., Cobb, S. R., Bird, A. <strong>Radically truncated MeCP2 rescues Rett syndrome-like neurological defects.</strong> Nature 550: 398-401, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29019980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29019980</a>] [<a href="https://doi.org/10.1038/nature24058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29019980">Tillotson et al. (2017)</a> found that mice expressing truncated MeCP2 lacking both the N- and C-terminal regions (approximately half of the native protein) are phenotypically near-normal, and those expressing a minimal MeCP2 additionally lacking a central domain survive for over 1 year with only mild symptoms. This minimal protein was able to prevent or reverse neurologic symptoms when introduced into MeCP2-deficient mice by genetic activation or virus-mediated delivery to the brain. <a href="#130" class="mim-tip-reference" title="Tillotson, R., Selfridge, J., Koerner, M. V., Gadalla, K. K. E., Guy, J., De Sousa, D., Hector, R. D., Cobb, S. R., Bird, A. <strong>Radically truncated MeCP2 rescues Rett syndrome-like neurological defects.</strong> Nature 550: 398-401, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29019980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29019980</a>] [<a href="https://doi.org/10.1038/nature24058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29019980">Tillotson et al. (2017)</a> concluded that despite evolutionary conservation of the entire MeCP2 protein sequence, the DNA and corepressor binding domains alone are sufficient to avoid Rett syndrome-like defects and may therefore have therapeutic utility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29019980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#79" class="mim-tip-reference" title="Li, C. H., Coffey, E. L., Dall'Agnese, A., Hannett, N. M., Tang, X., Henninger, J. E., Platt, J. M., Oksuz, O., Zamudio, A. V., Afeyan, L. K., Schuijers, J., Liu, X. S., Markoulaki, S., Lungjangwa, T., LeRoy, G., Svoboda, D. S., Wogram, E., Lee, T. I., Jaenisch, R., Young, R. A. <strong>MeCP2 links heterochromatin condensates and neurodevelopmental disease.</strong> Nature 586: 440-444, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32698189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32698189</a>] [<a href="https://doi.org/10.1038/s41586-020-2574-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32698189">Li et al. (2020)</a> showed that mouse Mecp2 was a dynamic component of heterochromatin condensates in cells and was stimulated by DNA to form liquid-like condensates. Several domains of Mecp2 contributed to formation of condensates, and mutations in human MECP2 associated with Rett syndrome disrupted the ability of MECP2 to form condensates. Condensates formed by Mecp2 selectively incorporated and concentrated heterochromatin cofactors rather than components of euchromatic transcriptionally active condensates. <a href="#79" class="mim-tip-reference" title="Li, C. H., Coffey, E. L., Dall'Agnese, A., Hannett, N. M., Tang, X., Henninger, J. E., Platt, J. M., Oksuz, O., Zamudio, A. V., Afeyan, L. K., Schuijers, J., Liu, X. S., Markoulaki, S., Lungjangwa, T., LeRoy, G., Svoboda, D. S., Wogram, E., Lee, T. I., Jaenisch, R., Young, R. A. <strong>MeCP2 links heterochromatin condensates and neurodevelopmental disease.</strong> Nature 586: 440-444, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32698189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32698189</a>] [<a href="https://doi.org/10.1038/s41586-020-2574-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32698189">Li et al. (2020)</a> proposed that MECP2 enhances separation of heterochromatin and euchromatin through its condensate partitioning properties, and that disruption of condensates may be a consequence of MECP2 mutations that cause Rett syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32698189" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#20" class="mim-tip-reference" title="Caballero, I. M., Hendrich, B. <strong>MeCP2 in neurons: closing in on the causes of Rett syndrome.</strong> Hum. Molec. Genet. 14: R19-R26, 2005. Note: Erratum: Hum. Molec. Genet. 14: 2089 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15809268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15809268</a>] [<a href="https://doi.org/10.1093/hmg/ddi102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15809268">Caballero and Hendrich (2005)</a> provided a review of the role of MECP2 in the developing brain, the targets of MECP2-mediated repression, and the possible effect of misexpressed gene targets leading to clinical manifestations of RTT. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15809268" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Rett Syndrome</em></strong></p><p>
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Rett syndrome (RTT; <a href="/entry/312750">312750</a>) is a progressive neurologic developmental disorder and one of the most common causes of mental retardation in females. Because RTT occurs almost exclusively in females, it had been proposed that RTT is caused by an X-linked dominant mutation with lethality in hemizygous males. Using a systematic mutation analysis of genes located in the Xq28 region containing the locus for Rett syndrome, <a href="#5" class="mim-tip-reference" title="Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., Zoghbi, H. Y. <strong>Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.</strong> Nature Genet. 23: 185-188, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508514</a>] [<a href="https://doi.org/10.1038/13810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508514">Amir et al. (1999)</a> identified mutations in the MECP2 gene as the cause of some cases of RTT. In 5 of 21 sporadic patients with RTT, <a href="#5" class="mim-tip-reference" title="Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., Zoghbi, H. Y. <strong>Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.</strong> Nature Genet. 23: 185-188, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508514</a>] [<a href="https://doi.org/10.1038/13810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508514">Amir et al. (1999)</a> found 3 de novo missense mutations in the region encoding the highly conserved methyl-binding domain of the MECP2 gene (<a href="#0001">300005.0001</a>, <a href="#0002">300005.0002</a>, <a href="#0007">300005.0007</a>), as well as a de novo frameshift and a de novo nonsense mutation (<a href="#0021">300005.0021</a>), both of which disrupted the transcription repression domain. Among 8 cases of familial Rett syndrome, <a href="#5" class="mim-tip-reference" title="Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., Zoghbi, H. Y. <strong>Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.</strong> Nature Genet. 23: 185-188, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508514</a>] [<a href="https://doi.org/10.1038/13810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508514">Amir et al. (1999)</a> found segregation of an additional missense mutation (<a href="#0008">300005.0008</a>) in 1 family with 2 affected half sisters. The mutation was not detected in their obligate carrier mother, suggesting that the mother was a germline mosaic for this mutation. The authors suggested that the findings point to abnormal epigenetic regulation as a mechanism underlying the pathogenesis of Rett syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508514" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#140" class="mim-tip-reference" title="Wan, M., Lee, S. S. J., Zhang, X., Houwink-Manville, I., Song, H.-R., Amir, R. E., Budden, S., Naidu, S., Pereira, J. L. P., Lo, I. F. M., Zoghbi, H. Y., Schanen, N. C., Francke, U. <strong>Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots.</strong> Am. J. Hum. Genet. 65: 1520-1529, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10577905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10577905</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10577905[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/302690" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10577905">Wan et al. (1999)</a> reviewed the mutations identified by <a href="#5" class="mim-tip-reference" title="Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., Zoghbi, H. Y. <strong>Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.</strong> Nature Genet. 23: 185-188, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508514</a>] [<a href="https://doi.org/10.1038/13810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508514">Amir et al. (1999)</a> and added 5 additional mutations (see, e.g., <a href="#0003">300005.0003</a>, <a href="#0020">300005.0020</a>). Of these, 5 were missense mutations, 5 were protein-truncating mutations, and 1 was a variant type of mutation. They found that missense mutations causing Rett syndrome were de novo and affected conserved domains of MECP2. All of the nucleotide substitutions involved C-T transitions at CpG hotspots. They presented evidence that some males with RTT-causing MECP2 mutations may survive to birth, and female heterozygotes with favorably skewed X-inactivation patterns may have little or no involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10577905+10508514" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Cheadle, J. P., Gill, H., Fleming, N., Maynard, J., Kerr, A., Leonard, H., Krawczak, M., Cooper, D. N., Lynch, S., Thomas, N., Hughes, H., Hulten, M., Ravine, D., Sampson, J. R., Clarke, A. <strong>Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location.</strong> Hum. Molec. Genet. 9: 1119-1129, 2000. Note: Erratum: Hum. Molec. Genet. 9: 1717 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10767337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10767337</a>] [<a href="https://doi.org/10.1093/hmg/9.7.1119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10767337">Cheadle et al. (2000)</a> identified mutations in 44 of 55 (80%) unrelated classic sporadic and familial RTT patients (see, e.g., <a href="#0004">300005.0004</a>), but in only 1 of 5 (20%) sporadic cases with suggestive, but nondiagnostic features of RTT. Twenty-one different mutations were identified (12 missense, 4 nonsense, and 5 frameshift mutations); 14 of these were novel. All missense mutations were located either in the methyl-CpG-binding domain or in the transcription repression domain. Nine recurrent mutations were characterized in a total of 33 unrelated cases (73% of all cases with MECP2 mutations). Significantly milder disease was noted in patients carrying missense mutations as compared with those with truncating mutations (P = 0.0023), and milder disease was associated with late as compared with early truncating mutations (P = 0.0190). <a href="#15" class="mim-tip-reference" title="Bienvenu, T., Carrie, A., de Roux, N., Vinet, M.-C., Jonveaux, P., Couvert, P., Villard, L., Arzimanoglou, A., Beldjord, C., Fontes, M., Tardieu, M., Chelly, J. <strong>MECP2 mutations account for most cases of typical forms of Rett syndrome.</strong> Hum. Molec. Genet. 9: 1377-1384, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10814719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10814719</a>] [<a href="https://doi.org/10.1093/hmg/9.9.1377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10814719">Bienvenu et al. (2000)</a> identified 30 mutations among 46 RTT patients, including 12 novel mutations (11 in exon 3 and 1 in exon 2). Mutations such as R270X (<a href="#0005">300005.0005</a>) and frameshift deletions in a (CCACC)n-rich region were found with multiple recurrences; most of the mutations were de novo. Although mutations in noncoding regions could not be excluded for 35% of their cases, the authors proposed that a putative second X-linked gene may exist. <a href="#62" class="mim-tip-reference" title="Huppke, P., Laccone, F., Kramer, N., Engel, W., Hanefeld, F. <strong>Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients.</strong> Hum. Molec. Genet. 9: 1369-1375, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10814718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10814718</a>] [<a href="https://doi.org/10.1093/hmg/9.9.1369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10814718">Huppke et al. (2000)</a> found mutations in 24 of 31 RTT patients; in at least 20 patients the mutation was de novo. Confirming 2 earlier studies, most mutations were truncating, and only a few were missense mutations. Several females carrying the same mutation displayed different phenotypes, suggesting that factors other than the type or position of mutations influence the severity of RTT. In 19 of 26 Japanese patients with sporadic Rett syndrome, <a href="#4" class="mim-tip-reference" title="Amano, K., Nomura, Y., Segawa, M., Yamakawa, K. <strong>Mutational analysis of the MECP2 gene in Japanese patients with Rett syndrome.</strong> J. Hum. Genet. 45: 231-236, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10944854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10944854</a>] [<a href="https://doi.org/10.1007/s100380070032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10944854">Amano et al. (2000)</a> identified 12 different mutations in the MECP2 gene, 8 of which were novel. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10814718+10944854+10767337+10814719" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="De Bona, C., Zappella, M., Hayek, G., Meloni, I., Vitelli, F., Bruttini, M., Cusano, R., Loffredo, P., Longo, I., Renieri, A. <strong>Preserved speech variant is allelic of classic Rett syndrome.</strong> Europ. J. Hum. Genet. 8: 325-330, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10854091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10854091</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200473" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10854091">De Bona et al. (2000)</a> explored the spectrum of mutations affecting the MECP2 gene in a group of 25 classic Rett syndrome girls and in 3 patients with the preserved speech variant (PVS) of Rett syndrome. They noted 2 hotspots: R270X (<a href="#0005">300005.0005</a>) and R294X (<a href="#0011">300005.0011</a>). Among the preserved speech variants, 2 patients carried deletions of 41 bp (<a href="#0012">300005.0012</a>) and 44 bp (<a href="#0014">300005.0014</a>), respectively, which were strikingly similar to deletions observed in classic Rett syndrome. Thus, the allelism of the variant form to the classic form was established. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10854091" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#148" class="mim-tip-reference" title="Xiang, F., Buervenich, S., Nicolao, P., Bailey, M. E. S., Zhang, Z., Anvret, M. <strong>Mutation screening in Rett syndrome patients.</strong> J. Med. Genet. 37: 250-255, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10745042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10745042</a>] [<a href="https://doi.org/10.1136/jmg.37.4.250" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10745042">Xiang et al. (2000)</a> reported mutation analysis of the MECP2 gene in 59 sporadic cases of Rett syndrome and 9 families with a total of 19 affected individuals. Mutations were found in 27 of the sporadic cases but in none of the familial cases. Mutation analysis of the UBE1 (<a href="/entry/314370">314370</a>), UBE2I (<a href="/entry/601661">601661</a>), GDX (<a href="/entry/312070">312070</a>), SOX3 (<a href="/entry/313430">313430</a>), GABRA3 (<a href="/entry/305660">305660</a>), and CDR2 (<a href="/entry/117340">117340</a>) genes, which the authors regarded as candidate genes on the basis of clinical, pathologic, and genetic features, was also performed in 10 'classical' cases. No mutations were found in any of these genes in any individuals. Gene expression of MECP2, GDX, GABRA3, and L1CAM (<a href="/entry/308840">308840</a>) was investigated by in situ hybridization studies of postmortem brain tissue samples from 6 affected individuals and 7 controls. No gross differences were observed in the neurons of several brain regions between normal controls and Rett patients. <a href="#19" class="mim-tip-reference" title="Buyse, I. M., Fang, P., Hoon, K. T., Amir, R. E., Zoghbi, H. Y., Roa, B. B. <strong>Diagnostic testing for Rett syndrome by DHPLC and direct sequencing analysis of the MECP2 gene: identification of several novel mutations and polymorphisms.</strong> Am. J. Hum. Genet. 67: 1428-1436, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11055898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11055898</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11055898[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/316913" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11055898">Buyse et al. (2000)</a> identified several novel mutations n the MECP2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10745042+11055898" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Bourdon, V., Philippe, C., Labrune, O., Amsallem, D., Arnould, C., Jonveaux, P. <strong>A detailed analysis of the MECP2 gene: prevalence of recurrent mutations and gross DNA rearrangements in Rett syndrome patients.</strong> Hum. Genet. 108: 43-50, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11214906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11214906</a>] [<a href="https://doi.org/10.1007/s004390000422" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11214906">Bourdon et al. (2001)</a> achieved a mutation detection rate of 79% among 47 cases of classic RTT and 25% among 8 nonclassic RTT cases. Combining their findings with those previously reported, the spectrum of mutations in the MECP2 gene associated with RTT encompassed missense (34%), nonsense (46%), and frameshift (20%) mutations. The occurrence of mutations mainly in exon 3 (89%) and the multiple recurrence of specific mutations pointed to mutation hotspots that could propose diagnostic strategies for RTT. Three missense mutations, R106W (<a href="#0008">300005.0008</a>), T158M (<a href="#0007">300005.0007</a>), and R306C (<a href="#0016">300005.0016</a>), represented about 23% of all mutations in their study and about 16 to 32% in the literature. Together with 4 nonsense mutations, a total of 7 mutations represented 64% of those found by <a href="#16" class="mim-tip-reference" title="Bourdon, V., Philippe, C., Labrune, O., Amsallem, D., Arnould, C., Jonveaux, P. <strong>A detailed analysis of the MECP2 gene: prevalence of recurrent mutations and gross DNA rearrangements in Rett syndrome patients.</strong> Hum. Genet. 108: 43-50, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11214906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11214906</a>] [<a href="https://doi.org/10.1007/s004390000422" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11214906">Bourdon et al. (2001)</a> and an even higher proportion (72%) in the patients studied by <a href="#5" class="mim-tip-reference" title="Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., Zoghbi, H. Y. <strong>Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.</strong> Nature Genet. 23: 185-188, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508514</a>] [<a href="https://doi.org/10.1038/13810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508514">Amir et al. (1999)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11214906+10508514" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 26 of 30 Danish RTT patients, <a href="#104" class="mim-tip-reference" title="Nielsen, J. B., Henriksen, K. F., Hansen, C., Silahtaroglu, A., Schwartz, M., Tommerup, N. <strong>MECP2 mutations in Danish patients with Rett syndrome: high frequency of mutations but no consistent correlations with clinical severity or with the X chromosome inactivation pattern.</strong> Europ. J. Hum. Genet. 9: 178-184, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11313756/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11313756</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200600" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11313756">Nielsen et al. (2001)</a> identified 15 different de novo mutations in the MECP2 gene, of which 5 were novel. Novel mutations included a 1-bp deletion (<a href="#0018">300005.0018</a>) and a 14-bp duplication (<a href="#0019">300005.0019</a>). The 30 patients were sporadic cases, chosen from 69 known RTT patients in Denmark because of availability of DNA samples. Twenty-seven of the patients were diagnosed with classic RTT and 3 as forme fruste variants with a milder phenotype. The authors performed direct sequencing of the coding region and parts of the 5-prime and 3-prime UTR. Nineteen of the 26 detected mutations were C-T transitions at CpG dinucleotides. Three of the 4 patients without identified mutations (all with classic RTT) were analyzed by FISH, and gross rearrangements of the MECP2 region were excluded. X-chromosome inactivation (XCI) was found to be random in 19 and skewed in 9 patients (2 were not informative); in 8 patients the paternal X chromosome was preferentially inactivated. The authors found no consistent correlation between the type (truncating or missense) or position of mutations and the severity of clinical presentation. Furthermore, the XCI pattern in peripheral blood did not seem to influence the score. The authors concluded that the clinical inclusion criteria are the most important factors in relation to the mutation detection rate. In a study of 116 patients, including 91 with classic and 25 with atypical RTT, <a href="#60" class="mim-tip-reference" title="Hoffbuhr, K., Devaney, J. M., LaFleur, B., Sirianni, N., Scacheri, C., Giron, J., Schuette, J., Innis, J., Marino, M., Philippart, M., Narayanan, V., Umansky, R., Kronn, D., Hoffman, E. P., Naidu, S. <strong>MeCP2 mutations in children with and without the phenotype of Rett syndrome.</strong> Neurology 56: 1486-1495, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11402105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11402105</a>] [<a href="https://doi.org/10.1212/wnl.56.11.1486" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11402105">Hoffbuhr et al. (2001)</a> identified causative mutations in the MECP2 gene in 63% of the patients, representing a total of 30 different mutations. Mutations were identified in 72% of patients with classic RTT, but in only one-third of patients with atypical RTT. The authors found 17 novel mutations, including a complex gene rearrangement involving 2 deletions and a duplication in 1 individual. The duplication was identical to a region within the 3-prime UTR, and represented the first report of involvement of this region in RTT. Mutations in the N terminus were significantly correlated with a more severe clinical presentation compared with mutations closer to the C terminus of MECP2. Skewed X-inactivation patterns were found in 2 asymptomatic carriers of MECP2 mutations and in 6 girls diagnosed with either atypical or classic RTT. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11402105+11313756" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 35 of 50 Italian girls with classic Rett syndrome, <a href="#103" class="mim-tip-reference" title="Nicolao, P., Carella, M., Giometto, B., Tavolato, B., Cattin, R., Giovannucci-Uzielli, M. L., Vacca, M., Regione, F. D., Piva, S., Bortoluzzi, S., Gasparini, P. <strong>DHPLC analysis of the MECP2 gene in Italian Rett patients.</strong> Hum. Mutat. 18: 132-140, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11462237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11462237</a>] [<a href="https://doi.org/10.1002/humu.1162" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11462237">Nicolao et al. (2001)</a> identified 19 different de novo MECP2 mutations, 8 of which were novel. In a total of 22 unrelated cases, 7 recurrent mutations were characterized. Initial DHPLC screening allowed the identification of 17 of the 19 mutations (90%); after optimal conditions were established, this figure increased to 100%, with all recurrent MECP2 mutations generating a characteristic chromatographic profile. They found a tendency in this series for milder disease to be associated with nonsense mutations as compared to patients carrying missense mutations, although the difference was not statistically significant (p = 0.077). <a href="#108" class="mim-tip-reference" title="Pan, H., Wang, Y.-P., Bao, X.-H., Meng, H.-D., Zhang, Y., Wu, X.-R., Shen, Y. <strong>MECP2 gene mutation analysis in Chinese patients with RETT syndrome.</strong> Europ. J. Hum. Genet. 10: 484-486, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12111643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12111643</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200827" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12111643">Pan et al. (2002)</a> identified 12 different mutations in the MECP2 gene in 17 out of 31 (55%) sporadic Chinese classic RTT patients. The mutations (4 missense, 3 nonsense, and 5 frameshift) were all in the third exon and 2 were novel. Truncating mutations within or downstream of the TRD or deletions in the C-terminal region were consistent with reduced clinical severity when compared with truncating mutations N-terminal to this domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12111643+11462237" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#132" class="mim-tip-reference" title="Trappe, R., Laccone, F., Cobilanschi, J., Meins, M., Huppke, P., Hanefeld, F., Engel, W. <strong>MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin.</strong> Am. J. Hum. Genet. 68: 1093-1101, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11309679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11309679</a>] [<a href="https://doi.org/10.1086/320109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11309679">Trappe et al. (2001)</a> analyzed the parental origin of MECP2 mutations in sporadic cases of RTT by analysis of linkage between the mutation in the MECP2 gene and intronic polymorphisms in 27 families with 15 different mutations, and found a high predominance of mutations of paternal origin (26 of 27 cases). The paternal origin was independent of type of mutation and was found for single-base exchanges as well as for deletions. Parents were not of especially advanced age. <a href="#132" class="mim-tip-reference" title="Trappe, R., Laccone, F., Cobilanschi, J., Meins, M., Huppke, P., Hanefeld, F., Engel, W. <strong>MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin.</strong> Am. J. Hum. Genet. 68: 1093-1101, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11309679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11309679</a>] [<a href="https://doi.org/10.1086/320109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11309679">Trappe et al. (2001)</a> concluded that de novo mutations in RTT occur almost exclusively on the paternally derived X chromosome and that this is probably the cause for the high female:male ratio observed in patients with RTT. Affected males have been described in a few cases of familial inheritance. Identification of the parental origin may be useful to distinguish between the sporadic form of RTT and a potentially familial form. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11309679" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#91" class="mim-tip-reference" title="Miltenberger-Miltenyi, G., Laccone, F. <strong>Mutations and polymorphisms in the human methyl CpG-binding protein MECP2.</strong> Hum. Mutat. 22: 107-115, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12872250/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12872250</a>] [<a href="https://doi.org/10.1002/humu.10243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12872250">Miltenberger-Miltenyi and Laccone (2003)</a> stated that 218 different mutations in the MECP2 gene had been reported in more than 2,100 patients. The mutations, which are responsible for up to 75% of classic RTT cases, are distributed along the whole gene and comprise all types of mutations. Almost all cases are sporadic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12872250" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Christodoulou, J., Grimm, A., Maher, T., Bennetts, B. <strong>RettBASE: the IRSA MECP2 variation database--a new mutation database in evolution.</strong> Hum. Mutat. 21: 466-472, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12673788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12673788</a>] [<a href="https://doi.org/10.1002/humu.10194" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12673788">Christodoulou et al. (2003)</a> described RettBASE, a database for mutations in the MECP2 gene responsible for Rett syndrome and other abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12673788" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#92" class="mim-tip-reference" title="Mnatzakanian, G. N., Lohi, H., Munteanu, I., Alfred, S. E., Yamada, T., MacLeod, P. J. M., Jones, J. R., Scherer, S. W., Schanen, N. C., Friez, M. J., Vincent, J. B., Minassian, B. A. <strong>A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome.</strong> Nature Genet. 36: 339-341, 2004. Note: Erratum: Nature Genet. 36: 540 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034579</a>] [<a href="https://doi.org/10.1038/ng1327" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15034579">Mnatzakanian et al. (2004)</a> screened the exon 1 sequence, which is used in the MECP2B isoform, in 19 girls with typical Rett syndrome in whom no mutations had been found in the other exons. In 1 affected individual, they identified an 11-bp deletion in exon 1 (<a href="#0028">300005.0028</a>). This deletion does not affect the expression of MECP2A, indicating that inactivation of the MECP2B isoform is sufficient to cause Rett syndrome. <a href="#10" class="mim-tip-reference" title="Bartholdi, D., Klein, A., Weissert, M., Koenig, N., Baumer, A., Boltshauser, E., Schinzel, A., Berger, W., Matyas, G. <strong>Clinical profiles of four patients with Rett syndrome carrying a novel exon 1 mutation or genomic rearrangement in the MECP2 gene.</strong> Clin. Genet. 69: 319-326, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16630165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16630165</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00604.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16630165">Bartholdi et al. (2006)</a> reported 2 unrelated girls with Rett syndrome caused by different mutations affecting exon 1 of the MECP2 gene (see, e.g., <a href="#0031">300005.0031</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16630165+15034579" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#80" class="mim-tip-reference" title="Li, M., Pan, H., Bao, X.-H., Zhang, Y.-Z., Wu, X.-R. <strong>MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome.</strong> J. Hum. Genet. 52: 38-47, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17089071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17089071</a>] [<a href="https://doi.org/10.1007/s10038-006-0079-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17089071">Li et al. (2007)</a> analyzed the sequence of the MECP2 gene in 121 unrelated Chinese patients with classical or atypical RTT for deletions and mutations. They identified 45 different MECP2 mutations in 102 of these patients. The T158M mutation (<a href="#0007">300005.0007</a>) was the most common (15.7%), followed in order of frequency by R168X (<a href="#0020">300005.0020</a>) at 11.8%, R133C (<a href="#0001">300005.0001</a>) at 6.9%, R270X (<a href="#0005">300005.0005</a>) at 6.9%, G269fs (<a href="#0003">300005.0003</a>) at 6.9%, R255X (<a href="#0021">300005.0021</a>) at 4.9%, and R306C (<a href="#0016">300005.0016</a>) at 3.9%. They identified 5 novel MECP2 mutations: 3 missense, 1 insertion, and a 22-bp deletion. Large deletions represented 10.5% of all identified MECP2 mutations. Mutations in exon 1 appeared to be rare. Cases without MECP2 mutations were screened for changes in the CDKL5 gene (<a href="/entry/300203">300203</a>). One synonymous mutation was found in exon 5. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17089071" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using multiplex ligation-dependent probe amplification (MLPA), <a href="#57" class="mim-tip-reference" title="Hardwick, S. A., Reuter, K., Williamson, S. L., Vasudevan, V., Donald, J., Slater, K., Bennetts, B., Bebbington, A., Leonard, H., Williams, S. R., Smith, R. L., Cloosterman, D., Christodoulou, J. <strong>Delineation of large deletions of the MECP2 gene in Rett syndrome patients, including a familial case with a male proband.</strong> Europ. J. Hum. Genet. 15: 1218-1229, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17712354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17712354</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201911" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17712354">Hardwick et al. (2007)</a> identified multiexonic deletions in the MECP2 gene in 12 (8.1%) of 149 apparently mutation-negative patients with Rett syndrome. All of the deletions involved exon 3, exon 4, or both. There was no correlation between phenotypic severity and deletion size. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17712354" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#129" class="mim-tip-reference" title="Thatcher, K. N., Peddada, S., Yasui, D. H., LaSalle, J. M. <strong>Homologous pairing of 15q11-13 imprinted domains in brain is developmentally regulated but deficient in Rett and autism samples.</strong> Hum. Molec. Genet. 14: 785-797, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15689352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15689352</a>] [<a href="https://doi.org/10.1093/hmg/ddi073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15689352">Thatcher et al. (2005)</a> tested a potential role for MECP2 in the homologous pairing of imprinted 15q11-q13 alleles. FISH analysis of control cerebral tissue samples demonstrated a significant increase in homologous pairing specific to chromosome 15 from infant to juvenile brain samples. Significant and specific deficiencies in the percentage of paired chromosome 15 alleles were observed in Rett syndrome (<a href="/entry/312750">312750</a>), Angelman syndrome (<a href="/entry/105830">105830</a>), and autism (<a href="/entry/209850">209850</a>) brain samples when compared with normal controls. Human neuroblastoma cells also showed a significant and specific increase in the percentage of chromosome 15q11-q13 paired alleles following induced differentiation in vitro. Transfection with a methylated oligonucleotide decoy specifically blocked binding of MECP2 to the SNURF/SNRPN (<a href="/entry/182279">182279</a>) promoter within 15q11-q13 and significantly lowered the percentage of paired 15q11-q13 alleles in human neuroblastoma cells. <a href="#129" class="mim-tip-reference" title="Thatcher, K. N., Peddada, S., Yasui, D. H., LaSalle, J. M. <strong>Homologous pairing of 15q11-13 imprinted domains in brain is developmentally regulated but deficient in Rett and autism samples.</strong> Hum. Molec. Genet. 14: 785-797, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15689352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15689352</a>] [<a href="https://doi.org/10.1093/hmg/ddi073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15689352">Thatcher et al. (2005)</a> suggested a role for MECP2 in chromosome organization in the developing brain and provided a potential mechanistic association between several related neurodevelopmental disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15689352" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Males with Mutations in the MECP2 Gene</em></strong></p><p>
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Males with mutations in the MECP2 gene can be categorized into 4 main groups. Rarely, males with an extra X chromosome or somatic mosaicism harboring a classic RTT mutation phenotypically show classic Rett syndrome. A second group includes karyotypically normal 46,XY males with MECP2 mutations that cause classic Rett syndrome in females; these males show a severe congenital encephalopathy with early death (<a href="/entry/300673">300673</a>). In a third group, males with MECP2 mutations that have not been identified in females with Rett syndrome show a variable phenotype of impaired intellectual development with spasticity and other features (MRXS13; <a href="/entry/300055">300055</a>). A fourth group of male patients has been reported with increased dosage of the MECP2 gene due to duplication; these patients have a severe form of impaired intellectual development, often with recurrent respiratory infections (MRXSL; <a href="/entry/300260">300260</a>). The phenotypes associated with MECP2 mutations in males is highly variable, but usually severe (<a href="#52" class="mim-tip-reference" title="Gomot, M., Gendrot, C., Verloes, A., Raynaud, M., David, A., Yntema, H. G., Dessay, S., Kalscheuer, V., Frints, S., Couvert, P., Briault, S., Blesson, S., Toutain, A., Chelly, J., Desportes, V., Moraine, C. <strong>MECP2 gene mutations in non-syndromic X-linked mental retardation: phenotype-genotype correlation.</strong> Am. J. Med. Genet. 123A: 129-139, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14598336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14598336</a>] [<a href="https://doi.org/10.1002/ajmg.a.20247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14598336">Gomot et al., 2003</a>; <a href="#138" class="mim-tip-reference" title="Villard, L. <strong>MECP2 mutations in males.</strong> J. Med. Genet. 44: 417-423, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17351020/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17351020</a>] [<a href="https://doi.org/10.1136/jmg.2007.049452" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17351020">Villard, 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17351020+14598336" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#90" class="mim-tip-reference" title="Meloni, I., Bruttini, M., Longo, I., Mari, F., Rizzolio, F., D'Adamo, P., Denvriendt, K., Fryns, J.-P., Toniolo, D., Renieri, A. <strong>A mutation in the Rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males.</strong> Am. J. Hum. Genet. 67: 982-985, 2000. Note: Erratum: Am. J. Hum. Genet. 67: 1365 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10986043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10986043</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10986043[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/303078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10986043">Meloni et al. (2000)</a> stated that there had been no reports of males with Rett syndrome with a mutation in the MECP2 gene who survived beyond the age of 1 year. They studied a 3-generation family in which 2 affected males showed a severe syndromic form of X-linked impaired intellectual development with progressive spasticity (MRXS13) and 2 obligate carrier females showed either normal or borderline intelligence. This family had previously been reported by <a href="#31" class="mim-tip-reference" title="Claes, S., Devriendt, K., D'Adamo, P., Meireleire, J., Raeymaekers, P., Toniolo, D., Cassiman, J.-J., Fryns, J.-P. <strong>X-linked severe mental retardation and a progressive neurological disorder in a Belgian family: clinical and genetic studies.</strong> Clin. Genet. 52: 155-161, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9377804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9377804</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1997.tb02536.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9377804">Claes et al. (1997)</a>, who mapped the disorder to Xq27.2-qter. <a href="#90" class="mim-tip-reference" title="Meloni, I., Bruttini, M., Longo, I., Mari, F., Rizzolio, F., D'Adamo, P., Denvriendt, K., Fryns, J.-P., Toniolo, D., Renieri, A. <strong>A mutation in the Rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males.</strong> Am. J. Hum. Genet. 67: 982-985, 2000. Note: Erratum: Am. J. Hum. Genet. 67: 1365 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10986043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10986043</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10986043[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/303078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10986043">Meloni et al. (2000)</a> found that the affected males and the carrier females had a mutation (E406X; <a href="#0009">300005.0009</a>) in the MECP2 gene, demonstrating that, in males, MECP2 can be responsible for severe mental retardation associated with neurologic disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10986043+9377804" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#107" class="mim-tip-reference" title="Orrico, A., Lam, C.-W., Galli, L., Dotti, M. T., Hayek, G., Tong, S.-F., Poon, P. M. K., Zappella, M., Federico, A., Sorrentino, V. <strong>MECP2 mutation in male patients with non-specific X-linked mental retardation.</strong> FEBS Lett. 481: 285-288, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11007980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11007980</a>] [<a href="https://doi.org/10.1016/s0014-5793(00)01994-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11007980">Orrico et al. (2000)</a> found a novel mutation (A140V; <a href="#0015">300005.0015</a>) in the MECP2 gene in a female with mild mental retardation, her similarly affected daughter, and her 4 adult sons with severe mental retardation with movement disorders, including tremor, bradykinesia, and pyramidal signs (MRXS13). The results indicated that not all MECP2 mutations are lethal in males and can result in a severe phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11007980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#35" class="mim-tip-reference" title="Couvert, P., Bienvenu, T., Aquaviva, C., Poirier, K., Moraine, C., Gendrot, C., Verloes, A., Andres, C., Le Fevre, A. C., Souville, I., Steffann, J., des Portes, V., Ropers, H.-H., Yntema, H. G., Fryns, J.-P., Briault, S., Chelly, J., Cherif, B. <strong>MECP2 is highly mutated in X-linked mental retardation.</strong> Hum. Molec. Genet. 10: 941-946, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11309367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11309367</a>] [<a href="https://doi.org/10.1093/hmg/10.9.941" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11309367">Couvert et al. (2001)</a> identified 2 mutations, not found in RTT, in families with nonspecific X-linked intellectual developmental disorder (MRXS13) (see, e.g., E137F; <a href="#0017">300005.0017</a>). Upon screening a cohort of 185 mentally retarded males who were negative for the expansions across the FRAXA CGG repeat, 2 were found to carry A140V. Two other patients also carried mutations. The authors found the frequency of mutations in the MECP2 gene comparable to the frequency of the CGG expansions in the FMR1 gene (<a href="/entry/309550">309550</a>), which causes fragile X syndrome (<a href="/entry/300624">300624</a>) and suggested systematic screening of MECP2 in mentally retarded patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11309367" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#149" class="mim-tip-reference" title="Ylisaukko-oja, T., Rehnstrom, K., Vanhala, R., Kempas, E., von Koskull, H., Tengstrom, C., Mustonen, A., Ounap, K., Lahdetie, J., Jarvela, I. <strong>MECP2 mutation analysis in patients with mental retardation.</strong> Am. J. Med. Genet. 132A: 121-124, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15578581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15578581</a>] [<a href="https://doi.org/10.1002/ajmg.a.30416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15578581">Ylisaukko-oja et al. (2005)</a> screened the MECP2 gene in 118 unrelated mentally retarded Finnish patients (103 males, 15 females). They identified 2 known polymorphisms in the coding sequence and 4 variants in the intronic or 3-prime UTR regions, but stated that none of these was likely to be causal. <a href="#149" class="mim-tip-reference" title="Ylisaukko-oja, T., Rehnstrom, K., Vanhala, R., Kempas, E., von Koskull, H., Tengstrom, C., Mustonen, A., Ounap, K., Lahdetie, J., Jarvela, I. <strong>MECP2 mutation analysis in patients with mental retardation.</strong> Am. J. Med. Genet. 132A: 121-124, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15578581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15578581</a>] [<a href="https://doi.org/10.1002/ajmg.a.30416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15578581">Ylisaukko-oja et al. (2005)</a> concluded that the evidence in their own and other mutation screening studies implies that MECP2 mutations do not represent a major cause of nonspecific mental retardation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15578581" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#93" class="mim-tip-reference" title="Moncla, A., Kpebe, A., Missirian, C., Mancini, J., Villard, L. <strong>Polymorphisms in the C-terminal domain of MECP2 in mentally handicapped boys: implications for genetic counselling.</strong> Europ. J. Hum. Genet. 10: 86-89, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11896461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11896461</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11896461">Moncla et al. (2002)</a> reviewed a total of 13 MECP2 mutations reported in males. The first cases demonstrated a variant phenotype of Rett syndrome characterized by severe neonatal encephalopathy and lethality in early childhood (<a href="/entry/300673">300673</a>). In those cases, the carrier mothers had totally skewed X-chromosome inactivation. Further mutations were associated with nonspecific X-linked mental retardation, but also sporadic cases were described with a wide spectrum of mental retardation varying from a severe form with an Angelman syndrome (<a href="/entry/105830">105830</a>) phenotype to moderately mentally retarded males. In a series of 23 unrelated boys with severe mental retardation either with a variant phenotype of Rett syndrome or an Angelman-like phenotype, <a href="#93" class="mim-tip-reference" title="Moncla, A., Kpebe, A., Missirian, C., Mancini, J., Villard, L. <strong>Polymorphisms in the C-terminal domain of MECP2 in mentally handicapped boys: implications for genetic counselling.</strong> Europ. J. Hum. Genet. 10: 86-89, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11896461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11896461</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11896461">Moncla et al. (2002)</a> identified 2 missense mutations in the C-terminal domain of the MECP2 gene. The first mutation was also detected in a healthy male cousin of the proband and the second mutation had been described previously as a polymorphism. The authors noted that the findings highlighted the need for extreme caution in the clinical interpretation of sequence variation in the MECP2 gene, before genetic counseling or prenatal diagnosis is proposed to the families involved. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11896461" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#150" class="mim-tip-reference" title="Yntema, H. G., Kleefstra, T., Oudakker, A. R., Romein, T., de Vries, B. B. A., Nellesen, W., Sistermans, E. A., Brunner, H. G., Hamel, B. C. J., van Bokhoven, H. <strong>Low frequency of MECP2 mutations in mentally retarded males.</strong> Europ. J. Hum. Genet. 10: 487-490, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12111644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12111644</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200836" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12111644">Yntema et al. (2002)</a> performed MECP2 mutation analysis in a cohort of 475 mentally retarded males who were negative for the FMR1 CGG repeat expansion. Fourteen different sequence changes were detected, 4 of which were previously reported as nonpathogenic variants and 5 that were novel silent changes. Five changes were possible novel mutations, including 4 amino acid changes and a deletion of 2 bases. For 3 of the 4 amino acid changes, segregation analysis revealed that the mutations could be traced in unaffected male family members. One missense mutation was inherited from the mother, but no other family members were available for further segregation analysis. This change, however, involved a nonconserved amino acid, making it unlikely that it had a dramatic effect on the MECP2 protein. The frequency of MECP2 mutations in the Dutch mentally retarded males was therefore 0.2% (1 of 475), and the study revealed the crucial importance of segregation analysis for low frequency mutations in order to distinguish them from rare polymorphisms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12111644" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#60" class="mim-tip-reference" title="Hoffbuhr, K., Devaney, J. M., LaFleur, B., Sirianni, N., Scacheri, C., Giron, J., Schuette, J., Innis, J., Marino, M., Philippart, M., Narayanan, V., Umansky, R., Kronn, D., Hoffman, E. P., Naidu, S. <strong>MeCP2 mutations in children with and without the phenotype of Rett syndrome.</strong> Neurology 56: 1486-1495, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11402105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11402105</a>] [<a href="https://doi.org/10.1212/wnl.56.11.1486" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11402105">Hoffbuhr et al. (2001)</a> identified MECP2 mutations in 2 males: a Klinefelter male with classic RTT (<a href="#0007">300005.0007</a>) and a hemizygous male infant with neonatal encephalopathy and early death and a novel 32-bp frameshift deletion (<a href="#0034">300005.0034</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11402105" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#70" class="mim-tip-reference" title="Kleefstra, T., Yntema, H. G., Oudakker, A. R., Romein, T., Sistermans, E., Nillessen, W., van Bokhoven, H., de Vries, B. B. A., Hamel, B. C. J. <strong>De novo MECP2 frameshift mutation in a boy with moderate mental retardation, obesity and gynaecomastia.</strong> Clin. Genet. 61: 359-362, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12081720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12081720</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2002.610507.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12081720">Kleefstra et al. (2002)</a> reported a 10-year-old boy with moderate mental retardation, emotional disturbances, hypotonia, obesity, and gynecomastia and a de novo 2-bp deletion in the MECP2 gene that resulted in a frameshift and premature stop codon. They pointed out that the clinical features were suggestive of Prader-Willi syndrome (<a href="/entry/176270">176270</a>). This was the first reported male with a de novo MECP2 mutation. Although most de novo MECP2 mutations in female patients with RTT are of paternal origin (<a href="#132" class="mim-tip-reference" title="Trappe, R., Laccone, F., Cobilanschi, J., Meins, M., Huppke, P., Hanefeld, F., Engel, W. <strong>MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin.</strong> Am. J. Hum. Genet. 68: 1093-1101, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11309679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11309679</a>] [<a href="https://doi.org/10.1086/320109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11309679">Trappe et al., 2001</a>), the example reported by <a href="#70" class="mim-tip-reference" title="Kleefstra, T., Yntema, H. G., Oudakker, A. R., Romein, T., Sistermans, E., Nillessen, W., van Bokhoven, H., de Vries, B. B. A., Hamel, B. C. J. <strong>De novo MECP2 frameshift mutation in a boy with moderate mental retardation, obesity and gynaecomastia.</strong> Clin. Genet. 61: 359-362, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12081720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12081720</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2002.610507.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12081720">Kleefstra et al. (2002)</a> indicated that de novo mutations can appear on the maternal allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12081720+11309679" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#74" class="mim-tip-reference" title="Laccone, F., Zoll, B., Huppke, P., Hanefeld, F., Pepinski, W., Trappe, R. <strong>MECP2 gene nucleotide changes and their pathogenicity in males: proceed with caution.</strong> J. Med. Genet. 39: 586-588, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12161600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12161600</a>] [<a href="https://doi.org/10.1136/jmg.39.8.586" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12161600">Laccone et al. (2002)</a> commented that some reported MECP2 mutations, those associated with male phenotypes in particular, may actually be rare genetic variants, and they cautioned against hasty interpretation of the pathogenicity of these nucleotide changes (see, e.g., <a href="#0023">300005.0023</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12161600" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By array comparative genomic hybridization (array CGH), <a href="#134" class="mim-tip-reference" title="Van Esch, H., Bauters, M., Ignatius, J., Jansen, M., Raynaud, M., Hollanders, K., Lugtenberg, D., Bienvenu, T., Jensen, L. R., Gecz, J., Moraine, C., Marynen, P., Fryns, J.-P., Froyen, G. <strong>Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males.</strong> Am. J. Hum. Genet. 77: 442-453, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16080119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16080119</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16080119[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/444549" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16080119">Van Esch et al. (2005)</a> identified a small duplication at Xq28 (<a href="#0030">300005.0030</a>) in a large family with a severe form of intellectual developmental disorder associated with progressive spasticity (MRXSL; <a href="/entry/300260">300260</a>). Screening by real-time quantification of 17 additional patients with mental retardation who had similar phenotypes revealed 3 more duplications. The duplications in the 4 patients varied in size from 0.4 to 0.8 Mb and harbored several genes, which, for each duplication, included the mental retardation-related genes L1CAM (<a href="/entry/308840">308840</a>) and MECP2. The proximal breakpoints were located within a 250-kb region centromeric to L1CAM, whereas the distal breakpoints were located in a 300-kb interval telomeric of MECP2. The size and location of each duplication was different in the 4 patients. The duplications segregated with the disease in the families, and asymptomatic carrier females showed complete skewing of X inactivation. Comparison of the clinical features in these patients and in a previously reported patient enabled refinement of the genotype-phenotype correlation and strongly suggested that increased dosage of MECP2 results in the mental retardation phenotype. The findings demonstrated that, in humans, not only impaired or abolished gene function but also increased MECP2 dosage causes a distinct phenotype. Duplication of the MECP2 region occurs frequently in male patients with a severe form of mental retardation, which justifies quantitative screening of MECP2 in this group of patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16080119" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#38" class="mim-tip-reference" title="del Gaudio, D., Fang, P., Scaglia, F., Ward, P. A., Craigen, W. J., Glaze, D. G., Neul, J. L., Patel, A., Lee, J. A., Irons, M., Berry, S. A., Pursley, A. A., and 12 others. <strong>Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males.</strong> Genet. Med. 8: 784-792, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17172942/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17172942</a>] [<a href="https://doi.org/10.1097/01.gim.0000250502.28516.3c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17172942">Del Gaudio et al. (2006)</a> reported 7 male patients with increased MECP2 gene copy number who manifested a progressive neurodevelopmental syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17172942" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Carvalho, C. M. B., Zhang, F., Liu, P., Patel, A., Sahoo, T., Bacino, C. A., Shaw, C., Peacock, S., Pursley, A., Tavyev, Y. J., Ramocki, M. B., Nawara, M., Obersztyn, E., Vianna-Morgante, A. M., Stankiewicz, P., Zoghbi, H. Y., Cheung, S. W., Lupski, J. R. <strong>Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching.</strong> Hum. Molec. Genet. 18: 2188-2203, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19324899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19324899</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19324899[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19324899">Carvalho et al. (2009)</a> investigated the potential mechanisms for MECP2 duplication and examined whether genomic architectural features may play a role in their origin using a 4-Mb tiling-path oligonucleotide array CGH assay. The 30 male patients analyzed showed a unique duplication varying in size from 250 kb to 2.6 Mb. In 77% of these nonrecurrent duplications, the distal breakpoints grouped within a 215-kb genomic interval, located 47 kb telomeric to the MECP2 gene. The genomic architecture of this region contains both direct and inverted low-copy repeat (LCR) sequences; this same region undergoes polymorphic structural variation in the general population. Array CGH analysis revealed complex rearrangements in 8 patients; in 6 patients the duplication contained an embedded triplicated segment, and in the other 2, stretches of nonduplicated sequences occurred within the duplicated region. Breakpoint junction sequencing was achieved in 4 duplications and identified an inversion in 1 patient, demonstrating further complexity. <a href="#23" class="mim-tip-reference" title="Carvalho, C. M. B., Zhang, F., Liu, P., Patel, A., Sahoo, T., Bacino, C. A., Shaw, C., Peacock, S., Pursley, A., Tavyev, Y. J., Ramocki, M. B., Nawara, M., Obersztyn, E., Vianna-Morgante, A. M., Stankiewicz, P., Zoghbi, H. Y., Cheung, S. W., Lupski, J. R. <strong>Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching.</strong> Hum. Molec. Genet. 18: 2188-2203, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19324899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19324899</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19324899[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19324899">Carvalho et al. (2009)</a> proposed that the presence of LCRs in the vicinity of the MECP2 gene may generate an unstable DNA structure that can induce DNA strand lesions, such as a collapsed fork, and facilitate a fork stalling and template switching (FoSTeS) event producing the complex rearrangements involving the MECP2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19324899" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Carvalho, C. M. B., Ramocki, M. B., Pehlivan, D., Franco, L. M., Gonzaga-Jauregui, C., Fang, P., McCall, A., Pivnick, E. K., Hines-Dowell, S., Seaver, L. H., Friehling, L., Lee, S., and 9 others. <strong>Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome.</strong> Nature Genet. 43: 1074-1081, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21964572/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21964572</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21964572[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.944" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21964572">Carvalho et al. (2011)</a> identified complex genomic rearrangements consisting of intermixed duplications and triplications of genomic segments at the MECP2 and the PLP1 (<a href="/entry/300401">300401</a>) loci. These complex rearrangements were characterized by a triplicated segment embedded within a duplication in 11 unrelated subjects. Notably, only 2 breakpoint junctions were generated during each rearrangement formation. All the complex rearrangement products shared a common genomic organization, duplication-inverted triplication-duplication (DUP-TRP/INV-DUP), in which the triplicated segment is inverted and located between directly oriented duplicated genomic segments. <a href="#22" class="mim-tip-reference" title="Carvalho, C. M. B., Ramocki, M. B., Pehlivan, D., Franco, L. M., Gonzaga-Jauregui, C., Fang, P., McCall, A., Pivnick, E. K., Hines-Dowell, S., Seaver, L. H., Friehling, L., Lee, S., and 9 others. <strong>Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome.</strong> Nature Genet. 43: 1074-1081, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21964572/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21964572</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21964572[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.944" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21964572">Carvalho et al. (2011)</a> provided evidence that the DUP-TRP/INV-DUP structures are mediated by inverted repeats that can be separated by more than 300 kb, a genomic architecture that apparently leads to susceptibility to such complex rearrangements. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21964572" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Atypical Rett Syndrome or Angelman-like Phenotype</em></strong></p><p>
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<a href="#144" class="mim-tip-reference" title="Watson, P., Black, G., Ramsden, S., Barrow, M., Super, M., Kerr, B., Clayton-Smith, J. <strong>Angelman syndrome phenotype associated with mutations in MECP2, a gene encoding a methyl CpG binding protein.</strong> J. Med. Genet. 38: 224-228, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11283202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11283202</a>] [<a href="https://doi.org/10.1136/jmg.38.4.224" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11283202">Watson et al. (2001)</a> identified MECP2 mutations in 5 of 47 patients with a clinical diagnosis of an Angelman-like syndrome (see <a href="/entry/105830">105830</a>) and no cytogenetic or molecular abnormality of chromosome 15q11-q13. Four of these patients were female and 1 male. By the time of diagnosis, 3 of the patients were showing signs of regression and had features suggestive of Rett syndrome; in the remaining 2, the clinical phenotype was still considered to be Angelman-like. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11283202" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#63" class="mim-tip-reference" title="Imessaoudene, B., Bonnefont, J.-P., Royer, G., Cormier-Daire, V., Lyonnet, S., Lyon, G., Munnich, A., Amiel, J. <strong>MECP2 mutation in non-fatal, non-progressive encephalopathy in a male.</strong> J. Med. Genet. 38: 171-174, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11238684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11238684</a>] [<a href="https://doi.org/10.1136/jmg.38.3.171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11238684">Imessaoudene et al. (2001)</a> identified MECP2 mutations in 6 of 78 patients with possible Angelman syndrome but with normal methylation pattern at the UBE3A locus (<a href="/entry/601623">601623</a>). Of these, 4 were females with a phenotype consistent with Rett syndrome, one was a female with progressive encephalopathy of neonatal onset, and one was a male with a nonprogressive encephalopathy of neonatal onset. This boy had a gly428-to-ser mutation (<a href="#0023">300005.0023</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11238684" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Autism</em></strong></p><p>
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As there is a resemblance between the phenotypes for autism (<a href="/entry/209850">209850</a>) and Rett syndrome, and 70% of individuals with autism show some degree of mental retardation, some questioned whether specific mutations within the coding region of MECP2 are involved in the etiology of infantile autism. <a href="#75" class="mim-tip-reference" title="Lam, C.-W., Yeung, W.-L., Ko, C.-H., Poon, P. M. K., Tong, S.-F., Chan, K.-Y., Lo, I. F. M., Chan, L. Y. S., Hui, J., Wong, V., Pang, C.-P., Lo, Y. M. D., Fok, T. F. <strong>Spectrum of mutations in the MECP2 gene in patients with infantile autism and Rett syndrome.</strong> J. Med. Genet. 37: E41, 2000. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11106359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11106359</a>] [<a href="https://doi.org/10.1136/jmg.37.12.e41" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11106359">Lam et al. (2000)</a> and <a href="#7" class="mim-tip-reference" title="Ashley-Koch, A. E., Carney, R. J., Wolpert, C. M., Cuccaro, M. L., Gilbert, J. R., Vance, J. M., Pericak-Vance, M. A. <strong>Screening for MECP2 mutations in females with autistic disorder. (Abstract)</strong> Am. J. Med. Genet. 105B: 632 only, 2001."None>Ashley-Koch et al. (2001)</a> identified mutations in the MECP2 gene in sporadic cases of autism, whereas no mutations were found in a sample of 59 autistic individuals by <a href="#139" class="mim-tip-reference" title="Vourc'h, P., Bienvenu, T., Beldjord, C., Chelly, J., Barthelemy, C., Muh, J. P., Andres, C. <strong>No mutations in the coding region of the Rett syndrome gene MECP2 in 59 autistic patients.</strong> Europ. J. Hum. Genet. 9: 556-558, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11464249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11464249</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200660" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11464249">Vourc'h et al. (2001)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11464249+11106359" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Beyer, K. S., Blasi, F., Bacchelli, E., Klauck, S. M., Maestrini, E., Poustka, A., International Molecular Genetic Study of Autism Consortium (IMGSAC). <strong>Mutation analysis of the coding sequence of the MECP2 gene in infantile autism.</strong> Hum. Genet. 111: 305-309, 2002. Note: Erratum: Hum. Genet. 112: 437 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12384770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12384770</a>] [<a href="https://doi.org/10.1007/s00439-002-0786-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12384770">Beyer et al. (2002)</a> systematically screened for MECP2 mutations in 152 autistic patients from 134 German families and 50 unrelated patients from the affected relative-pair sample of the International Molecular Genetic Study of Autism Consortium (IMGSAC), and identified 14 sequence variants. Eleven variants were excluded from having an etiologic role as they were either silent mutations, did not cosegregate with autism in the pedigrees of the patients, or represented known polymorphisms. The etiologic relevance of the 3 remaining mutations could not be ruled out, although they were not localized within functional domains of MECP2 and may be rare polymorphisms. Given the large size of the sample, <a href="#14" class="mim-tip-reference" title="Beyer, K. S., Blasi, F., Bacchelli, E., Klauck, S. M., Maestrini, E., Poustka, A., International Molecular Genetic Study of Autism Consortium (IMGSAC). <strong>Mutation analysis of the coding sequence of the MECP2 gene in infantile autism.</strong> Hum. Genet. 111: 305-309, 2002. Note: Erratum: Hum. Genet. 112: 437 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12384770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12384770</a>] [<a href="https://doi.org/10.1007/s00439-002-0786-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12384770">Beyer et al. (2002)</a> concluded that mutations in the coding region of MECP2 do not play a major role in autism susceptibility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12384770" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Carney, R. M., Wolpert, C. M., Ravan, S. A., Shahbazian, M., Ashley-Koch, A., Cuccaro, M. L., Vance, J. M., Pericak-Vance, M. A. <strong>Identification of MeCP2 mutations in a series of females with autistic disorder.</strong> Pediat. Neurol. 28: 205-211, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12770674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12770674</a>] [<a href="https://doi.org/10.1016/s0887-8994(02)00624-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12770674">Carney et al. (2003)</a> analyzed 69 females clinically diagnosed with autistic disorder for the presence of mutations in the MECP2 gene. Two autistic disorder females were found to have de novo mutations in the MECP2 gene, one a 41-bp deletion beginning at nucleotide 1157 (<a href="#0012">300005.0012</a>), the other an arg294-to-ter mutation (<a href="#0011">300005.0011</a>), which is one of the most common RTT mutations in MECP2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12770674" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Rett syndrome and Angelman syndrome, an imprinted disorder caused by maternal 15q11-q13 or UBE3A deficiency, have phenotypic and genetic overlap with autism. <a href="#116" class="mim-tip-reference" title="Samaco, R. C., Hogart, A., LaSalle, J. M. <strong>Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3.</strong> Hum. Molec. Genet. 14: 483-492, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15615769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15615769</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15615769[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddi045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15615769">Samaco et al. (2005)</a> tested the hypothesis that MECP2 deficiency may affect the level of expression of UBE3A and neighboring autism candidate gene GABRB3 (<a href="/entry/137192">137192</a>) without necessarily affecting imprinted expression. Multiple quantitative methods revealed significant defects in UBE3A expression in 2 different Mecp2-deficient mouse strains, as well as Rett, Angelman, and autism brain samples compared with control samples. Although no difference was observed in the allelic expression of several imprinted transcripts in Mecp2-null mouse brain, Ube3a sense expression was significantly reduced, consistent with the decrease in protein. The nonimprinted GABRB3 gene also showed significantly reduced expression in multiple Rett, Angelman, and autism brain samples, as well as Mecp2-deficient mice. <a href="#116" class="mim-tip-reference" title="Samaco, R. C., Hogart, A., LaSalle, J. M. <strong>Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3.</strong> Hum. Molec. Genet. 14: 483-492, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15615769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15615769</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15615769[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddi045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15615769">Samaco et al. (2005)</a> proposed an overlapping pathway of gene dysregulation within chromosome 15q11-q13 in Rett syndrome, Angelman syndrome, and autism, and implicated MECP2 in the regulation of UBE3A and GABRB3 expression in the postnatal mammalian brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15615769" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#83" class="mim-tip-reference" title="Makedonski, K., Abuhatzira, L., Kaufman, Y., Razin, A., Shemer, R. <strong>MeCP2 deficiency in Rett syndrome causes epigenetic aberrations at the PWS/AS imprinting center that affects UBE3A expression.</strong> Hum. Molec. Genet. 14: 1049-1058, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15757975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15757975</a>] [<a href="https://doi.org/10.1093/hmg/ddi097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15757975">Makedonski et al. (2005)</a> showed that UBE3A mRNA and protein were significantly reduced in human and mouse MECP2-deficient brains. Reduced UBE3A level was associated with biallelic production of the UBE3A antisense RNA (SNHG14; <a href="/entry/616259">616259</a>). In addition, MECP2 deficiency resulted in elevated histone H3 acetylation and H3(K4) methylation and reduced H3(K9) methylation at the PWS/AS imprinting center, with no effect on DNA methylation or SNRPN (<a href="/entry/182279">182279</a>) expression. <a href="#83" class="mim-tip-reference" title="Makedonski, K., Abuhatzira, L., Kaufman, Y., Razin, A., Shemer, R. <strong>MeCP2 deficiency in Rett syndrome causes epigenetic aberrations at the PWS/AS imprinting center that affects UBE3A expression.</strong> Hum. Molec. Genet. 14: 1049-1058, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15757975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15757975</a>] [<a href="https://doi.org/10.1093/hmg/ddi097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15757975">Makedonski et al. (2005)</a> concluded that MECP2 deficiency causes epigenetic aberrations at the PWS imprinting center. These changes in histone modifications may result in loss of imprinting of the UBE3A antisense gene in the brain, increase in UBE3A antisense RNA level, and, consequently, reduction in UBE3A production. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15757975" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between variation in the MECP2 gene and susceptibility to systemic lupus erythematosus, see SLEB15 (<a href="/entry/300809">300809</a>).</p><p><strong><em>Effects of Mutations on Protein Function</em></strong></p><p>
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<a href="#42" class="mim-tip-reference" title="Dragich, J., Houwink-Manville, I., Schanen, C. <strong>Rett syndrome: a surprising result of mutation in MECP2.</strong> Hum. Molec. Genet. 9: 2365-2375, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11005791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11005791</a>] [<a href="https://doi.org/10.1093/hmg/9.16.2365" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11005791">Dragich et al. (2000)</a> reviewed the structure, function, and effect of mutations on the activity of MECP2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11005791" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By Southwestern and gel shift binding analyses of MECP2 proteins with RTT-causing mutations in conserved residues of the MBD, <a href="#8" class="mim-tip-reference" title="Ballestar, E., Yusufzai, T. M., Wolffe, A. P. <strong>Effects of Rett syndrome mutations of the methyl-CpG binding domain of the transcriptional repressor MeCP2 on selectivity for association with methylated DNA.</strong> Biochemistry 39: 7100-7106, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10852707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10852707</a>] [<a href="https://doi.org/10.1021/bi0001271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10852707">Ballestar et al. (2000)</a> determined that arg106-to-trp (<a href="#0008">300005.0008</a>), arg133- to-cys (<a href="#0001">300005.0001</a>), and phe155-to-ser (<a href="#0002">300005.0002</a>) had dramatically reduced (100-fold) capacities to bind mono- and polymethylated DNA compared with wildtype MECP2. Another mutation, thr158-to-met (T158M; <a href="#0007">300005.0007</a>), which occurs at a nonconserved MBD residue near the C-terminal side of the MBD, bound methylated DNA only 2-fold less well than wildtype. <a href="#8" class="mim-tip-reference" title="Ballestar, E., Yusufzai, T. M., Wolffe, A. P. <strong>Effects of Rett syndrome mutations of the methyl-CpG binding domain of the transcriptional repressor MeCP2 on selectivity for association with methylated DNA.</strong> Biochemistry 39: 7100-7106, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10852707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10852707</a>] [<a href="https://doi.org/10.1021/bi0001271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10852707">Ballestar et al. (2000)</a> noted that T158M is one of the most common mutations in RTT patients. Although the T158 residue is located in the MBD, the authors suggested that it may have other roles related to the function of MECP2, possibly involving interactions with the TRD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10852707" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#154" class="mim-tip-reference" title="Yusufzai, T. M., Wolffe, A. P. <strong>Functional consequences of Rett syndrome mutations on human MeCP2.</strong> Nucleic Acids Res. 28: 4172-4179, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11058114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11058114</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11058114[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/nar/28.21.4172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11058114">Yusufzai and Wolffe (2000)</a> studied the consequences of MECP2 mutations on the ability of MECP2 protein to bind specifically to methylated DNA and its transcription repression capabilities in Xenopus oocytes. <a href="#154" class="mim-tip-reference" title="Yusufzai, T. M., Wolffe, A. P. <strong>Functional consequences of Rett syndrome mutations on human MeCP2.</strong> Nucleic Acids Res. 28: 4172-4179, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11058114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11058114</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11058114[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/nar/28.21.4172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11058114">Yusufzai and Wolffe (2000)</a> found that all missense mutations within the methyl-binding domain impaired selectivity for methylated DNA, and that all nonsense mutations that truncate all or some of the transcriptional repression domain affected the ability to repress transcription and had decreased levels of stability in vivo. Two missense mutations, one in the TRD (arg306-to-cys) and one in the C terminus (glu397-to-lys), had no noticeable effects on MECP2 function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11058114" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#141" class="mim-tip-reference" title="Wan, M., Zhao, K., Lee, S. S. J., Francke, U. <strong>MECP2 truncating mutations cause histone H4 hyperacetylation in Rett syndrome.</strong> Hum. Molec. Genet. 10: 1085-1092, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11331619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11331619</a>] [<a href="https://doi.org/10.1093/hmg/10.10.1085" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11331619">Wan et al. (2001)</a> examined mutant MECP2 expression and global histone acetylation levels in clonal cell cultures from a female RTT patient with one mutant allele on the active X chromosome, as well as in cells from a male hemizygous for a 1-bp deletion mutation (<a href="#0003">300005.0003</a>). Both mutant alleles generated stable RNA transcripts, but no intact MECP2 protein was detected by Western blot analysis. Western blot analysis further revealed that histone H4, but not H3, was hyperacetylated, specifically at lysine-16. The authors hypothesized that subsequent overexpression of MECP2 target genes may play a role in the pathogenesis of RTT. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11331619" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#76" class="mim-tip-reference" title="LaSalle, J. M., Goldstine, J., Balmer, D., Greco, C. M. <strong>Quantitative localization of heterogeneous methyl-CpG-binding protein 2 (MeCP2) expression phenotypes in normal and Rett syndrome brain by laser scanning cytometry.</strong> Hum. Molec. Genet. 10: 1729-1740, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11532982/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11532982</a>] [<a href="https://doi.org/10.1093/hmg/10.17.1729" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11532982">LaSalle et al. (2001)</a> quantitated the level and distribution of wildtype and mutant MECP2 protein in situ by immunofluorescence and laser scanning cytometry of brain biopsies and tissue arrays. Cellular heterogeneity in MECP2 expression level was observed in normal brain with a subpopulation of cells exhibiting high expression and the remainder exhibiting low expression. MECP2 expression was significantly higher in CNS compared with non-CNS tissues; MECP2 neurons exhibiting high expression were more numerous in layer IV of the cerebrum, and MECP2 neurons exhibiting low expression were more numerous in the granular layer of the cerebellum. MECP2 mutant-expressing cells were randomly localized in Rett cerebrum and cerebellum and showed normal MECP2 expression with N-terminal-specific anti-MECP2. The authors suggested that mutations in the MECP2 gene in RTT are only manifested in cells highly expressing in the MECP2 protein. <a href="#124" class="mim-tip-reference" title="Shahbazian, M. D., Zoghbi, H. Y. <strong>Rett syndrome and MeCP2: linking epigenetics and neuronal function.</strong> Am. J. Hum. Genet. 71: 1259-1272, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12442230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12442230</a>] [<a href="https://doi.org/10.1086/345360" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12442230">Shahbazian and Zoghbi (2002)</a> reviewed the manner in which the linking of epigenetics and neuronal function is revealed by studies of the MECP2 gene in Rett syndrome. Originally thought to be a protein that functions as a global transcriptional repressor, MECP2 is actually specialized for a function in neurons of the CNS. Mouse models reproduce virtually every aspect of RTT, including highly specialized hand-wringing behaviors, which suggests that the pathways leading from dysfunctional MECP2 to each of these features are conserved between humans and mice. Given that, in humans, the phenotypic outcome of MECP2 truncation mutations depends on the position of the truncation, different regions of the protein may interact with particular proteins or complexes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11532982+12442230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Balmer, D., Arredondo, J., Samaco, R. C., LaSalle, J. M. <strong>MECP2 mutations in Rett syndrome adversely affect lymphocyte growth, but do not affect imprinted gene expression in blood or brain.</strong> Hum. Genet. 110: 545-552, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12107440/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12107440</a>] [<a href="https://doi.org/10.1007/s00439-002-0724-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12107440">Balmer et al. (2002)</a> performed single cell cloning of T lymphocytes from 4 RTT patients with MECP2 mutations to isolate cells expressing mutant MECP2. Mutant-expressing clones were present at a significantly lower frequency (P less than 0.0001) than wildtype clones. These results demonstrated that although MECP2 is not essential for lymphocyte growth, expression of the MECP2 mutation causes a growth disadvantage in cultured clonal T cells by reducing the response to mitogenic stimulation. Mutant MECP2 was expressed at normal transcript and protein levels, and exhibited no significant effect on acetylated histones or methyl-binding protein-3 (MBD3; <a href="/entry/603573">603573</a>) levels. Examination of the expression of 5 imprinted genes suggested that MECP2 does not have an essential role in the silencing of these genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12107440" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#73" class="mim-tip-reference" title="Kudo, S., Nomura, Y., Segawa, M., Fujita, N., Nakao, M., Hammer, S., Schanen, C., Terai, I., Tamura, M. <strong>Functional characterisation of MeCP2 mutations found in male patients with X linked mental retardation.</strong> J. Med. Genet. 39: 132-136, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11836365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11836365</a>] [<a href="https://doi.org/10.1136/jmg.39.2.132" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11836365">Kudo et al. (2002)</a> noted that 2 MECP2 mutations, A140V (<a href="#0015">300005.0015</a>) and E137G (<a href="#0017">300005.0017</a>), had been found in male patients with nonspecific X-linked mental retardation. Using mouse L929 cells, <a href="#73" class="mim-tip-reference" title="Kudo, S., Nomura, Y., Segawa, M., Fujita, N., Nakao, M., Hammer, S., Schanen, C., Terai, I., Tamura, M. <strong>Functional characterisation of MeCP2 mutations found in male patients with X linked mental retardation.</strong> J. Med. Genet. 39: 132-136, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11836365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11836365</a>] [<a href="https://doi.org/10.1136/jmg.39.2.132" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11836365">Kudo et al. (2002)</a> found that expression of these mutant proteins showed clear focal heterochromatin staining patterns indistinguishable from that of wildtype protein, indicating that the 2 mutants retained their ability to bind methyl-CpG. Another mutant, R106W (<a href="#0008">300005.0008</a>), which had been identified in Rett syndrome, had impaired heterochromatin staining. Using a Drosophila cell line, the authors showed that the A140V mutant retained transcriptional repression activity, whereas the Rett mutant R106W did not. The E137G mutant had impaired transcriptional repression activity. <a href="#73" class="mim-tip-reference" title="Kudo, S., Nomura, Y., Segawa, M., Fujita, N., Nakao, M., Hammer, S., Schanen, C., Terai, I., Tamura, M. <strong>Functional characterisation of MeCP2 mutations found in male patients with X linked mental retardation.</strong> J. Med. Genet. 39: 132-136, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11836365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11836365</a>] [<a href="https://doi.org/10.1136/jmg.39.2.132" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11836365">Kudo et al. (2002)</a> concluded that the A140V and E137G Mecp2 mutants exhibited mild impairment of protein function compared to the mutants identified in Rett syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11836365" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#145" class="mim-tip-reference" title="Weaving, L. S., Williamson, S. L., Bennetts, B., Davis, M., Ellaway, C. J., Leonard, H., Thong, M.-K., Delatycki, M., Thompson, E. M., Laing, N., Christodoulou, J. <strong>Effects of MECP2 mutation type, location and X-inactivation in modulating Rett syndrome phenotype.</strong> Am. J. Med. Genet. 118A: 103-114, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12655490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12655490</a>] [<a href="https://doi.org/10.1002/ajmg.a.10053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12655490">Weaving et al. (2003)</a> reported a large MECP2 screening project in patients diagnosed with Rett syndrome. Composite phenotype severity scores did not correlate with mutation type, domain affected, or X inactivation. Other correlations, including head circumference, height, presence of speech, and age at development of hand stereotypies, suggested that truncating mutations and mutations affecting the MBD tend to lead to a more severe phenotype. Skewed X inactivation was found in 31 (43%) of 72 patients tested, primarily in those with truncating mutations and mutations affecting the MBD. <a href="#145" class="mim-tip-reference" title="Weaving, L. S., Williamson, S. L., Bennetts, B., Davis, M., Ellaway, C. J., Leonard, H., Thong, M.-K., Delatycki, M., Thompson, E. M., Laing, N., Christodoulou, J. <strong>Effects of MECP2 mutation type, location and X-inactivation in modulating Rett syndrome phenotype.</strong> Am. J. Med. Genet. 118A: 103-114, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12655490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12655490</a>] [<a href="https://doi.org/10.1002/ajmg.a.10053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12655490">Weaving et al. (2003)</a> concluded that it is likely that X inactivation modulates the phenotype in RTT. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12655490" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of genotype/phenotype correlations, <a href="#119" class="mim-tip-reference" title="Schanen, C., Houwink, E. J. F., Dorrani, N., Lane, J., Everett, R., Feng, A., Cantor, R. M., Percy, A. <strong>Phenotypic manifestations of MECP2 mutations in classical and atypical Rett syndrome.</strong> Am. J. Med. Genet. 126A: 129-140, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15057977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15057977</a>] [<a href="https://doi.org/10.1002/ajmg.a.20571" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15057977">Schanen et al. (2004)</a> analyzed 85 Rett syndrome patients with mutation in the MECP2 gene. Sixty-five (76%) carried 1 of the 8 common mutations. Patients with missense mutations had lower total severity scores and better language performance than those with nonsense mutations. No difference was noted between severity scores for mutations in the MBD and the TRD. However, patients with missense mutations in TRD had the best overall scores and better preservation of head growth and language skills. Analysis of specific mutation groups demonstrated a striking difference for patients with the R306C mutation (<a href="#0016">300005.0016</a>), including better overall score, later regression, and better language with less motor impairment. Indeed, these patients as a group accounted for the differences in overall scores between the missense and nonsense groups. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15057977" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Bartholdi, D., Klein, A., Weissert, M., Koenig, N., Baumer, A., Boltshauser, E., Schinzel, A., Berger, W., Matyas, G. <strong>Clinical profiles of four patients with Rett syndrome carrying a novel exon 1 mutation or genomic rearrangement in the MECP2 gene.</strong> Clin. Genet. 69: 319-326, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16630165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16630165</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00604.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16630165">Bartholdi et al. (2006)</a> reported 2 unrelated girls with Rett syndrome caused by different mutations affecting exon 1 of the MECP2 gene (see, e.g., <a href="#0031">300005.0031</a>). The phenotype of both girls was more severe than that of 2 additional unrelated girls with Rett syndrome caused by MECP2 mutations not affecting exon 1. The authors speculated that MECP2 mutations involving exon 1 result in a more severe phenotype because MECP2B is more abundantly expressed in the brain than MECP2A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16630165" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 110 patients with Rett syndrome in whom an MECP2 mutation was not identified, <a href="#6" class="mim-tip-reference" title="Archer, H. L., Whatley, S. D., Evans, J. C., Ravine, D., Huppke, P., Kerr, A., Bunyan, D., Kerr, B., Sweeney, E., Davies, S. J., Reardon, W., Horn, J., and 14 others. <strong>Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett syndrome patients. (Letter)</strong> J. Med. Genet. 43: 451-456, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16183801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16183801</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16183801[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2005.033464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16183801">Archer et al. (2006)</a> used dosage analysis to detect large deletions in 37.8% (14 of 37) patients with classic Rett syndrome and 7.5% (4 of 53) patients with atypical Rett syndrome. Most large deletions contained a breakpoint in the deletion prone region of exon 4. Five patients with large MECP2 deletions had additional congenital anomalies, which was significantly more than in RTT patients with other MECP2 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16183801" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#114" class="mim-tip-reference" title="Robertson, L., Hall, S. E., Jacoby, P., Ellaway, C., de Klerk, N., Leonard, H. <strong>The association between behavior and genotype in Rett syndrome using the Australian Rett Syndrome Database.</strong> Am. J. Med. Genet. 141B: 177-183, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16389588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16389588</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16389588[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.b.30270" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16389588">Robertson et al. (2006)</a> compared the behavioral profile of cases in the Australian Rett Syndrome Database with those of a British study using the Rett Syndrome Behavioral Questionnaire (<a href="#96" class="mim-tip-reference" title="Mount, R. H., Charman, T., Hastings, R. P., Reilly, S., Cass, H. <strong>The Rett Syndrome Behaviour Questionnaire (RSBQ): refining the behavioural phenotype of Rett syndrome.</strong> J. Child. Psychol. Psychiat. 43: 1099-1110, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12455930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12455930</a>] [<a href="https://doi.org/10.1111/1469-7610.00236" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12455930">Mount et al., 2002</a>). Behavioral patterns were compared to MECP2 gene findings in the probands. Fear/anxiety was more commonly reported in those individuals with R133C and R306C. The R294X mutation (<a href="#0011">300005.0011</a>) was more likely to be associated with mood difficulties and body rocking but less likely to have hand behaviors and to display repetitive face movements. Hand behaviors were more commonly reported in those with R270X (<a href="#0005">300005.0005</a>) or R255X (<a href="#0021">300005.0021</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16389588+12455930" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Bebbington, A., Anderson, A., Ravine, D., Fyfe, S., Pineda, M, de Klerk, N., Ben-Zeev, B., Yatawara, N., Percy, A., Kaufmann, W.E., Leonard, H. <strong>Investigating genotype-phenotype relationships in Rett syndrome using an international data set.</strong> Neurology 70: 868-875, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18332345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18332345</a>] [<a href="https://doi.org/10.1212/01.wnl.0000304752.50773.ec" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18332345">Bebbington et al. (2008)</a> investigated genotype/phenotype correlations of 276 cases of Rett syndrome reported in a large global database. Among the most common mutations, R270X and R255X were associated with the most severe phenotype, and R133C (<a href="#0001">300005.0001</a>) and R294X were associated with the mildest phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18332345" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#117" class="mim-tip-reference" title="Saunders, C. J., Minassian, B. E., Chow, E. W. C., Zhao, W., Vincent, J. B. <strong>Novel exon 1 mutations in MECP2 implicate isoform MeCP2_1 in classical Rett syndrome.</strong> Am. J. Med. Genet. 149A: 1019-1023, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19365833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19365833</a>] [<a href="https://doi.org/10.1002/ajmg.a.32776" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19365833">Saunders et al. (2009)</a> identified 4 patients with classic Rett syndrome associated with mutations in exon 1 of the MECP2 gene, affecting the MeCP2_e1 isoform. Three of the mutations were predicted to result in absent translation of the isoform. Three of the mutations were proven to be de novo; the fourth was likely de novo, but the unaffected father was not available for DNA analysis. Two of the patients had previously tested negative for MECP2 mutation, which at the time only included sequencing of exons 2 to 4 of the gene (MeCP2_e2 isoform). The findings suggested that mutations affecting exon 1 of MECP2 is important in the etiology of RTT. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19365833" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#146" class="mim-tip-reference" title="Willard, H. F., Hendrich, B. D. <strong>Breaking the silence in Rett syndrome.</strong> Nature Genet. 23: 127-128, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508498</a>] [<a href="https://doi.org/10.1038/13751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508498">Willard and Hendrich (1999)</a> pointed out that the finding that MECP2 is mutated in Rett syndrome (<a href="/entry/312750">312750</a>) fits well with what is known about Mecp2 deficiency in mice (<a href="#128" class="mim-tip-reference" title="Tate, P., Skarnes, W., Bird, A. <strong>The methyl-CpG binding protein MeCP2 is essential for embryonic development in the mouse.</strong> Nature Genet. 12: 205, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8563762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8563762</a>] [<a href="https://doi.org/10.1038/ng0296-205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8563762">Tate et al., 1996</a>). Male mouse embryonic stem (ES) cells in which Mecp2 is disrupted cannot support development, consistent with the possible male lethality of RTT. In contrast, chimeric mice, in which a small proportion of cells are derived from Mecp2-deficient ES cells, are viable. These animals might provide a model for RTT, as female RTT patients are also mosaic for MECP2-expressing and MECP2-deficient cells because of random X-chromosome inactivation. They also pointed out that Rett syndrome is one of a number of human diseases involving abnormal chromatin assembly or remodeling, with consequent epigenetic effects on expression of one or more genes that are themselves not mutated. Other examples include the imprinting defects and the discovery of a defect in phosphorylation of histone H3 by ribosomal protein S6 kinase (RPS6KA3; <a href="/entry/300075">300075</a>) in Coffin-Lowry syndrome (<a href="/entry/303600">303600</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8563762+10508498" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Chen, R. Z., Akbarian, S., Tudor, M., Jaenisch, R. <strong>Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice.</strong> Nature Genet. 27: 327-331, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242118/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242118</a>] [<a href="https://doi.org/10.1038/85906" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242118">Chen et al. (2001)</a> generated mice deficient in MECP2. Contrary to the conclusion of <a href="#128" class="mim-tip-reference" title="Tate, P., Skarnes, W., Bird, A. <strong>The methyl-CpG binding protein MeCP2 is essential for embryonic development in the mouse.</strong> Nature Genet. 12: 205, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8563762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8563762</a>] [<a href="https://doi.org/10.1038/ng0296-205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8563762">Tate et al. (1996)</a>, <a href="#28" class="mim-tip-reference" title="Chen, R. Z., Akbarian, S., Tudor, M., Jaenisch, R. <strong>Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice.</strong> Nature Genet. 27: 327-331, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242118/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242118</a>] [<a href="https://doi.org/10.1038/85906" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242118">Chen et al. (2001)</a> demonstrated that disruption of Mecp2 does not lead to embryonic lethality. Mecp2-null mice were normal until 5 weeks of age, when they began to develop disease, leading to death between 6 and 12 weeks. The initial manifestations of abnormal behavior included nervousness, body trembling, pila erection, and occasional hard respiration at 5 weeks of age. A significant portion of mutant mice became overweight, and most exhibited signs of physical deterioration by 8 weeks of age. At late stages of the disease, mutants were hypoactive, trembled when handled, and often began to lose weight. Most mutants died at approximately 10 weeks of age. Heterozygous mutant females seemed normal for the first 4 months but began to show symptoms such as weight gain, reduced activity, and ataxic gait at a later age. Autopsy showed a substantial reduction in both brain weight and neuronal cell size but no obvious structural defects or signs of neurodegeneration. Brain-specific deletion of Mecp2 at embryonic day 12 resulted in a phenotype identical to that of the null mutation, indicating that the phenotype is caused by Mecp2 deficiency in the central nervous system (CNS) rather than in peripheral tissues. Deletion of Mecp2 in postnatal CNS neurons led to a similar neuronal phenotype, although at a later age. <a href="#28" class="mim-tip-reference" title="Chen, R. Z., Akbarian, S., Tudor, M., Jaenisch, R. <strong>Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice.</strong> Nature Genet. 27: 327-331, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242118/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242118</a>] [<a href="https://doi.org/10.1038/85906" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242118">Chen et al. (2001)</a> concluded that the role of MECP2 is not restricted to the immature brain but becomes critical in mature neurons. MECP2 deficiency in these neurons is sufficient to cause neuronal dysfunction with symptomatic manifestation similar to Rett syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8563762+11242118" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using similar methods, <a href="#55" class="mim-tip-reference" title="Guy, J., Hendrich, B., Holmes, M., Martin, J. E., Bird, A. <strong>A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome.</strong> Nature Genet. 27: 322-326, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242117</a>] [<a href="https://doi.org/10.1038/85899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242117">Guy et al. (2001)</a> replaced exons 3 and 4 of MECP2. They also found that mice homozygous or hemizygous for the replacement were viable and fertile. <a href="#55" class="mim-tip-reference" title="Guy, J., Hendrich, B., Holmes, M., Martin, J. E., Bird, A. <strong>A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome.</strong> Nature Genet. 27: 322-326, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242117</a>] [<a href="https://doi.org/10.1038/85899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242117">Guy et al. (2001)</a> found that body weight varied depending upon genetic background. The Mecp2-null mutation on a C57BL/6 background gave rise to animals that were substantially underweight from 4 weeks of age with full penetrance. After crossing to a 129 strain, F1 animals showed a reverse effect. Instead of losing weight, male Mecp2-null mice were the same weight as wildtype littermates until 8 weeks, when survivors became significantly heavier than sibs with an obvious increase in deposited fat. Other aspects of the phenotype including behavioral defects were not affected by altered genetic background. Mecp2-null male and female mice showed no initial phenotype, but both developed a stiff uncoordinated gait and reduced spontaneous movement between 3 and 8 weeks of age. Most animals subsequently developed hindlimb clasping and irregular breathing. Pathologic analysis of symptomatic animals revealed no obvious histologic abnormalities in a range of organs. In particular, the brain showed no unusual features of cortical lamination, ectopias, or other abnormalities. Variable progression of symptoms led ultimately to rapid weight loss and death at approximately 54 days. After several months heterozygous female mice also showed behavioral symptoms. The overlapping delay before symptom onset in humans and mice, despite the profoundly different rates of development, raises the possibility that stability of brain function, not brain development per se, is compromised by the absence of MECP2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11242117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#123" class="mim-tip-reference" title="Shahbazian, M. D., Young, J. I., Yuva-Paylor, L. A., Spencer, C. M., Antalffy, B. A., Noebels, J. L., Armstrong, D. L., Paylor, R., Zoghbi, H. Y. <strong>Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3.</strong> Neuron 35: 243-254, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12160743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12160743</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00768-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12160743">Shahbazian et al. (2002)</a> generated mice expressing a truncated Mecp2 protein similar to those found in RTT. They showed that although the truncated Mecp2 protein in these mice localized normally to heterochromatic domains in vivo, histone H3 (<a href="/entry/142780">142780</a>) was hyperacetylated. <a href="#123" class="mim-tip-reference" title="Shahbazian, M. D., Young, J. I., Yuva-Paylor, L. A., Spencer, C. M., Antalffy, B. A., Noebels, J. L., Armstrong, D. L., Paylor, R., Zoghbi, H. Y. <strong>Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3.</strong> Neuron 35: 243-254, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12160743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12160743</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00768-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12160743">Shahbazian et al. (2002)</a> suggested that the elevated levels of histone H3 acetylation provided in vivo evidence for the role of MECP2 in the modification of chromatin architecture. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12160743" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#72" class="mim-tip-reference" title="Kriaucionis, S., Bird, A. <strong>DNA methylation and Rett syndrome.</strong> Hum. Molec. Genet. 12: R221-R227, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12928486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12928486</a>] [<a href="https://doi.org/10.1093/hmg/ddg286" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12928486">Kriaucionis and Bird (2003)</a> reviewed the basic properties of Mecp2 in the context of a mouse model of Rett syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12928486" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By binding to methylated CpG dinucleotide promoter regions, MECP2 acts as a transcriptional repressor; its absence might therefore result in widespread aberrant gene transcription, leading to the phenotype of Rett syndrome. Considering this potentially broad action of MECP2 on expression and the complexity of the brain, especially during development, <a href="#85" class="mim-tip-reference" title="Matarazzo, V., Ronnett, G. V. <strong>Temporal and regional differences in the olfactory proteome as a consequence of MeCP2 deficiency.</strong> Proc. Nat. Acad. Sci. 101: 7763-7768, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15128950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15128950</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15128950[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0307083101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15128950">Matarazzo and Ronnett (2004)</a> approached the consequences of MECP2 deficiency in a mouse model by using a temporal and regional proteomic strategy. They used the olfactory system (olfactory epithelium and bulb) because its attributes make it an excellent developmental model system. They found evidence of temporal and regional proteomic pattern differences between wildtype and Mecp2 deficient mice. These changes in protein expression were segregated into 5 groups based on biologic function: cytoskeleton arrangement, chromatin modeling, energy metabolism, cell signaling, and neuroprotection. By combining the proteomic results with the RNA levels of the identified proteins, the authors showed that protein expression changes are the consequence of differences in mRNA level or posttranslational modifications. <a href="#85" class="mim-tip-reference" title="Matarazzo, V., Ronnett, G. V. <strong>Temporal and regional differences in the olfactory proteome as a consequence of MeCP2 deficiency.</strong> Proc. Nat. Acad. Sci. 101: 7763-7768, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15128950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15128950</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15128950[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0307083101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15128950">Matarazzo and Ronnett (2004)</a> concluded that brain regions and ages must be carefully considered when investigating MECP2 deficiency, and that not only transcription should be taken into account as a source of these changes, but also posttranslational protein modifications. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15128950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Collins, A. L., Levenson, J. M., Vilaythong, A. P., Richman, R., Armstrong, D. L., Noebels, J. L., Sweatt, J. D., Zoghbi, H. Y. <strong>Mild overexpression of MeCP2 causes a progressive neurological disorder in mice.</strong> Hum. Molec. Genet. 13: 2679-2689, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15351775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15351775</a>] [<a href="https://doi.org/10.1093/hmg/ddh282" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15351775">Collins et al. (2004)</a> generated transgenic mice that overexpressed wildtype human MECP2 as a model of MECP2 duplication syndrome (MRXSL; <a href="/entry/300260">300260</a>). Detailed neurobehavioral and electrophysiologic studies in these mice, which express MECP2 at 2-fold wildtype levels, demonstrated onset of phenotypes around 10 weeks of age. Mice displayed enhanced motor and contextual learning and enhanced synaptic plasticity in the hippocampus. After 20 weeks of age, mice developed seizures, hypoactivity, and spasticity, and 30% of mice died by 1 year of age. <a href="#34" class="mim-tip-reference" title="Collins, A. L., Levenson, J. M., Vilaythong, A. P., Richman, R., Armstrong, D. L., Noebels, J. L., Sweatt, J. D., Zoghbi, H. Y. <strong>Mild overexpression of MeCP2 causes a progressive neurological disorder in mice.</strong> Hum. Molec. Genet. 13: 2679-2689, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15351775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15351775</a>] [<a href="https://doi.org/10.1093/hmg/ddh282" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15351775">Collins et al. (2004)</a> concluded that MECP2 levels must be tightly regulated in vivo and that even mild overexpression of this protein may be detrimental. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15351775" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To search for Mecp2 target genes in mouse brain that might be dysregulated in individuals with Rett syndrome, <a href="#61" class="mim-tip-reference" title="Horike, S., Cai, S., Miyano, M., Cheng, J.-F., Kohwi-Shigematsu, T. <strong>Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome.</strong> Nature Genet. 37: 31-40, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15608638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15608638</a>] [<a href="https://doi.org/10.1038/ng1491" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15608638">Horike et al. (2005)</a> used a modified chromatin immunoprecipitation-based cloning strategy. The strategy was based on the assumption that Mecp2 target genes were located close to the binding sites of Mecp2 in vivo. They identified Dlx5 (<a href="/entry/600028">600028</a>) as a direct target gene of Mecp2 and found that human DLX5 had lost its maternal-specific imprinted status in lymphoblastoid cells of patients with RTT. They also found that Mecp2-mediated histone modification and formation of a higher-order chromatin-loop structure specifically associated with silent chromatin at the Dlx5-Dlx6 locus. In contrast to the findings of <a href="#61" class="mim-tip-reference" title="Horike, S., Cai, S., Miyano, M., Cheng, J.-F., Kohwi-Shigematsu, T. <strong>Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome.</strong> Nature Genet. 37: 31-40, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15608638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15608638</a>] [<a href="https://doi.org/10.1038/ng1491" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15608638">Horike et al. (2005)</a>, <a href="#120" class="mim-tip-reference" title="Schule, B., Li, H. H., Fisch-Kohl, C., Purmann, C., Francke, U. <strong>DLX5 and DLX6 expression is biallelic and not modulated by MeCP2 deficiency.</strong> Am. J. Hum. Genet. 81: 492-506, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17701895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17701895</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17701895[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/520063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17701895">Schule et al. (2007)</a> found no increased expression of Dlx5 or Dlx6 (<a href="/entry/600030">600030</a>) in mutant Mecp2 mice and disputed the 'chromatin-loop structure' hypothesis suggested by <a href="#61" class="mim-tip-reference" title="Horike, S., Cai, S., Miyano, M., Cheng, J.-F., Kohwi-Shigematsu, T. <strong>Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome.</strong> Nature Genet. 37: 31-40, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15608638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15608638</a>] [<a href="https://doi.org/10.1038/ng1491" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15608638">Horike et al. (2005)</a>. Furthermore, <a href="#120" class="mim-tip-reference" title="Schule, B., Li, H. H., Fisch-Kohl, C., Purmann, C., Francke, U. <strong>DLX5 and DLX6 expression is biallelic and not modulated by MeCP2 deficiency.</strong> Am. J. Hum. Genet. 81: 492-506, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17701895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17701895</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17701895[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/520063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17701895">Schule et al. (2007)</a> found no evidence that Dlx5 or Dlx6 are imprinted in mouse or human cells and indicated that Mecp2 does not play a role in imprinting. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15608638+17701895" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#95" class="mim-tip-reference" title="Moretti, P., Bouwknecht, J. A., Teague, R., Paylor, R., Zoghbi, H. Y. <strong>Abnormalities of social interactions and home-cage behavior in a mouse model of Rett syndrome.</strong> Hum. Molec. Genet. 14: 205-220, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15548546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15548546</a>] [<a href="https://doi.org/10.1093/hmg/ddi016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15548546">Moretti et al. (2005)</a> studied home cage behavior and social interactions in a mouse model of RTT. Young adult mutant mice showed abnormal home cage diurnal activity in the absence of motor skill deficits. Mutant mice showed deficits in nest building, decreased nest use, and impaired social interaction. They also took less initiative and were less decisive approaching unfamiliar males and spent less time in close vicinity to them in several social interaction paradigms. Abnormalities of diurnal activity and social behavior in Mecp2-mutant mice were reminiscent of the sleep/wake dysfunction and autistic features of RTT. <a href="#95" class="mim-tip-reference" title="Moretti, P., Bouwknecht, J. A., Teague, R., Paylor, R., Zoghbi, H. Y. <strong>Abnormalities of social interactions and home-cage behavior in a mouse model of Rett syndrome.</strong> Hum. Molec. Genet. 14: 205-220, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15548546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15548546</a>] [<a href="https://doi.org/10.1093/hmg/ddi016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15548546">Moretti et al. (2005)</a> suggested that MECP2 may regulate expression and/or function of genes involved in social behavior. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15548546" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using cDNA microarrays, <a href="#105" class="mim-tip-reference" title="Nuber, U. A., Kriaucionis, S., Roloff, T. C., Guy, J., Selfridge, J., Steinhoff, C., Schulz, R., Lipkowitz, B., Ropers, H. H., Holmes, M. C., Bird, A. <strong>Up-regulation of glucocorticoid-regulated genes in a mouse model of Rett syndrome.</strong> Hum. Molec. Genet. 14: 2247-2256, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16002417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16002417</a>] [<a href="https://doi.org/10.1093/hmg/ddi229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16002417">Nuber et al. (2005)</a> found that Mecp2-null mice differentially expressed several genes that are induced during the stress response by glucocorticoids. Increased levels of mRNAs for SGK1 (<a href="/entry/602958">602958</a>) and FK506-binding protein-51 (FKBP5; <a href="/entry/602623">602623</a>) were observed before and after onset of neurologic symptoms, but plasma glucocorticoid was not significantly elevated in Mecp2-null mice. MeCP2 binds to Fkbp5 and Sgk1 in brain and may function as a modulator of glucocorticoid-inducible gene expression. Given the known deleterious effect of glucocorticoid exposure on brain development, <a href="#105" class="mim-tip-reference" title="Nuber, U. A., Kriaucionis, S., Roloff, T. C., Guy, J., Selfridge, J., Steinhoff, C., Schulz, R., Lipkowitz, B., Ropers, H. H., Holmes, M. C., Bird, A. <strong>Up-regulation of glucocorticoid-regulated genes in a mouse model of Rett syndrome.</strong> Hum. Molec. Genet. 14: 2247-2256, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16002417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16002417</a>] [<a href="https://doi.org/10.1093/hmg/ddi229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16002417">Nuber et al. (2005)</a> proposed that disruption of MeCP2-dependent regulation of stress-responsive genes may contribute to the symptoms of Rett syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16002417" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#87" class="mim-tip-reference" title="McGill, B. E., Bundle, S. F., Yaylaoglu, M. B., Carson, J. P., Thaller, C., Zoghbi, H. Y. <strong>Enhanced anxiety and stress-induced corticosterone release are associated with increased Crh expression in a mouse model of Rett syndrome.</strong> Proc. Nat. Acad. Sci. 103: 18267-18272, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17108082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17108082</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17108082[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0608702103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17108082">McGill et al. (2006)</a> found that male mice with a truncated Mecp2 allele displayed increased anxiety-like behavior and an abnormal stress response, similar to patients with RTT. The changes were associated with increased serum corticosterone levels, suggesting an enhanced physiologic response to stress. Further studies showed that the mutant mice overexpressed Crh (<a href="/entry/122560">122560</a>) in the paraventricular nucleus of the hypothalamus, the central amygdala, and the stria terminalis. Mutant Mecp2 did not bind the Crh promoter, whereas wildtype Mecp2 preferentially bound a repressed form of the Crh promoter, The findings suggested that Mecp2 regulates Crh expression and that Crh overexpression may underlie certain features of mouse models of Rett syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17108082" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Chang, Q., Khare, G., Dani, V., Nelson, S., Jaenisch, R. <strong>The disease progression of Mecp2 mutant mice is affected by level of BDNF expression.</strong> Neuron 49: 341-348, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16446138/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16446138</a>] [<a href="https://doi.org/10.1016/j.neuron.2005.12.027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16446138">Chang et al. (2006)</a> found that Mecp2-mutant mice had decreased levels of Bdnf (<a href="/entry/113505">113505</a>) in the brain, at about 70% of wildtype levels. Bdnf expression depended on neuronal activity, and the authors hypothesized that Mecp2 deficiency reduces neuronal activity, thereby indirectly causing decreased BDNF protein levels. Mice with conditional deletion of Bdnf showed some anatomic similarities to Mecp2-mutant mice, including smaller brain size, smaller CA2 neurons, smaller glomerulus size, and a characteristic hindlimb-clasping phenotype. Furthermore, deletion of Bdnf in Mecp2 mutants caused an earlier onset of RTT-like symptoms. Overexpression of human BDNF in Mecp2 mutant mice extended the life span, rescued a locomotor defect, and reversed an electrophysiologic deficit observed in Mecp2 mutants. The results provided in vivo evidence for a functional interaction between Mecp2 and Bdnf and showed the physiologic significance of altered BDNF expression/signaling in RTT disease progression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16446138" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In cultured rat neurons, <a href="#155" class="mim-tip-reference" title="Zhou, Z., Hong, E. J., Cohen, S., Zhao, W., Ho, H. H., Schmidt, L., Chen, W. G., Lin, Y., Savner, E., Griffith, E. C., Hu, L., Steen, J. A. J., Weitz, C. J., Greenberg, M. E. <strong>Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation.</strong> Neuron 52: 255-269, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17046689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17046689</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17046689[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2006.09.037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17046689">Zhou et al. (2006)</a> found that neuronal activity and subsequent calcium influx triggered the de novo phosphorylation of Mecp2 at serine-421. Mecp2 ser421 phosphorylation was induced selectively in the rat brain in vivo in response to physiologic stimuli, including pharmacologically induced seizures and light. The phosphorylation of Mecp2 appeared to relieve transcriptional repression of Bdnf, and overall controlled the ability of Mecp2 to regulate dendritic patterning and spine morphogenesis, Phosphorylation of Mecp2 was not observed in other tissues besides brain. These findings suggested that, by triggering MECP2 phosphorylation, neuronal activity regulates a program of gene expression that mediates nervous system maturation. Disruption of this process in individuals with mutations in MECP2 may underlie the neural-specific pathology of RTT. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17046689" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#142" class="mim-tip-reference" title="Wang, H., Chan, S., Ogier, M., Hellard, D., Wang, Q., Smith, C., Katz, D. M. <strong>Dysregulation of brain-derived neurotrophic factor expression and neurosecretory function in Mecp2 null mice.</strong> J. Neurosci. 26: 10911-10915, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17050729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17050729</a>] [<a href="https://doi.org/10.1523/JNEUROSCI.1810-06.2006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17050729">Wang et al. (2006)</a> observed that although Mecp2-deficient mouse neurons released increased amounts of Bdnf, the overall levels of Bdnf were decreased compared to controls. These findings suggested that loss of Mecp2 function disrupts transynaptic Bdnf signaling. Mecp2-null adrenal chromaffin cells also showed increased exocytic function compared to wildtype cells. Thus, other features of RTT, such as autonomic dysfunction, may be associated with abnormal neuropeptide and catecholamine secretion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17050729" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The persistent viability of mutant neurons in patients with Rett syndrome raised the possibility that reexpression of MECP2 might restore full function and thereby reverse RTT. Alternatively, MECP2 may be essential for neuronal development during a specific time window, after which damage caused by its absence is irreversible. To distinguish these possibilities, <a href="#54" class="mim-tip-reference" title="Guy, J., Gan, J., Selfridge, J., Cobb, S., Bird, A. <strong>Reversal of neurological defects in a mouse model of Rett syndrome.</strong> Science 315: 1143-1147, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17289941/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17289941</a>] [<a href="https://doi.org/10.1126/science.1138389" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17289941">Guy et al. (2007)</a> created a mouse model in which the endogenous Mecp2 gene was silenced by insertion of a lox-Stop cassette, but could be conditionally activated under the control of its own promoter and regulatory elements by cassette deletion. Using this method they demonstrated robust phenotypic reversal, as activation of Mecp2 expression led to striking loss of advanced neurologic symptoms in both the immature and mature adult animals. <a href="#54" class="mim-tip-reference" title="Guy, J., Gan, J., Selfridge, J., Cobb, S., Bird, A. <strong>Reversal of neurological defects in a mouse model of Rett syndrome.</strong> Science 315: 1143-1147, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17289941/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17289941</a>] [<a href="https://doi.org/10.1126/science.1138389" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17289941">Guy et al. (2007)</a> concluded that developmental absence of MECP2 does not irreversibly damage neurons, which suggested that Rett syndrome is not strictly a neurodevelopmental disorder. The delayed onset of behavioral and long-term potentiation phenotypes in Mecp2 heterozygous females emphasized the initial functional integrity of Mecp2-deficient neurons and fit with the proposal that MECP2 is required to stabilize and maintain the mature neuronal state. The restoration of neuronal function by late expression of Mecp2 suggested that the molecular preconditions for normal MECP2 activity are preserved in its absence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17289941" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#47" class="mim-tip-reference" title="Fyffe, S. L., Neul, J. L., Samaco, R. C., Chao, H.-T., Ben-Shachar, S., Moretti, P., McGill, B. E., Goulding, E. H., Sullivan, E., Tecott, L. H., Zoghbi, H. Y. <strong>Deletion of Mecp2 in Sim1-expressing neurons reveals a critical role for MeCP2 in feeding behavior, aggression, and the response to stress.</strong> Neuron 59: 947-958, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18817733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18817733</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18817733[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2008.07.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18817733">Fyffe et al. (2008)</a> generated conditional transgenic mice with loss of Mecp2 expression in Sim1 (<a href="/entry/603128">603128</a>)-expressing neurons in the hypothalamus. The mutant animals showed increased anxiety-like behavior and abnormal physiologic responses to stress, including increased serum cortisol, that was similar to that observed when Mecp2 is inactivated in the entire brain. In addition, these mice were aggressive, hyperphagic, and obese, indicating dysfunction of the regulation of social and feeding behaviors. Other behaviors observed in humans with MECP2 mutations, such as motor coordination problems and learning and memory deficits, were not observed, suggesting a specific role for MECP2 in the hypothalamus. <a href="#47" class="mim-tip-reference" title="Fyffe, S. L., Neul, J. L., Samaco, R. C., Chao, H.-T., Ben-Shachar, S., Moretti, P., McGill, B. E., Goulding, E. H., Sullivan, E., Tecott, L. H., Zoghbi, H. Y. <strong>Deletion of Mecp2 in Sim1-expressing neurons reveals a critical role for MeCP2 in feeding behavior, aggression, and the response to stress.</strong> Neuron 59: 947-958, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18817733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18817733</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18817733[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2008.07.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18817733">Fyffe et al. (2008)</a> noted that the experimental protocol used in this study could enable mapping of the neuroanatomic origins of complex behaviors seen in MECP2-related disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18817733" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#67" class="mim-tip-reference" title="Kerr, B., Alvarez-Saavedra, M., Saez, M. A., Saona, A., Young, J. I. <strong>Defective body-weight regulation, motor control and abnormal social interactions in Mecp2 hypomorphic mice.</strong> Hum. Molec. Genet. 17: 1707-1717, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18321865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18321865</a>] [<a href="https://doi.org/10.1093/hmg/ddn061" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18321865">Kerr et al. (2008)</a> generated mice with conditional expression of a hypomorphic Mecp2 allele (about 50% of wildtype) in the brain, caused by a disruption of the 3-prime noncoding region of the gene. Male mutant mice had increased body weight, increased fat, and subtle paw clasping at about 6 weeks of age. Behavioral studies showed that male mutant mice had similar spontaneous exploration and novelty-induced locomotor activity as wildtype mice, but showed defects in fine motor control as well as decreased social behavior. Expression of Mecp2 in the mutant mice was particularly decreased in the hypothalamus, which controls energy homeostasis. Overall, the hypomorphic Mecp2 mouse phenotype was much less severe than the phenotype caused by lack of functional Mecp2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18321865" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Similar studies by <a href="#115" class="mim-tip-reference" title="Samaco, R. C., Fryer, J. D., Ren, J., Fyffe, S., Chai, H.-T., Sun, Y., Greer, J. J., Zoghbi, H. Y., Neul, J. L. <strong>A partial loss of function allele of methyl-CpG-binding protein 2 predicts a human neurodevelopmental disorder.</strong> Hum. Molec. Genet. 17: 1718-1727, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18321864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18321864</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18321864[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18321864">Samaco et al. (2008)</a> found that male mice carrying a Mecp2 hypomorphic (50% of wildtype) allele had a mild increase in body weight and decreased motor coordination. Behavioral abnormalities included decreased pain recognition, decreased acoustic startle response and prepulse inhibition, decreased social interactions, and decreased nest-building behavior compared to wildtype mice. Hypomorphic mice also showed decreased hippocampal- and amygdala-dependent learning, decreased anxiety, and altered breathing patterns. <a href="#115" class="mim-tip-reference" title="Samaco, R. C., Fryer, J. D., Ren, J., Fyffe, S., Chai, H.-T., Sun, Y., Greer, J. J., Zoghbi, H. Y., Neul, J. L. <strong>A partial loss of function allele of methyl-CpG-binding protein 2 predicts a human neurodevelopmental disorder.</strong> Hum. Molec. Genet. 17: 1718-1727, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18321864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18321864</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18321864[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18321864">Samaco et al. (2008)</a> suggested that there is tight regulation of MECP2 levels in the brain, suggesting a dynamic role for MECP2 in neuronal function, and they predicted that changes in MECP2 dosage may result in human neurodevelopmental disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18321864" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Ben-Shachar, S., Chahrour, M., Thaller, C., Shaw, C. A., Zoghbi, H. Y. <strong>Mouse models of MeCP2 disorders share gene expression changes in the cerebellum and hypothalamus.</strong> Hum. Molec. Genet. 18: 2431-2442, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19369296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19369296</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19369296[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19369296">Ben-Shachar et al. (2009)</a> studied gene expression patterns in the cerebellum of Mecp2-null and MECP2-Tg mice, modeling RTT and MECP2 duplication syndrome (<a href="/entry/300260">300260</a>), respectively. Abnormal MECP2 dosage caused alterations in the expression of hundreds of genes in the cerebellum. The majority of genes were upregulated in MECP2-Tg mice and downregulated in Mecp2-null mice, consistent with a role for MECP2 as a modulator that can both increase and decrease gene expression. Many of the genes altered in the cerebellum, particularly those increased by the presence of MECP2 and decreased in its absence, were similarly altered in the hypothalamus. <a href="#13" class="mim-tip-reference" title="Ben-Shachar, S., Chahrour, M., Thaller, C., Shaw, C. A., Zoghbi, H. Y. <strong>Mouse models of MeCP2 disorders share gene expression changes in the cerebellum and hypothalamus.</strong> Hum. Molec. Genet. 18: 2431-2442, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19369296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19369296</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19369296[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19369296">Ben-Shachar et al. (2009)</a> suggested that either gain or loss of MeCP2 may result in gene expression changes in multiple brain regions and that some of these changes may be global. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19369296" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#133" class="mim-tip-reference" title="Tropea, D., Giacometti, E., Wilson, N. R., Beard, C., McCurry, C., Fu, D. D., Flannery, R., Jaenisch, R., Sur, M. <strong>Partial reversal of Rett syndrome-like symptoms in MeCP2 mutant mice.</strong> Proc. Nat. Acad. Sci. 106: 2029-2034, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19208815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19208815</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19208815[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0812394106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19208815">Tropea et al. (2009)</a> found that systemic treatment of Mecp2 mutant mice with an active peptide fragment of IGF1 (<a href="/entry/147440">147440</a>) extended their life span, improved locomotor function, ameliorated breathing patterns, and reduced heart rate irregularity. Postmortem brains of treated mice showed increased weight, improved neuron spine density in the motor cortex, increased synaptic amplitude, and increased staining for PSD95 (<a href="/entry/602887">602887</a>) compared to untreated mice. The findings suggested that IGF1 treatment can improve synaptic maturation and transmission. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19208815" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Chao, H.-T., Chen, H., Samaco, R. C., Xue, M., Chahrour, M., Yoo, J., Neul, J. L., Gong, S., Lu, H.-C., Heintz, N., Ekker, M., Rubenstein, J. L. R., Noebels, J. L., Rosenmund, C., Zoghbi, H. Y. <strong>Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.</strong> Nature 468: 263-269, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21068835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21068835</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21068835[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09582" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21068835">Chao et al. (2010)</a> generated mice lacking Mecp2 from GABA-releasing neurons, designated Viaat-Mecp2(-/y), and showed that they recapitulate numerous Rett syndrome and autistic features, including repetitive behaviors. Viaat-Mecp2(-/y) mice were indistinguishable from controls until approximately 5 weeks of age, when they began to exhibit repetitive behavior such as forelimb stereotypies reminiscent of midline hand-wringing that characterizes Rett syndrome and hindlimb clasping. Viaat-Mecp2(-/y) mice spent 300% more time grooming than wildtype mice, leading to fur loss and epidermal lesions in group- and single-housed mice. Viaat-Mecp2(-/y) mice showed progressive motor dysfunction. The mice also developed motor weakness and by 12 weeks showed a trend toward reduced activity, becoming clearly hypoactive by 19 weeks. MeCP2 deficiency in GABAergic neurons also impaired hippocampal learning and memory. Roughly one-half of Viaat-Mecp2(-/y) mice died by 26 weeks of age after a period of marked weight loss. Coinciding with the weight loss, mice developed severe respiratory dysfunction. Next, <a href="#26" class="mim-tip-reference" title="Chao, H.-T., Chen, H., Samaco, R. C., Xue, M., Chahrour, M., Yoo, J., Neul, J. L., Gong, S., Lu, H.-C., Heintz, N., Ekker, M., Rubenstein, J. L. R., Noebels, J. L., Rosenmund, C., Zoghbi, H. Y. <strong>Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.</strong> Nature 468: 263-269, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21068835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21068835</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21068835[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09582" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21068835">Chao et al. (2010)</a> generated male conditional deletion mice, designed Dlx5/6-Mecp2(-/y), missing MeCP2 from a subset of forebrain GABAergic neurons. These mice showed repetitive behavior, impaired motor coordination, increased social interaction preference, reduced acoustic startle response, and enhanced prepulse inhibition. In contrast to Viaat-Mecp2(-/y) mice, Dlx5/6-Mecp2(-/y) mice survived at least 80 weeks without apparent alterations in respiratory function. MeCP2-deficient GABAergic neurons showed reduced inhibitory quantal size, consistent with a presynaptic reduction in glutamic acid decarboxylase-1 (GAD1; <a href="/entry/605363">605363</a>) and -2 (GAD2; <a href="/entry/138275">138275</a>) levels. <a href="#26" class="mim-tip-reference" title="Chao, H.-T., Chen, H., Samaco, R. C., Xue, M., Chahrour, M., Yoo, J., Neul, J. L., Gong, S., Lu, H.-C., Heintz, N., Ekker, M., Rubenstein, J. L. R., Noebels, J. L., Rosenmund, C., Zoghbi, H. Y. <strong>Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.</strong> Nature 468: 263-269, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21068835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21068835</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21068835[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09582" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21068835">Chao et al. (2010)</a> concluded that MeCP2 is critical for normal function of GABA-releasing neurons and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21068835" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#88" class="mim-tip-reference" title="McGraw, C. M., Samaco, R. C., Zoghbi, H. Y. <strong>Adult neural function requires MeCP2.</strong> Science 333: 186 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21636743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21636743</a>] [<a href="https://doi.org/10.1126/science.1206593" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21636743">McGraw et al. (2011)</a> developed an adult-onset model of Rett syndrome by crossing mice harboring a floxed Mecp2 allele and tamoxifen-inducible CreER allele to delete Mecp2 when animals were fully mature. Thus, Mecp2 expression was eliminated only during adult life. Mice lacking Mecp2 as adults (AKO) developed symptoms of disease and behavioral deficits similar to germline-null (KO) mice. By 10 weeks after dosing, AKO mice were less active, had abnormal gait, and developed hindlimb clasping, similar to 10- to 11-week-old knockout mice. AKO mice also developed motor abnormalities and impaired nesting ability, as observed in knockout mice. In addition, both AKO and KO mice showed impaired learning and memory. Adult deletion of Mecp2 also demonstrated that some genes whose expression levels are sensitive to Mecp2 abundance are altered in its absence. In total, <a href="#88" class="mim-tip-reference" title="McGraw, C. M., Samaco, R. C., Zoghbi, H. Y. <strong>Adult neural function requires MeCP2.</strong> Science 333: 186 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21636743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21636743</a>] [<a href="https://doi.org/10.1126/science.1206593" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21636743">McGraw et al. (2011)</a> tested 10 genes whose expression levels were known to be altered in knockout mice, and 60% were significantly altered in AKO mice compared with wildtype controls. However, 4 of these altered genes (Htr1a, <a href="/entry/109760">109760</a>; Oprk1, <a href="/entry/165196">165196</a>; Tac1, <a href="/entry/162320">162320</a>; and Nxph4, <a href="/entry/604637">604637</a>) were also significantly altered in control Mecp2(flox) mice, suggesting increased sensitivity of these loci to Mecp2 function. Finally, both AKO and KO mice died prematurely with similar median time to death (13 weeks after dosing period (n = 20) vs 13.3 weeks of life (n = 13), respectively). <a href="#88" class="mim-tip-reference" title="McGraw, C. M., Samaco, R. C., Zoghbi, H. Y. <strong>Adult neural function requires MeCP2.</strong> Science 333: 186 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21636743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21636743</a>] [<a href="https://doi.org/10.1126/science.1206593" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21636743">McGraw et al. (2011)</a> argued that their results suggested that the temporal association of disease with the postnatal period of neurodevelopment may be unrelated to any developmental or stage-restricted function of MeCP2, at least in mouse models. They also suggested that the mature brain is dependent on Mecp2 function and that any therapies for Rett syndrome would be required to be continuously maintained. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21636743" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#40" class="mim-tip-reference" title="Derecki, N. C., Cronk, J. C., Lu, Z., Xu, E., Abbott, S. B. G., Guyenet, P. G., Kipnis, J. <strong>Wild-type microglia arrest pathology in a mouse model of Rett syndrome.</strong> Nature 484: 105-109, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22425995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22425995</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22425995[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10907" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22425995">Derecki et al. (2012)</a> examined the role of microglia in a murine model of Rett syndrome and showed that transplantation of wildtype bone marrow into irradiation-conditioned Mecp2-null hosts resulted in engraftment of brain parenchyma by bone marrow-derived myeloid cells of microglial phenotype and arrest of disease development. However, when cranial irradiation was blocked by lead shield and microglial engraftment was prevented, disease was not arrested. Similarly, targeted expression of MECP2 in myeloid cells, driven by Lysm(cre) on an Mecp2-null background, markedly attenuated disease symptoms. Thus, through multiple approaches, wildtype Mecp2-expressing microglia within the context of an Mecp2-null male mouse arrested numerous facets of disease pathology: life span was increased, breathing patterns were normalized, apneas were reduced, body weight was increased to near that of wildtype, and locomotor activity was improved. Mecp2 +/- females also showed significant improvements as a result of wildtype microglial engraftment. These benefits mediated by wildtype microglia, however, were diminished when phagocytic activity was inhibited pharmacologically by using annexin V to block phosphatidylserine residues on apoptotic targets, thus preventing recognition and engulfment by tissue-resident phagocytes. <a href="#40" class="mim-tip-reference" title="Derecki, N. C., Cronk, J. C., Lu, Z., Xu, E., Abbott, S. B. G., Guyenet, P. G., Kipnis, J. <strong>Wild-type microglia arrest pathology in a mouse model of Rett syndrome.</strong> Nature 484: 105-109, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22425995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22425995</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22425995[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10907" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22425995">Derecki et al. (2012)</a> concluded that their results suggested the importance of microglial activity in Rett syndrome, implicated microglia as major players in the pathophysiology of Rett syndrome, and suggested bone marrow transplantation as a possible therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22425995" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Mutations in exon 2 of the MECP2 gene (isoform Mecp2_e2 only) have never been reported in Rett syndrome. <a href="#64" class="mim-tip-reference" title="Itoh, M., Tahimic, C. G. T., Ide, S., Otsuki, A., Sasaoka, T., Noguchi, S., Oshimura, M., Goto, Y., Kurimasa, A. <strong>Methyl CpG-binding protein isoform MeCP2_e2 is dispensable for Rett syndrome phenotypes but essential for embryo viability and placenta development.</strong> J. Biol. Chem. 287: 13859-13867, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22375006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22375006</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22375006[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M111.309864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22375006">Itoh et al. (2012)</a> generated mice with selective loss of the Mecp2_e2 isoform due to excision of exon 2. Mutant mice were indistinguishable from wildtype mice and showed no neurologic deficits or morphologic brain anomalies, indicating that isoform Mecp2_e1 is sufficient to carry out normal protein function in the brain. However, there were reduced births of progeny that carried a Mecp_e2-null allele of maternal origin. Specifically, there was a 76% reduction in Xe2-/Y males and a 44% reduction in Xe2-/X females born to X/Xe2- females and wildtype males. In Xe2-/X and Xe2-/Y pairings, Xe2-/Y and Xe2-/Xe2- births were reduced by 50 and 60%, respectively. Placentas of embryos carrying a maternal e2-null allele showed increased apoptosis and had increased expression of Peg1 (MEST; <a href="/entry/601029">601029</a>), indicating impaired silencing of Peg1 due to lack of Mecp2_e2. <a href="#64" class="mim-tip-reference" title="Itoh, M., Tahimic, C. G. T., Ide, S., Otsuki, A., Sasaoka, T., Noguchi, S., Oshimura, M., Goto, Y., Kurimasa, A. <strong>Methyl CpG-binding protein isoform MeCP2_e2 is dispensable for Rett syndrome phenotypes but essential for embryo viability and placenta development.</strong> J. Biol. Chem. 287: 13859-13867, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22375006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22375006</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22375006[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M111.309864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22375006">Itoh et al. (2012)</a> concluded that Mecp2_e2 is dispensable for RTT-associated neurologic phenotypes, and that Mecp2_e2 is required for placenta and embryonic viability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22375006" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Buchovecky, C. M., Turley, S. D., Brown, H. M., Kyle, S. M., McDonald, J. G., Liu, B., Pieper, A. A., Huang, W., Katz, D. M., Russell, D. W., Shendure, J., Justice, M. J. <strong>A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome.</strong> Nature Genet. 45: 1013-1020, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23892605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23892605</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23892605[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2714" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23892605">Buchovecky et al. (2013)</a> found that 2 different strains of Mecp2-null mice showed abnormal brain cholesterol metabolism and perturbed liver lipid profiles. Pharmacologic inhibition of cholesterol synthesis via statin drugs or inactivation of the Sqle gene (<a href="/entry/602019">602019</a>) at least partly improved health, motor symptoms, and life span of Mecp2-null mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23892605" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#81" class="mim-tip-reference" title="Liu, Z., Li, X., Zhang, J.-T., Cai, Y.-J., Cheng, T.-L., Cheng, C., Wang, Y., Zhang, C.-C., Nie, Y. H., Chen, Z.-F., Bian, W.-J., Zhang, L., and 14 others. <strong>Autism-like behaviours and germline transmission in transgenic monkeys overexpressing MeCP2.</strong> Nature 530: 98-102, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26808898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26808898</a>] [<a href="https://doi.org/10.1038/nature16533" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26808898">Liu et al. (2016)</a> reported that lentivirus-based transgenic cynomolgus monkeys (Macaca fascicularis) expressing human MeCP2 in the brain exhibit autism-like behaviors and show germline transmission of the transgene. Expression of the MECP2 transgene was confirmed by Western blotting and immunostaining of brain tissues of transgenic monkeys. Genomic integration sites of the transgenes were characterized by a deep-sequencing-based method. As compared to wildtype monkeys, MECP2 transgenic monkeys exhibited a higher frequency of repetitive circular locomotion and increased stress responses, as measured by the threat-related anxiety and defensive test. The transgenic monkeys showed less interaction with wildtype monkeys within the same group, and also a reduced interaction time when paired with other transgenic monkeys in social interaction tests. The cognitive functions of the transgenic monkeys were largely normal in the Wisconsin general test apparatus, although some showed signs of stereotypic cognitive behaviors. <a href="#81" class="mim-tip-reference" title="Liu, Z., Li, X., Zhang, J.-T., Cai, Y.-J., Cheng, T.-L., Cheng, C., Wang, Y., Zhang, C.-C., Nie, Y. H., Chen, Z.-F., Bian, W.-J., Zhang, L., and 14 others. <strong>Autism-like behaviours and germline transmission in transgenic monkeys overexpressing MeCP2.</strong> Nature 530: 98-102, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26808898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26808898</a>] [<a href="https://doi.org/10.1038/nature16533" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26808898">Liu et al. (2016)</a> generated 5 F1 offspring of MECP2 transgenic monkeys by intracytoplasmic sperm injection with sperm from 1 F0 transgenic monkey, showing germline transmission and Mendelian segregation of several MECP2 transgenes in the F1 progeny. Moreover, F1 transgenic monkeys also showed reduced social interactions when tested in pairs, as compared to wildtype monkeys of similar age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26808898" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>X-Chromosome Inactivation Studies</em></strong></p><p>
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Using quantitative laser scanning cytometry, <a href="#17" class="mim-tip-reference" title="Braunschweig, D., Simcox, T., Samaco, R. C., LaSalle, J. M. <strong>X-chromosome inactivation ratios affect wild-type MeCP2 expression within mosaic Rett syndrome and Mecp2-/+ mouse brain.</strong> Hum. Molec. Genet. 13: 1275-1286, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15115765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15115765</a>] [<a href="https://doi.org/10.1093/hmg/ddh142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15115765">Braunschweig et al. (2004)</a> showed that Mecp2 -/+ female mice exhibited uniform regional distribution of Mecp2 mutant-expressing cells in brain, but unbalanced X-chromosome inactivation (XCI) in the population, thus favoring expression of the Mecp2 wildtype allele. In addition, the level of Mecp2 expression in Mecp2 wildtype-expressing cells from Mecp2 -/+ mice was significantly lower than those from Mecp2 +/+ age-matched controls. The negative effect of Mecp2 mutation on wildtype Mecp2 expression correlated with the percentage of Mecp2 mutant-expressing cells in the cortex. Similar results were observed in 2 RTT females with identical MECP2 mutations but different XCI ratios. <a href="#17" class="mim-tip-reference" title="Braunschweig, D., Simcox, T., Samaco, R. C., LaSalle, J. M. <strong>X-chromosome inactivation ratios affect wild-type MeCP2 expression within mosaic Rett syndrome and Mecp2-/+ mouse brain.</strong> Hum. Molec. Genet. 13: 1275-1286, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15115765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15115765</a>] [<a href="https://doi.org/10.1093/hmg/ddh142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15115765">Braunschweig et al. (2004)</a> concluded that Mecp2-mutant neurons affect the development of surrounding neurons in a non-cell-autonomous manner, and that environmental influences may affect the level of Mecp2 expression in wildtype neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15115765" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In transgenic female mice heterozygous for a truncating Mecp2(308) mutation <a href="#152" class="mim-tip-reference" title="Young, J. I., Zoghbi, H. Y. <strong>X-chromosome inactivation patterns are unbalanced and affect the phenotypic outcome in a mouse model of Rett syndrome.</strong> Am. J. Hum. Genet. 74: 511-520, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14973779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14973779</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14973779[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/382228" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14973779">Young and Zoghbi (2004)</a> found that XCI patterns were unbalanced in more than 60% of the animals, favoring expression of the wildtype allele. None of the animals had nonrandom XCI favoring the mutant allele. Primary neuronal cell cultures from the mutant mice showed selective survival of neurons in which the wildtype X chromosome was active. Phenotypic manifestations, including tremor, grooming, and stereotypic forepaw movements, were highly variable in the mutant female mice. There was a correlation between the pattern of XCI, expressed as the percentage of neurons with the wildtype allele active, and phenotype; significantly fewer abnormal phenotypes were observed when a large percentage of neurons had skewing toward expression of the wildtype X chromosome. <a href="#152" class="mim-tip-reference" title="Young, J. I., Zoghbi, H. Y. <strong>X-chromosome inactivation patterns are unbalanced and affect the phenotypic outcome in a mouse model of Rett syndrome.</strong> Am. J. Hum. Genet. 74: 511-520, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14973779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14973779</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14973779[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/382228" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14973779">Young and Zoghbi (2004)</a> noted that previous reports had suggested that the majority of human patients with Rett syndrome have balanced translocations (<a href="#122" class="mim-tip-reference" title="Shahbazian, M. D., Sun, Y., Zoghbi, H. Y. <strong>Balanced X chromosome inactivation patterns in the Rett syndrome brain.</strong> Am. J. Med. Genet. 111: 164-168, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12210344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12210344</a>] [<a href="https://doi.org/10.1002/ajmg.10557" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12210344">Shahbazian et al., 2002</a>), and suggested that this finding may be due to ascertainment bias; there may be females with MECP2 mutations who are asymptomatic or unrecognized due to skewed XCI. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14973779+12210344" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#143" class="mim-tip-reference" title="Watson, C. M., Pelka, G. J., Radziewic, T., Shahbazian, M. D., Christodoulou, J., Williamson, S. L., Tam, P. P. L. <strong>Reduced proportion of Purkinje cells expressing paternally derived mutant Mecp2(308) allele in female mouse cerebellum is not due to a skewed primary pattern of X-chromosome inactivation.</strong> Hum. Molec. Genet. 14: 1851-1861, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15888476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15888476</a>] [<a href="https://doi.org/10.1093/hmg/ddi191" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15888476">Watson et al. (2005)</a> assessed patterns of XCI in embryos and adult brains of mice heterozygous for the Mecp2(308) allele. There was no difference in the staining patterns of wildtype and heterozygous mutant embryos at embryonic day 9.5, suggesting that Mecp2 has no effect on the primary pattern of XCI. At 20 weeks of age, there was no significant difference between XCI patterns in the Purkinje cells in the cerebellum of heterozygous mutant and wildtype mice when the mutant allele was inherited from the mother. However, when the mutant allele was paternally inherited, a significant difference was detected. An estimation of the Purkinje cell precursor number based on XCI mosaicism revealed that, when the mutation was paternally inherited, the precursor number was less than that in wildtype mice. Therefore, the number of precursor cells allocated to the Purkinje cell lineage may be affected by a paternally inherited mutation in Mecp2. The pattern of XCI in cultured fibroblasts significantly correlated with patterns in the Purkinje cells in mutant animals but not in wildtype mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15888476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>39 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=300005[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28934904 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28934904;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28934904" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28934904" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012578 OR RCV000030666 OR RCV000081202 OR RCV000169934 OR RCV000170107 OR RCV000445570 OR RCV000460141 OR RCV000624907 OR RCV001257757 OR RCV002273925 OR RCV003984804 OR RCV004734512" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012578, RCV000030666, RCV000081202, RCV000169934, RCV000170107, RCV000445570, RCV000460141, RCV000624907, RCV001257757, RCV002273925, RCV003984804, RCV004734512" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012578...</a>
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<p>In a sporadic case of Rett syndrome (RTT; <a href="/entry/312750">312750</a>), <a href="#5" class="mim-tip-reference" title="Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., Zoghbi, H. Y. <strong>Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.</strong> Nature Genet. 23: 185-188, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508514</a>] [<a href="https://doi.org/10.1038/13810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508514">Amir et al. (1999)</a> found a 471C-T transition in the MECP2 gene, resulting in an arg133-to-cys (R133C) amino acid substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508514" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By analysis of genotype/phenotype correlations of Rett syndrome cases reported in a large global database, <a href="#11" class="mim-tip-reference" title="Bebbington, A., Anderson, A., Ravine, D., Fyfe, S., Pineda, M, de Klerk, N., Ben-Zeev, B., Yatawara, N., Percy, A., Kaufmann, W.E., Leonard, H. <strong>Investigating genotype-phenotype relationships in Rett syndrome using an international data set.</strong> Neurology 70: 868-875, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18332345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18332345</a>] [<a href="https://doi.org/10.1212/01.wnl.0000304752.50773.ec" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18332345">Bebbington et al. (2008)</a> found that R133C and R294X (<a href="#0011">300005.0011</a>) were associated with the mildest phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18332345" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#112" class="mim-tip-reference" title="Renieri, A., Mari, F., Mencarelli, M. A., Scala, E., Ariani, F., Longo, I., Meloni, I., Cevenini, G., Pini, G., Hayek, G., Zappella, M. <strong>Diagnostic criteria for the Zappella variant of Rett syndrome (the preserved speech variant).</strong> Brain Dev. 31: 208-216, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18562141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18562141</a>] [<a href="https://doi.org/10.1016/j.braindev.2008.04.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18562141">Renieri et al. (2009)</a> identified the R133C mutation in 7 patients with a milder form called Zappella variant Rett syndrome (see <a href="/entry/312750">312750</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18562141" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28934905 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28934905;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28934905" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28934905" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a sporadic case of Rett syndrome (RTT; <a href="/entry/312750">312750</a>), <a href="#5" class="mim-tip-reference" title="Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., Zoghbi, H. Y. <strong>Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.</strong> Nature Genet. 23: 185-188, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508514</a>] [<a href="https://doi.org/10.1038/13810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508514">Amir et al. (1999)</a> identified a 538T-C transition in the MECP2 gene, resulting in a phe155-to-ser (F155S) amino acid substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508514" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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ENCEPHALOPATHY, NEONATAL SEVERE, DUE TO MECP2 MUTATION, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs61750241 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61750241;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs61750241" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs61750241" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a woman with motor coordination problems, mild learning disability, and skewed X inactivation, <a href="#140" class="mim-tip-reference" title="Wan, M., Lee, S. S. J., Zhang, X., Houwink-Manville, I., Song, H.-R., Amir, R. E., Budden, S., Naidu, S., Pereira, J. L. P., Lo, I. F. M., Zoghbi, H. Y., Schanen, N. C., Francke, U. <strong>Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots.</strong> Am. J. Hum. Genet. 65: 1520-1529, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10577905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10577905</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10577905[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/302690" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10577905">Wan et al. (1999)</a> identified a 1-bp deletion (806delG) in the MECP2 gene, resulting in a val288-to-ter (V288X) substitution in the transcription repression domain. The same mutation was found in her sister and daughter, who were affected with classic Rett syndrome (RTT; <a href="/entry/312750">312750</a>), and in her hemizygous son, who died from congenital encephalopathy (<a href="/entry/300673">300673</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10577905" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#77" class="mim-tip-reference" title="Leuzzi, V., Di Sabato, M. L., Zollino, M., Montanaro, M. L., Seri, S. <strong>Early-onset encephalopathy and cortical myoclonus in a boy with MECP2 gene mutation.</strong> Neurology 63: 1968-1970, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15557528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15557528</a>] [<a href="https://doi.org/10.1212/01.wnl.0000144350.97844.94" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15557528">Leuzzi et al. (2004)</a> reported a 28-month-old boy with the 806delG mutation. The patient's mother did not carry the mutation, suggesting germline mosaicism or a de novo mutation. After a normal pregnancy and cesarean section, the patient was markedly hypotonic with weak suction and vomiting. He showed chaotic ocular movements, masticatory automatisms, and brief seizure-like episodes. Brain MRI was normal. Examination at age 10 months showed microcephaly, severe developmental delay, axial hypotonia, limb rigidity, hyperreflexia, lack of purposeful hand movements, and poor eye contact. In addition, he had paroxysmal myoclonic movements of the upper limbs that were unresponsive to conventional antiepileptic drugs. Neurophysiologic investigations showed arrhythmic multifocal myoclonus that was of cortical origin, although not associated with cortical hyperexcitability. The findings were similar to those observed in patients with Rett syndrome and believed to result from reduced dendritic branching and circuitry derangement (<a href="#53" class="mim-tip-reference" title="Guerrini, R., Bonanni, P., Parmeggiani, L., Santucci, M., Parmeggiani, A., Sartucci, F. <strong>Cortical reflex myoclonus in Rett syndrome.</strong> Ann. Neurol. 43: 472-479, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9546328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9546328</a>] [<a href="https://doi.org/10.1002/ana.410430410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9546328">Guerrini et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15557528+9546328" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#80" class="mim-tip-reference" title="Li, M., Pan, H., Bao, X.-H., Zhang, Y.-Z., Wu, X.-R. <strong>MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome.</strong> J. Hum. Genet. 52: 38-47, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17089071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17089071</a>] [<a href="https://doi.org/10.1007/s10038-006-0079-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17089071">Li et al. (2007)</a> referred to this mutation as G269fs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17089071" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267608372 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608372;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267608372" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs267608372" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient with classic Rett syndrome (RTT; <a href="/entry/312750">312750</a>), <a href="#27" class="mim-tip-reference" title="Cheadle, J. P., Gill, H., Fleming, N., Maynard, J., Kerr, A., Leonard, H., Krawczak, M., Cooper, D. N., Lynch, S., Thomas, N., Hughes, H., Hulten, M., Ravine, D., Sampson, J. R., Clarke, A. <strong>Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location.</strong> Hum. Molec. Genet. 9: 1119-1129, 2000. Note: Erratum: Hum. Molec. Genet. 9: 1717 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10767337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10767337</a>] [<a href="https://doi.org/10.1093/hmg/9.7.1119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10767337">Cheadle et al. (2000)</a> identified a de novo 44-bp deletion in exon 3 of the MECP2 gene. The deletion begins at base 1152, 3-prime to the transcription repression domain, and is predicted to produce a truncated protein of 388 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10767337" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs61750240 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61750240;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs61750240?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs61750240" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs61750240" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012586 OR RCV000081212 OR RCV000146359 OR RCV000169940 OR RCV000515283 OR RCV000624100 OR RCV001196907 OR RCV001705588 OR RCV004540996" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012586, RCV000081212, RCV000146359, RCV000169940, RCV000515283, RCV000624100, RCV001196907, RCV001705588, RCV004540996" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012586...</a>
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<p>In 3 of 31 patients with Rett syndrome (RTT; <a href="/entry/312750">312750</a>), <a href="#62" class="mim-tip-reference" title="Huppke, P., Laccone, F., Kramer, N., Engel, W., Hanefeld, F. <strong>Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients.</strong> Hum. Molec. Genet. 9: 1369-1375, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10814718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10814718</a>] [<a href="https://doi.org/10.1093/hmg/9.9.1369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10814718">Huppke et al. (2000)</a> identified an 808C-T transition in the MECP2 gene, resulting in a premature stop codon (arg270-to-ter; R270X) in exon 3. <a href="#15" class="mim-tip-reference" title="Bienvenu, T., Carrie, A., de Roux, N., Vinet, M.-C., Jonveaux, P., Couvert, P., Villard, L., Arzimanoglou, A., Beldjord, C., Fontes, M., Tardieu, M., Chelly, J. <strong>MECP2 mutations account for most cases of typical forms of Rett syndrome.</strong> Hum. Molec. Genet. 9: 1377-1384, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10814719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10814719</a>] [<a href="https://doi.org/10.1093/hmg/9.9.1377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10814719">Bienvenu et al. (2000)</a> found the same mutation in 5 of 46 Rett syndrome patients studied. <a href="#37" class="mim-tip-reference" title="De Bona, C., Zappella, M., Hayek, G., Meloni, I., Vitelli, F., Bruttini, M., Cusano, R., Loffredo, P., Longo, I., Renieri, A. <strong>Preserved speech variant is allelic of classic Rett syndrome.</strong> Europ. J. Hum. Genet. 8: 325-330, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10854091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10854091</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200473" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10854091">De Bona et al. (2000)</a> identified the R270X mutation in 4 unrelated individuals with Rett syndrome, indicating that it represents a hotspot. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10814718+10854091+10814719" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#131" class="mim-tip-reference" title="Topcu, M., Akyerli, C., Sayi, A., Toruner, G. A., Kocoglu, S. R., Cimbis, M., Ozcelik, T. <strong>Somatic mosaicism for a MECP2 mutation associated with classic Rett syndrome in a boy.</strong> Europ. J. Hum. Genet. 10: 77-81, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11896459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11896459</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200745" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11896459">Topcu et al. (2002)</a> reported a boy with features of classic Rett syndrome and a normal karyotype, with somatic mosaicism for the truncating R270X mutation. The mutation abolished an NlaIV restriction site, and densitometric scanning of the restriction fragments revealed that the allele ratio was approximately 36 to 64 for the mutant-to-normal allele. <a href="#131" class="mim-tip-reference" title="Topcu, M., Akyerli, C., Sayi, A., Toruner, G. A., Kocoglu, S. R., Cimbis, M., Ozcelik, T. <strong>Somatic mosaicism for a MECP2 mutation associated with classic Rett syndrome in a boy.</strong> Europ. J. Hum. Genet. 10: 77-81, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11896459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11896459</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200745" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11896459">Topcu et al. (2002)</a> speculated that the somatic mosaicism could be the result of an early postzygotic mutation or chimerism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11896459" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 524 females with Rett syndrome and an identified MECP2 mutation, <a href="#65" class="mim-tip-reference" title="Jian, L., Archer, H. L., Ravine, D., Kerr, A., de Klerk, N., Christodoulou, J., Bailey, M. E. S., Laurvick, C., Leonard, H. <strong>p.R270X MECP2 mutation and mortality in Rett syndrome.</strong> Europ. J. Hum. Genet. 13: 1235-1238, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16077729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16077729</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201479" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16077729">Jian et al. (2005)</a> prospectively analyzed mortality data and found significant differences in survival among the 8 most common mutations; survival among cases with the R270X mutation was reduced compared to all the other mutations (p = 0.01). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16077729" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By analysis of genotype/phenotype correlations of Rett syndrome cases reported in a large global database, <a href="#11" class="mim-tip-reference" title="Bebbington, A., Anderson, A., Ravine, D., Fyfe, S., Pineda, M, de Klerk, N., Ben-Zeev, B., Yatawara, N., Percy, A., Kaufmann, W.E., Leonard, H. <strong>Investigating genotype-phenotype relationships in Rett syndrome using an international data set.</strong> Neurology 70: 868-875, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18332345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18332345</a>] [<a href="https://doi.org/10.1212/01.wnl.0000304752.50773.ec" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18332345">Bebbington et al. (2008)</a> found that R270X and R255X (<a href="#0021">300005.0021</a>) were associated with the most severe phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18332345" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267608464 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608464;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267608464" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs267608464" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000144113 OR RCV000170199" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144113, RCV000170199" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144113...</a>
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<p>In a patient with classic Rett syndrome (RTT; <a href="/entry/312750">312750</a>), <a href="#62" class="mim-tip-reference" title="Huppke, P., Laccone, F., Kramer, N., Engel, W., Hanefeld, F. <strong>Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients.</strong> Hum. Molec. Genet. 9: 1369-1375, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10814718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10814718</a>] [<a href="https://doi.org/10.1093/hmg/9.9.1369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10814718">Huppke et al. (2000)</a> found a 378A-2G transition in the splice acceptor site 5-prime to exon 3 of the MECP2 gene. The mutation was predicted to affect all 4 domains of the protein: the nuclear localization signal (NLS), transcription repression domain (TRD), methyl-CpG-binding domain (MBD), and C-terminal segment (CTS). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10814718" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 RETT SYNDROME</strong>
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ENCEPHALOPATHY, NEONATAL SEVERE, DUE TO MECP2 MUTATION, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28934906 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28934906;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28934906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28934906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012580 OR RCV000133129 OR RCV000169935 OR RCV000170109 OR RCV000170110 OR RCV000623451 OR RCV000763199 OR RCV001813975 OR RCV002247328 OR RCV002273926 OR RCV003984805 OR RCV004540995" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012580, RCV000133129, RCV000169935, RCV000170109, RCV000170110, RCV000623451, RCV000763199, RCV001813975, RCV002247328, RCV002273926, RCV003984805, RCV004540995" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012580...</a>
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<p>In a sporadic patient with Rett syndrome (RTT; <a href="/entry/312750">312750</a>), <a href="#5" class="mim-tip-reference" title="Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., Zoghbi, H. Y. <strong>Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.</strong> Nature Genet. 23: 185-188, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508514</a>] [<a href="https://doi.org/10.1038/13810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508514">Amir et al. (1999)</a> identified a 547C-T transition in the MECP2 gene, resulting in a thr158-to-met (T148M) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508514" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#137" class="mim-tip-reference" title="Villard, L., Kpebe, A., Cardoso, C., Chelly, J., Tardieu, M., Fontes, M. <strong>Two affected boys in a Rett syndrome family: clinical and molecular findings.</strong> Neurology 55: 1188-1193, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11071498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11071498</a>] [<a href="https://doi.org/10.1212/wnl.55.8.1188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11071498">Villard et al. (2000)</a> reported a family in which a daughter had classic Rett syndrome and her 2 brothers died in infancy from severe encephalopathy (<a href="/entry/300673">300673</a>). The affected girl and 1 brother tested showed the T158M mutation. The unaffected carrier mother had a completely biased pattern of X-chromosome inactivation that favored expression of the normal allele. One of the affected boys showed severe mental retardation and hypotonia soon after birth and died at age 11 months. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11071498" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28934907 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28934907;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28934907" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28934907" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012585 OR RCV000255874 OR RCV000552837 OR RCV001000318 OR RCV001195924 OR RCV002247329 OR RCV002311513 OR RCV003224092 OR RCV004794330" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012585, RCV000255874, RCV000552837, RCV001000318, RCV001195924, RCV002247329, RCV002311513, RCV003224092, RCV004794330" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012585...</a>
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<p>In 2 affected half sisters of a family with Rett syndrome (RTT; <a href="/entry/312750">312750</a>), <a href="#5" class="mim-tip-reference" title="Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., Zoghbi, H. Y. <strong>Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.</strong> Nature Genet. 23: 185-188, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508514</a>] [<a href="https://doi.org/10.1038/13810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508514">Amir et al. (1999)</a> identified a 390C-T transition in the MECP2 gene, resulting in an arg106-to-trp (R106W) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508514" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC 13</strong>
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MECP2, GLU406TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs61753965 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61753965;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs61753965?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs61753965" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs61753965" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs63094662 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63094662;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs63094662?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs63094662" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs63094662" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012588 OR RCV000146349" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012588, RCV000146349" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012588...</a>
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<p>In affected males in a family reported by <a href="#31" class="mim-tip-reference" title="Claes, S., Devriendt, K., D'Adamo, P., Meireleire, J., Raeymaekers, P., Toniolo, D., Cassiman, J.-J., Fryns, J.-P. <strong>X-linked severe mental retardation and a progressive neurological disorder in a Belgian family: clinical and genetic studies.</strong> Clin. Genet. 52: 155-161, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9377804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9377804</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1997.tb02536.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9377804">Claes et al. (1997)</a> as having syndromic X-linked intellectual developmental disorder with progressive spasticity (MRXS13; <a href="/entry/300055">300055</a>), <a href="#90" class="mim-tip-reference" title="Meloni, I., Bruttini, M., Longo, I., Mari, F., Rizzolio, F., D'Adamo, P., Denvriendt, K., Fryns, J.-P., Toniolo, D., Renieri, A. <strong>A mutation in the Rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males.</strong> Am. J. Hum. Genet. 67: 982-985, 2000. Note: Erratum: Am. J. Hum. Genet. 67: 1365 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10986043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10986043</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10986043[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/303078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10986043">Meloni et al. (2000)</a> found a 1216C-T transition in exon 3 of the MECP2 gene, resulting in a glu406ter (E406X) nonsense mutation. The authors suggested that the position of the mutation near the end of the protein may explain the nonlethal male phenotype. Males showed delayed development (first steps at 2 to 5.5 years) and were never able to speak. They had facial hypotonia, sialorrhea, and a habitus suggesting complicated spastic paraplegia; their head circumferences were at the 75th to 90th percentile. One of them had choreoathetotic movements in the right arm, and global bradyarrhythmia as indicated by electroencephalogram, and bilateral juvenile cataract; he was confined to a wheelchair and died from pneumonia at age 39 years. <a href="#90" class="mim-tip-reference" title="Meloni, I., Bruttini, M., Longo, I., Mari, F., Rizzolio, F., D'Adamo, P., Denvriendt, K., Fryns, J.-P., Toniolo, D., Renieri, A. <strong>A mutation in the Rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males.</strong> Am. J. Hum. Genet. 67: 982-985, 2000. Note: Erratum: Am. J. Hum. Genet. 67: 1365 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10986043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10986043</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10986043[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/303078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10986043">Meloni et al. (2000)</a> compared the phenotypic findings with those of Rett syndrome (<a href="/entry/312750">312750</a>). Similarities included absence of language, ataxic gait, seizures, grinding of teeth, and sialorrhea. Moreover, spastic paraparesis is a frequent end-stage finding in Rett syndrome. Salient differences included absence of growth retardation, of loss of acquired purposeful hand skills, and of acquired microcephaly. Microcephaly is one of the major diagnostic criteria of Rett syndrome, in contrast with the macrocephaly in the family studied by <a href="#90" class="mim-tip-reference" title="Meloni, I., Bruttini, M., Longo, I., Mari, F., Rizzolio, F., D'Adamo, P., Denvriendt, K., Fryns, J.-P., Toniolo, D., Renieri, A. <strong>A mutation in the Rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males.</strong> Am. J. Hum. Genet. 67: 982-985, 2000. Note: Erratum: Am. J. Hum. Genet. 67: 1365 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10986043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10986043</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10986043[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/303078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10986043">Meloni et al. (2000)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10986043+9377804" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267608434 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608434;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267608434" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs267608434" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012589 OR RCV000133026" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012589, RCV000133026" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012589...</a>
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<p>In a male with a progressive neurologic disorder (see Rett syndrome; <a href="/entry/312750">312750</a>), <a href="#32" class="mim-tip-reference" title="Clayton-Smith, J., Watson, P., Ramsden, S., Black, G. C. M. <strong>Somatic mutation in MECP2 as a non-fatal neurodevelopmental disorder in males.</strong> Lancet 356: 830-832, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11022934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11022934</a>] [<a href="https://doi.org/10.1016/s0140-6736(00)02661-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11022934">Clayton-Smith et al. (2000)</a> identified a 2-bp deletion at nucleotide 211 of the MECP2 gene, resulting in a frameshift. This change created a novel restriction site for Cfo1. The mutation was not identified in either parent or in any of 100 normal X chromosomes. The patient was found to be somatic mosaic for the mutation, which explained the lack of embryonic lethality. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11022934" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs61751362 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61751362;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs61751362?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs61751362" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs61751362" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012590 OR RCV000012591 OR RCV000081215 OR RCV000474366 OR RCV000515413 OR RCV000624805 OR RCV001420261 OR RCV003984806 OR RCV004545726" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012590, RCV000012591, RCV000081215, RCV000474366, RCV000515413, RCV000624805, RCV001420261, RCV003984806, RCV004545726" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012590...</a>
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<p><strong><em>Rett Syndrome</em></strong></p><p>
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<a href="#37" class="mim-tip-reference" title="De Bona, C., Zappella, M., Hayek, G., Meloni, I., Vitelli, F., Bruttini, M., Cusano, R., Loffredo, P., Longo, I., Renieri, A. <strong>Preserved speech variant is allelic of classic Rett syndrome.</strong> Europ. J. Hum. Genet. 8: 325-330, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10854091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10854091</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200473" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10854091">De Bona et al. (2000)</a> identified an 880C-T transition in the MECP2 gene, leading to an arg294-to-ter (R294X) nonsense mutation in 4 unrelated patients with Rett syndrome (RTT; <a href="/entry/312750">312750</a>), thus indicating that this represents a hotspot. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10854091" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By analysis of genotype/phenotype correlations of Rett syndrome cases reported in a large global database, <a href="#11" class="mim-tip-reference" title="Bebbington, A., Anderson, A., Ravine, D., Fyfe, S., Pineda, M, de Klerk, N., Ben-Zeev, B., Yatawara, N., Percy, A., Kaufmann, W.E., Leonard, H. <strong>Investigating genotype-phenotype relationships in Rett syndrome using an international data set.</strong> Neurology 70: 868-875, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18332345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18332345</a>] [<a href="https://doi.org/10.1212/01.wnl.0000304752.50773.ec" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18332345">Bebbington et al. (2008)</a> found that R133C (<a href="#0001">300005.0001</a>) and R294X were associated with the mildest phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18332345" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Autism, Susceptibility to, X-Linked 3</em></strong></p><p>
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<a href="#21" class="mim-tip-reference" title="Carney, R. M., Wolpert, C. M., Ravan, S. A., Shahbazian, M., Ashley-Koch, A., Cuccaro, M. L., Vance, J. M., Pericak-Vance, M. A. <strong>Identification of MeCP2 mutations in a series of females with autistic disorder.</strong> Pediat. Neurol. 28: 205-211, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12770674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12770674</a>] [<a href="https://doi.org/10.1016/s0887-8994(02)00624-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12770674">Carney et al. (2003)</a> identified this mutation in a female with classic autism disorder (AUTSX3; <a href="/entry/300496">300496</a>) who had most of the diagnostic features of RTT. Analysis for skewed X chromosome inactivation in blood leukocytes showed that she had a 29% pattern. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12770674" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267608327 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608327;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267608327" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs267608327" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012592 OR RCV000132895 OR RCV000168701 OR RCV000169930 OR RCV000170099 OR RCV000645107 OR RCV002251999" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012592, RCV000132895, RCV000168701, RCV000169930, RCV000170099, RCV000645107, RCV002251999" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012592...</a>
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<p><strong><em>Rett Syndrome, Zappella Variant</em></strong></p><p>
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In a patient with Zappella variant, also known as preserved speech variant, Rett syndrome (see <a href="/entry/312750">312750</a>), <a href="#37" class="mim-tip-reference" title="De Bona, C., Zappella, M., Hayek, G., Meloni, I., Vitelli, F., Bruttini, M., Cusano, R., Loffredo, P., Longo, I., Renieri, A. <strong>Preserved speech variant is allelic of classic Rett syndrome.</strong> Europ. J. Hum. Genet. 8: 325-330, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10854091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10854091</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200473" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10854091">De Bona et al. (2000)</a> found a 41-bp deletion in the MECP2 gene beginning at nucleotide 1157. The DNA deletion resulted in a deletion of 14 amino acids beginning with codon 386 with a frameshift and stop codon at 404. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10854091" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Autism, Susceptibility to, X-Linked 3</em></strong></p><p>
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<a href="#21" class="mim-tip-reference" title="Carney, R. M., Wolpert, C. M., Ravan, S. A., Shahbazian, M., Ashley-Koch, A., Cuccaro, M. L., Vance, J. M., Pericak-Vance, M. A. <strong>Identification of MeCP2 mutations in a series of females with autistic disorder.</strong> Pediat. Neurol. 28: 205-211, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12770674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12770674</a>] [<a href="https://doi.org/10.1016/s0887-8994(02)00624-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12770674">Carney et al. (2003)</a> identified a female with classic autism disorder (AUTSX3; <a href="/entry/300496">300496</a>) who had this mutation in MECP2. She had virtually none of the diagnostic criteria for Rett syndrome. Analysis of X chromosome inactivation in blood leukocytes showed borderline skewing, with a 31% pattern. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12770674" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267608592 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608592;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267608592" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs267608592" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient with classic Rett syndrome (RTT; <a href="/entry/312750">312750</a>), <a href="#37" class="mim-tip-reference" title="De Bona, C., Zappella, M., Hayek, G., Meloni, I., Vitelli, F., Bruttini, M., Cusano, R., Loffredo, P., Longo, I., Renieri, A. <strong>Preserved speech variant is allelic of classic Rett syndrome.</strong> Europ. J. Hum. Genet. 8: 325-330, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10854091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10854091</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200473" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10854091">De Bona et al. (2000)</a> found a 41-bp deletion beginning at nucleotide 1159 of the MECP2 gene. The DNA deletion resulted in deletion of 14 amino acids beginning with codon 387 as well as a frameshift with a stop codon at codon 404. Remarkably, the 1157del41 mutation (<a href="#0012">300005.0012</a>) also has a 41-bp deletion with loss of 14 amino acids and a stop at 404; however, that mutation caused the preserved speech variant, whereas the 1159del41 mutation caused classic Rett syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10854091" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs61752992 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61752992;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs61752992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs61752992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012595 OR RCV000132932 OR RCV000169931 OR RCV000169932 OR RCV000170102 OR RCV000170103 OR RCV000415090 OR RCV000491803 OR RCV000624849 OR RCV000768267 OR RCV001002125 OR RCV001420272 OR RCV003989323 OR RCV004528867" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012595, RCV000132932, RCV000169931, RCV000169932, RCV000170102, RCV000170103, RCV000415090, RCV000491803, RCV000624849, RCV000768267, RCV001002125, RCV001420272, RCV003989323, RCV004528867" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012595...</a>
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<p>In a patient with Zappella variant Rett syndrome, also known as preserved speech variant (see <a href="/entry/312750">312750</a>), <a href="#37" class="mim-tip-reference" title="De Bona, C., Zappella, M., Hayek, G., Meloni, I., Vitelli, F., Bruttini, M., Cusano, R., Loffredo, P., Longo, I., Renieri, A. <strong>Preserved speech variant is allelic of classic Rett syndrome.</strong> Europ. J. Hum. Genet. 8: 325-330, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10854091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10854091</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200473" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10854091">De Bona et al. (2000)</a> found a 44-bp deletion beginning at nucleotide 1159 of the MECP2 gene, and resulting in deletion of 15 amino acids beginning with codon 387 and stopping with a frameshift and a stop codon at 404. Remarkably, the deletion began at the same nucleotide as in the 1159del41 mutation (<a href="#0013">300005.0013</a>) and led to a stop at the same codon, 404, but in this case caused the preserved speech variant rather than classic Rett syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10854091" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28934908 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28934908;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs28934908?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28934908" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28934908" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012596 OR RCV000020628 OR RCV000224266 OR RCV000414791 OR RCV000544176 OR RCV001004016 OR RCV001197458 OR RCV001249626 OR RCV001257756 OR RCV001374894 OR RCV002326676 OR RCV002466399 OR RCV004734513 OR RCV004819207" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012596, RCV000020628, RCV000224266, RCV000414791, RCV000544176, RCV001004016, RCV001197458, RCV001249626, RCV001257756, RCV001374894, RCV002326676, RCV002466399, RCV004734513, RCV004819207" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012596...</a>
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<p>In an adult mother and daughter with mildly impaired intellectual development, speech difficulties, and gait disturbances, <a href="#107" class="mim-tip-reference" title="Orrico, A., Lam, C.-W., Galli, L., Dotti, M. T., Hayek, G., Tong, S.-F., Poon, P. M. K., Zappella, M., Federico, A., Sorrentino, V. <strong>MECP2 mutation in male patients with non-specific X-linked mental retardation.</strong> FEBS Lett. 481: 285-288, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11007980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11007980</a>] [<a href="https://doi.org/10.1016/s0014-5793(00)01994-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11007980">Orrico et al. (2000)</a> identified a 493C-T transition in the MECP2 gene, resulting in an ala140-to-val (A140V) substitution in a highly conserved region in the alpha helix of the methyl-CpG binding domain. Four of the mother's adult sons who inherited the mutation had severe mental retardation, impaired language development, and movement disorders with tremor and bradykinesia (MRXS13; <a href="/entry/300055">300055</a>). The mutation was not present in the normal father or in 300 X chromosomes from normal individuals. The pattern of X-chromosome inactivation in the mother and daughter were close to random. The authors suggested that missense mutations such as A140V may correlate with milder disease than those resulting from truncating mutations, possibly through the presence of residual protein function. <a href="#41" class="mim-tip-reference" title="Dotti, M. T., Orrico, A., De Stefano, N., Battisti, C., Sicurelli, F., Severi, S., Lam, C. W., Galli, L., Sorrentino, V., Federico, A. <strong>A Rett syndrome MECP2 mutation that causes mental retardation in men.</strong> Neurology 58: 226-230, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11805248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11805248</a>] [<a href="https://doi.org/10.1212/wnl.58.2.226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11805248">Dotti et al. (2002)</a> reviewed the clinical findings of the family reported by <a href="#107" class="mim-tip-reference" title="Orrico, A., Lam, C.-W., Galli, L., Dotti, M. T., Hayek, G., Tong, S.-F., Poon, P. M. K., Zappella, M., Federico, A., Sorrentino, V. <strong>MECP2 mutation in male patients with non-specific X-linked mental retardation.</strong> FEBS Lett. 481: 285-288, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11007980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11007980</a>] [<a href="https://doi.org/10.1016/s0014-5793(00)01994-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11007980">Orrico et al. (2000)</a> and noted that although the mental retardation and neurologic signs were more pronounced in the men than in the women, the women did demonstrate abnormalities. Features present in all 6 family members included slowly progressive spastic paraparesis/pyramidal signs, distal atrophy of the legs, and mild dysmorphic features. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11007980+11805248" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 males with nonspecific sporadic mental retardation, <a href="#35" class="mim-tip-reference" title="Couvert, P., Bienvenu, T., Aquaviva, C., Poirier, K., Moraine, C., Gendrot, C., Verloes, A., Andres, C., Le Fevre, A. C., Souville, I., Steffann, J., des Portes, V., Ropers, H.-H., Yntema, H. G., Fryns, J.-P., Briault, S., Chelly, J., Cherif, B. <strong>MECP2 is highly mutated in X-linked mental retardation.</strong> Hum. Molec. Genet. 10: 941-946, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11309367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11309367</a>] [<a href="https://doi.org/10.1093/hmg/10.9.941" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11309367">Couvert et al. (2001)</a> identified the A140V mutation. No other clinical details were provided. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11309367" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#147" class="mim-tip-reference" title="Winnepenninckx, B., Errijgers, V., Hayez-Delatte, F., Reyniers, E., Kooy, R. F. <strong>Identification of a family with nonspecific mental retardation (MRX79) with the A140V mutation in the MECP2 gene: is there a need for routine screening?</strong> Hum. Mutat. 20: 249-252, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12325019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12325019</a>] [<a href="https://doi.org/10.1002/humu.10130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12325019">Winnepenninckx et al. (2002)</a> identified the A140V mutation in 5 affected males from a large kindred with X-linked mental retardation, which the authors designated MRX79 (<a href="/entry/300055">300055</a>). Variable clinical features included delayed psychomotor development, tremor, mood instability, and hyperkinetic behavior. Four carrier females in the family appeared to be unaffected. <a href="#147" class="mim-tip-reference" title="Winnepenninckx, B., Errijgers, V., Hayez-Delatte, F., Reyniers, E., Kooy, R. F. <strong>Identification of a family with nonspecific mental retardation (MRX79) with the A140V mutation in the MECP2 gene: is there a need for routine screening?</strong> Hum. Mutat. 20: 249-252, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12325019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12325019</a>] [<a href="https://doi.org/10.1002/humu.10130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12325019">Winnepenninckx et al. (2002)</a> referred to several other reports of the A140V mutation and estimated that this mutation occurs in approximately 1% of all X-linked mental retardation families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12325019" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#69" class="mim-tip-reference" title="Klauck, S. M., Lindsay, S., Beyer, K. S., Splitt, M., Burn, J., Poustka, A. <strong>A mutation hot spot for nonspecific X-linked mental retardation in the MECP2 gene causes the PPM-X syndrome.</strong> Am. J. Hum. Genet. 70: 1034-1037, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11885030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11885030</a>] [<a href="https://doi.org/10.1086/339553" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11885030">Klauck et al. (2002)</a> identified the A140V mutation in affected members of a pedigree with mental retardation associated with psychosis, pyramidal signs, and macroorchidism, designated PPMX, and consistent with MRXS13. They pointed out that there had been independent reports of 2 patients with familial mental retardation and 2 patients with sporadic mental retardation caused by this mutation in the MECP2 gene. They suggested that A140V is a hotspot for mutation, resulting in moderate to severe mental retardation in males. They designed a simple and reliable PCR approach for detection of the A140V mutation as a prescreen in unexplained cases of mental retardation before further extensive mutation analyses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11885030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Cohen, D., Lazar, G., Couvert, P., Desportes, V., Lippe, D., Mazet, P., Heron, D. <strong>MECP2 mutation in a boy with language disorder and schizophrenia. (Letter)</strong> Am. J. Psychiat. 159: 148-149, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11772708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11772708</a>] [<a href="https://doi.org/10.1176/appi.ajp.159.1.148-a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11772708">Cohen et al. (2002)</a> identified the A140V mutation in a boy with a developmental language disorder and onset of psychosis and childhood schizophrenia (see <a href="/entry/300055">300055</a>) at age 12 years. His unaffected mother also carried the mutation. The report expanded the phenotypic spectrum of males with the A140V mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11772708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#138" class="mim-tip-reference" title="Villard, L. <strong>MECP2 mutations in males.</strong> J. Med. Genet. 44: 417-423, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17351020/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17351020</a>] [<a href="https://doi.org/10.1136/jmg.2007.049452" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17351020">Villard (2007)</a> stated that the A140V mutation had never been reported in a girl with classic Rett syndrome (<a href="/entry/312750">312750</a>), suggesting that it results in serious disorders only when present in male patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17351020" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28935468 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28935468;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28935468" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28935468" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 unrelated patients with Rett syndrome (RTT; <a href="/entry/312750">312750</a>), <a href="#16" class="mim-tip-reference" title="Bourdon, V., Philippe, C., Labrune, O., Amsallem, D., Arnould, C., Jonveaux, P. <strong>A detailed analysis of the MECP2 gene: prevalence of recurrent mutations and gross DNA rearrangements in Rett syndrome patients.</strong> Hum. Genet. 108: 43-50, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11214906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11214906</a>] [<a href="https://doi.org/10.1007/s004390000422" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11214906">Bourdon et al. (2001)</a> found a 916C-T transition in exon 3 of the MECP2 gene resulting in an arg306-to-cys (R306C) amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11214906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The R306C mutation was also found in heterozygous state by <a href="#59" class="mim-tip-reference" title="Heilstedt, H. A., Shahbazian, M. D., Lee, B. <strong>Infantile hypotonia as a presentation of Rett syndrome.</strong> Am. J. Med. Genet. 111: 238-242, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12210319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12210319</a>] [<a href="https://doi.org/10.1002/ajmg.10633" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12210319">Heilstedt et al. (2002)</a> in a girl with atypical Rett syndrome manifested by developmental delay and hypotonia without evidence of an initial period of normal development. The mother did not carry the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12210319" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of patients with mutations in the MECP2 gene, <a href="#119" class="mim-tip-reference" title="Schanen, C., Houwink, E. J. F., Dorrani, N., Lane, J., Everett, R., Feng, A., Cantor, R. M., Percy, A. <strong>Phenotypic manifestations of MECP2 mutations in classical and atypical Rett syndrome.</strong> Am. J. Med. Genet. 126A: 129-140, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15057977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15057977</a>] [<a href="https://doi.org/10.1002/ajmg.a.20571" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15057977">Schanen et al. (2004)</a> found that the group of patients with the R306C mutation had a better prognosis, including better overall phenotype severity scores, later regression, and better speech with less motor impairment, than other mutation groups. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15057977" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs61748392 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61748392;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs61748392" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs61748392" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012598 OR RCV001230698 OR RCV001566839" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012598, RCV001230698, RCV001566839" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012598...</a>
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<p>In affected members of a 4-generation family with syndromic intellectual developmental disorder (MRXS13; <a href="/entry/300055">300055</a>) described by <a href="#50" class="mim-tip-reference" title="Gendrot, C., Ronce, N., Raynaud, M., Ayrault, A.-D., Dourlens, J., Castelnau, P., Muh, J.-P., Chelly, J., Moraine, C. <strong>X-linked nonspecific mental retardation (MRX16) mapping to distal Xq28: linkage study and neuropsychological data in a large family.</strong> Am. J. Med. Genet. 83: 411-418, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10232754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10232754</a>]" pmid="10232754">Gendrot et al. (1999)</a>, <a href="#35" class="mim-tip-reference" title="Couvert, P., Bienvenu, T., Aquaviva, C., Poirier, K., Moraine, C., Gendrot, C., Verloes, A., Andres, C., Le Fevre, A. C., Souville, I., Steffann, J., des Portes, V., Ropers, H.-H., Yntema, H. G., Fryns, J.-P., Briault, S., Chelly, J., Cherif, B. <strong>MECP2 is highly mutated in X-linked mental retardation.</strong> Hum. Molec. Genet. 10: 941-946, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11309367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11309367</a>] [<a href="https://doi.org/10.1093/hmg/10.9.941" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11309367">Couvert et al. (2001)</a> found an A-G transition in the MECP2 gene, resulting in a glu137-to-gly (E137G) substitution in the methyl-CpG-binding domain. <a href="#52" class="mim-tip-reference" title="Gomot, M., Gendrot, C., Verloes, A., Raynaud, M., David, A., Yntema, H. G., Dessay, S., Kalscheuer, V., Frints, S., Couvert, P., Briault, S., Blesson, S., Toutain, A., Chelly, J., Desportes, V., Moraine, C. <strong>MECP2 gene mutations in non-syndromic X-linked mental retardation: phenotype-genotype correlation.</strong> Am. J. Med. Genet. 123A: 129-139, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14598336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14598336</a>] [<a href="https://doi.org/10.1002/ajmg.a.20247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14598336">Gomot et al. (2003)</a> noted that some affected male patients in the family reported by <a href="#50" class="mim-tip-reference" title="Gendrot, C., Ronce, N., Raynaud, M., Ayrault, A.-D., Dourlens, J., Castelnau, P., Muh, J.-P., Chelly, J., Moraine, C. <strong>X-linked nonspecific mental retardation (MRX16) mapping to distal Xq28: linkage study and neuropsychological data in a large family.</strong> Am. J. Med. Genet. 83: 411-418, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10232754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10232754</a>]" pmid="10232754">Gendrot et al. (1999)</a> had features seen in classic Rett syndrome, including regression of written and oral language, verbal and motor stereopathies, clumsiness, and spasticity. Female carriers of the mutation were unaffected but did not show remarkable X-inactivation patterns. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11309367+14598336+10232754" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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MECP2, 1-BP DEL, 76C
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs61754426 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61754426;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs61754426" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs61754426" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000133236 OR RCV001808401" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000133236, RCV001808401" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000133236...</a>
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<p>In a sporadic patient with classic Rett syndrome (RTT; <a href="/entry/312750">312750</a>), <a href="#104" class="mim-tip-reference" title="Nielsen, J. B., Henriksen, K. F., Hansen, C., Silahtaroglu, A., Schwartz, M., Tommerup, N. <strong>MECP2 mutations in Danish patients with Rett syndrome: high frequency of mutations but no consistent correlations with clinical severity or with the X chromosome inactivation pattern.</strong> Europ. J. Hum. Genet. 9: 178-184, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11313756/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11313756</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200600" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11313756">Nielsen et al. (2001)</a> detected a 1-bp deletion at nucleotide 76 of the MECP2 gene, which resulted in a truncated protein of 31 amino acids. X-chromosome inactivation was random and the phenotype was no more severe than that of patients with a deletion in the 3-prime end of the gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11313756" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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MECP2, 14-BP DUP, NT766
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267608524 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608524;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267608524" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs267608524" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000133235" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000133235" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000133235</a>
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<p>In a sporadic patient with classic Rett syndrome (RTT; <a href="/entry/312750">312750</a>), <a href="#104" class="mim-tip-reference" title="Nielsen, J. B., Henriksen, K. F., Hansen, C., Silahtaroglu, A., Schwartz, M., Tommerup, N. <strong>MECP2 mutations in Danish patients with Rett syndrome: high frequency of mutations but no consistent correlations with clinical severity or with the X chromosome inactivation pattern.</strong> Europ. J. Hum. Genet. 9: 178-184, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11313756/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11313756</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200600" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11313756">Nielsen et al. (2001)</a> detected a 14-bp duplication beginning at nucleotide 766 of the MECP2 gene. The mutation was predicted to introduce a stop codon downstream after 32 missense amino acids, leading to a truncated protein of 292 amino acids missing part of the TRD domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11313756" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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MECP2, ARG168TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs61748421 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61748421;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs61748421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs61748421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012601 OR RCV000133143 OR RCV000224869 OR RCV000545521 OR RCV000626872 OR RCV002311514 OR RCV003984807 OR RCV004532326" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012601, RCV000133143, RCV000224869, RCV000545521, RCV000626872, RCV002311514, RCV003984807, RCV004532326" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012601...</a>
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<p><a href="#140" class="mim-tip-reference" title="Wan, M., Lee, S. S. J., Zhang, X., Houwink-Manville, I., Song, H.-R., Amir, R. E., Budden, S., Naidu, S., Pereira, J. L. P., Lo, I. F. M., Zoghbi, H. Y., Schanen, N. C., Francke, U. <strong>Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots.</strong> Am. J. Hum. Genet. 65: 1520-1529, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10577905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10577905</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10577905[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/302690" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10577905">Wan et al. (1999)</a> identified an arg168-to-ter (R168X) mutation in the MECP2 gene in 6 unrelated sporadic cases of Rett syndrome (RTT; <a href="/entry/312750">312750</a>), as well as in 2 affected sisters and their normal mother. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10577905" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs61749721 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61749721;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs61749721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs61749721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012602 OR RCV000081209 OR RCV000169938 OR RCV000515183 OR RCV000553858 OR RCV001813976 OR RCV002273928 OR RCV002313706 OR RCV003989103 OR RCV004545727 OR RCV004698464" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012602, RCV000081209, RCV000169938, RCV000515183, RCV000553858, RCV001813976, RCV002273928, RCV002313706, RCV003989103, RCV004545727, RCV004698464" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012602...</a>
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<p>In a patient with sporadic Rett syndrome (RTT; <a href="/entry/312750">312750</a>), <a href="#5" class="mim-tip-reference" title="Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., Zoghbi, H. Y. <strong>Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.</strong> Nature Genet. 23: 185-188, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508514</a>] [<a href="https://doi.org/10.1038/13810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508514">Amir et al. (1999)</a> identified an 837C-T transition in the MECP2 gene, resulting in a nonsense mutation arg255-to-ter (R255X). <a href="#27" class="mim-tip-reference" title="Cheadle, J. P., Gill, H., Fleming, N., Maynard, J., Kerr, A., Leonard, H., Krawczak, M., Cooper, D. N., Lynch, S., Thomas, N., Hughes, H., Hulten, M., Ravine, D., Sampson, J. R., Clarke, A. <strong>Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location.</strong> Hum. Molec. Genet. 9: 1119-1129, 2000. Note: Erratum: Hum. Molec. Genet. 9: 1717 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10767337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10767337</a>] [<a href="https://doi.org/10.1093/hmg/9.7.1119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10767337">Cheadle et al. (2000)</a>, <a href="#15" class="mim-tip-reference" title="Bienvenu, T., Carrie, A., de Roux, N., Vinet, M.-C., Jonveaux, P., Couvert, P., Villard, L., Arzimanoglou, A., Beldjord, C., Fontes, M., Tardieu, M., Chelly, J. <strong>MECP2 mutations account for most cases of typical forms of Rett syndrome.</strong> Hum. Molec. Genet. 9: 1377-1384, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10814719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10814719</a>] [<a href="https://doi.org/10.1093/hmg/9.9.1377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10814719">Bienvenu et al. (2000)</a>, and <a href="#62" class="mim-tip-reference" title="Huppke, P., Laccone, F., Kramer, N., Engel, W., Hanefeld, F. <strong>Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients.</strong> Hum. Molec. Genet. 9: 1369-1375, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10814718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10814718</a>] [<a href="https://doi.org/10.1093/hmg/9.9.1369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10814718">Huppke et al. (2000)</a> each found an R255X mutation in the methyl-CpG-binding protein in multiple patients with Rett syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10814718+10767337+10508514+10814719" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By analysis of genotype/phenotype correlations of Rett syndrome cases reported in a large global database, <a href="#11" class="mim-tip-reference" title="Bebbington, A., Anderson, A., Ravine, D., Fyfe, S., Pineda, M, de Klerk, N., Ben-Zeev, B., Yatawara, N., Percy, A., Kaufmann, W.E., Leonard, H. <strong>Investigating genotype-phenotype relationships in Rett syndrome using an international data set.</strong> Neurology 70: 868-875, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18332345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18332345</a>] [<a href="https://doi.org/10.1212/01.wnl.0000304752.50773.ec" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18332345">Bebbington et al. (2008)</a> found that R270X (<a href="#0005">300005.0005</a>) and R255X were associated with the most severe phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18332345" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1557134946 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1557134946;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1557134946" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1557134946" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000170257 OR RCV002472329" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000170257, RCV002472329" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000170257...</a>
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<p>In a family in which 3 males in 2 generations had mildly impaired intellectual development (MRXS13; <a href="/entry/300055">300055</a>), <a href="#151" class="mim-tip-reference" title="Yntema, H. G., Oudakker, A. R., Kleefstra, T., Hamel, B. C. J., van Bokhoven, H., Chelly, J., Kalscheuer, V. M., Fryns, J.-P., Raynaud, M., Moizard, M.-P., Moraine, C. <strong>In-frame deletion in MECP2 causes mild nonspecific mental retardation. (Letter)</strong> Am. J. Med. Genet. 107: 81-83, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11807877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11807877</a>] [<a href="https://doi.org/10.1002/ajmg.10085" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11807877">Yntema et al. (2002)</a> found an in-frame deletion of 240 basepairs (1161_1400del) from the MECP2 gene, resulting in the loss of 80 amino acids at the C-terminal end of the protein downstream of the transcription repression domain. There were no morphologic or neurologic anomalies. <a href="#52" class="mim-tip-reference" title="Gomot, M., Gendrot, C., Verloes, A., Raynaud, M., David, A., Yntema, H. G., Dessay, S., Kalscheuer, V., Frints, S., Couvert, P., Briault, S., Blesson, S., Toutain, A., Chelly, J., Desportes, V., Moraine, C. <strong>MECP2 gene mutations in non-syndromic X-linked mental retardation: phenotype-genotype correlation.</strong> Am. J. Med. Genet. 123A: 129-139, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14598336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14598336</a>] [<a href="https://doi.org/10.1002/ajmg.a.20247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14598336">Gomot et al. (2003)</a> provided follow-up of the family reported by <a href="#151" class="mim-tip-reference" title="Yntema, H. G., Oudakker, A. R., Kleefstra, T., Hamel, B. C. J., van Bokhoven, H., Chelly, J., Kalscheuer, V. M., Fryns, J.-P., Raynaud, M., Moizard, M.-P., Moraine, C. <strong>In-frame deletion in MECP2 causes mild nonspecific mental retardation. (Letter)</strong> Am. J. Med. Genet. 107: 81-83, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11807877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11807877</a>] [<a href="https://doi.org/10.1002/ajmg.10085" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11807877">Yntema et al. (2002)</a>. One obligate female carrier had markedly skewed X inactivation (0:100%). Affected males had various mood or behavioral problems, including emotional disturbance and aggression. Two had verbal stereotypies. Mental regression did not occur. <a href="#52" class="mim-tip-reference" title="Gomot, M., Gendrot, C., Verloes, A., Raynaud, M., David, A., Yntema, H. G., Dessay, S., Kalscheuer, V., Frints, S., Couvert, P., Briault, S., Blesson, S., Toutain, A., Chelly, J., Desportes, V., Moraine, C. <strong>MECP2 gene mutations in non-syndromic X-linked mental retardation: phenotype-genotype correlation.</strong> Am. J. Med. Genet. 123A: 129-139, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14598336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14598336</a>] [<a href="https://doi.org/10.1002/ajmg.a.20247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14598336">Gomot et al. (2003)</a> suggested that the relatively pure mental retardation phenotype in this family without severe motor abnormalities may be explained by the distal localization of the in-frame deletion in MECP2. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11807877+14598336" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs61753971 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61753971;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs61753971?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs61753971" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs61753971" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012604 OR RCV000132982 OR RCV001719695 OR RCV002260597 OR RCV002371770 OR RCV004540997" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012604, RCV000132982, RCV001719695, RCV002260597, RCV002371770, RCV004540997" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012604...</a>
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<p>In a male with nonprogressive encephalopathy of neonatal onset (<a href="/entry/300673">300673</a>), <a href="#63" class="mim-tip-reference" title="Imessaoudene, B., Bonnefont, J.-P., Royer, G., Cormier-Daire, V., Lyonnet, S., Lyon, G., Munnich, A., Amiel, J. <strong>MECP2 mutation in non-fatal, non-progressive encephalopathy in a male.</strong> J. Med. Genet. 38: 171-174, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11238684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11238684</a>] [<a href="https://doi.org/10.1136/jmg.38.3.171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11238684">Imessaoudene et al. (2001)</a> identified a 1282G-A transition in the MECP2 gene, resulting in a gly428-to-ser (G428S) substitution. They suggested that the patient's grandfather, whose DNA was unavailable, was mosaic for the G428S mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11238684" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#74" class="mim-tip-reference" title="Laccone, F., Zoll, B., Huppke, P., Hanefeld, F., Pepinski, W., Trappe, R. <strong>MECP2 gene nucleotide changes and their pathogenicity in males: proceed with caution.</strong> J. Med. Genet. 39: 586-588, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12161600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12161600</a>] [<a href="https://doi.org/10.1136/jmg.39.8.586" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12161600">Laccone et al. (2002)</a> questioned the validity of the G428S substitution as the disease-causing mutation. They identified the G428S substitution in a boy with severe encephalopathy and untreatable seizures who died at 18 months of age. They noted that the patient with the G428S mutation described by <a href="#63" class="mim-tip-reference" title="Imessaoudene, B., Bonnefont, J.-P., Royer, G., Cormier-Daire, V., Lyonnet, S., Lyon, G., Munnich, A., Amiel, J. <strong>MECP2 mutation in non-fatal, non-progressive encephalopathy in a male.</strong> J. Med. Genet. 38: 171-174, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11238684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11238684</a>] [<a href="https://doi.org/10.1136/jmg.38.3.171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11238684">Imessaoudene et al. (2001)</a> had a less severe phenotype and that the G428S change was more consistent with a rare genetic variant, as the grandpaternal mosaicism could not be proven. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12161600+11238684" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1557135251 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1557135251;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1557135251" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1557135251" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012605 OR RCV000170146 OR RCV002508196 OR RCV003638635 OR RCV003991021" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012605, RCV000170146, RCV002508196, RCV003638635, RCV003991021" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012605...</a>
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<p><a href="#144" class="mim-tip-reference" title="Watson, P., Black, G., Ramsden, S., Barrow, M., Super, M., Kerr, B., Clayton-Smith, J. <strong>Angelman syndrome phenotype associated with mutations in MECP2, a gene encoding a methyl CpG binding protein.</strong> J. Med. Genet. 38: 224-228, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11283202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11283202</a>] [<a href="https://doi.org/10.1136/jmg.38.4.224" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11283202">Watson et al. (2001)</a> reported a 52-bp deletion in the MECP2 gene in a girl with an Angelman-like phenotype (<a href="/entry/105830">105830</a>) who had some features of Rett syndrome (RTT; <a href="/entry/312750">312750</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11283202" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs61748396 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61748396;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs61748396" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs61748396" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012606 OR RCV000133106 OR RCV000170108 OR RCV000623504 OR RCV000729616 OR RCV001049210" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012606, RCV000133106, RCV000170108, RCV000623504, RCV000729616, RCV001049210" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012606...</a>
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<p>In a girl with an Angelman-like phenotype (<a href="/entry/105830">105830</a>) with some features of Rett syndrome (RTT; <a href="/entry/312750">312750</a>), <a href="#144" class="mim-tip-reference" title="Watson, P., Black, G., Ramsden, S., Barrow, M., Super, M., Kerr, B., Clayton-Smith, J. <strong>Angelman syndrome phenotype associated with mutations in MECP2, a gene encoding a methyl CpG binding protein.</strong> J. Med. Genet. 38: 224-228, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11283202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11283202</a>] [<a href="https://doi.org/10.1136/jmg.38.4.224" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11283202">Watson et al. (2001)</a> reported a 497C-G transition in the MECP2 gene, resulting in premature termination of the protein at residue 141 (Y141X). This mutation had been reported in girls with Rett syndrome (<a href="#5" class="mim-tip-reference" title="Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., Zoghbi, H. Y. <strong>Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.</strong> Nature Genet. 23: 185-188, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508514</a>] [<a href="https://doi.org/10.1038/13810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508514">Amir et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11283202+10508514" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894864 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894864;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104894864" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs104894864" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012607 OR RCV000132997" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012607, RCV000132997" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012607...</a>
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<p><a href="#82" class="mim-tip-reference" title="Maiwald, R., Bonte, A., Jung, H., Bitter, P., Storm, Z., Laccone, F., Herkenrath, P. <strong>De novo MECP2 mutation in a 46,XX male patient with Rett syndrome. (Letter)</strong> Neurogenetics 4: 107-108, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12481990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12481990</a>] [<a href="https://doi.org/10.1007/s10048-002-0137-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12481990">Maiwald et al. (2002)</a> described a 46,XX male with Rett syndrome (RTT; <a href="/entry/312750">312750</a>) caused by a glu455-to-ter (E455X) mutation in exon 4 of the MECP2 gene. The boy was heterozygous for the mutation, which was of paternal origin and led to a premature termination of the protein downstream of the transcriptional repression domain. Upon amniocentesis performed because of advanced maternal age, a female karyotype was detected in the sonographically male fetus. Both the phenotype and the karyotype were confirmed after birth, and the absence of mullerian structures was demonstrated by ultrasonography. Motor development was delayed; he was able to sit only at 14 months of age. He was still not able to walk and there was no speech at the age of 24 months. At the age of 2 years, he showed truncal muscular hypotonia, microcephaly, spasticity, and convergent strabismus of the left eye. There was a loss of purposeful hand skills at approximately 6 months of age, and a deceleration of head growth at approximately 7 months. The clinical appearance of the boy resembled female Rett cases, which was explained by the karyotype. In addition, preferential expression of the normal allele may have contributed to the rather mild phenotype. Similar features had been described in male patients with MECP2 mutations and a Klinefelter karyotype (46,XXY). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12481990" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28935168 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28935168;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28935168" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28935168" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012608 OR RCV000498874" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012608, RCV000498874" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012608...</a>
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<p>In a patient with Rett syndrome (RTT; <a href="/entry/312750">312750</a>), <a href="#19" class="mim-tip-reference" title="Buyse, I. M., Fang, P., Hoon, K. T., Amir, R. E., Zoghbi, H. Y., Roa, B. B. <strong>Diagnostic testing for Rett syndrome by DHPLC and direct sequencing analysis of the MECP2 gene: identification of several novel mutations and polymorphisms.</strong> Am. J. Hum. Genet. 67: 1428-1436, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11055898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11055898</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11055898[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/316913" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11055898">Buyse et al. (2000)</a> identified a 298C-G change in the MECP2 gene, resulting in a leu100-to-val (L100V) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11055898" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#56" class="mim-tip-reference" title="Hammer, S., Dorrani, N., Hartiala, J., Stein, S., Schanen, N. C. <strong>Rett syndrome in a 47,XXX patient with a de novo MECP2 mutation.</strong> Am. J. Med. Genet. 122A: 223-226, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12966522/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12966522</a>] [<a href="https://doi.org/10.1002/ajmg.a.20320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12966522">Hammer et al. (2003)</a> reported a 5-year-old girl with a 47,XXX karyotype who had relatively mild atypical Rett syndrome leading initially to a diagnosis of infantile autism with regression. Mutation analysis identified a de novo L100V mutation in the MECP2 gene. The supernumerary X chromosome was maternally derived. X-inactivation patterns indicated preferential inactivation of the paternal allele. The authors suggested that the patient illustrated the importance of allele dosage on phenotypic expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12966522" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs786205042 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205042;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs786205042" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs786205042" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000170288 OR RCV001245569" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000170288, RCV001245569" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000170288...</a>
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<p>In a patient with typical Rett syndrome (RTT; <a href="/entry/312750">312750</a>), <a href="#92" class="mim-tip-reference" title="Mnatzakanian, G. N., Lohi, H., Munteanu, I., Alfred, S. E., Yamada, T., MacLeod, P. J. M., Jones, J. R., Scherer, S. W., Schanen, N. C., Friez, M. J., Vincent, J. B., Minassian, B. A. <strong>A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome.</strong> Nature Genet. 36: 339-341, 2004. Note: Erratum: Nature Genet. 36: 540 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034579</a>] [<a href="https://doi.org/10.1038/ng1327" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15034579">Mnatzakanian et al. (2004)</a> identified an 11-bp deletion in exon 1 of the MECP2 gene. This mutation was not found in either of the patient's parents, in her brother, or in 200 control individuals. This mutation eliminates expression of the MECP2B isoform (which uses exons 1, 3, and 4) but does not affect the expression of MECP2A, the previously described isoform of MECP2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15034579" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#110" class="mim-tip-reference" title="Ravn, K., Nielsen, J. B., Schwartz, M. <strong>Mutations found within exon 1 of MECP2 in Danish patients with Rett syndrome. (Letter)</strong> Clin. Genet. 67: 532-533, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15857422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15857422</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2005.00444.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15857422">Ravn et al. (2005)</a> identified the 11-bp deletion in exon 1 of the MECP2 gene in a Danish patient with typical Rett syndrome. The authors emphasized the importance of mutation screening of MECP2 exon 1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15857422" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#118" class="mim-tip-reference" title="Saxena, A., de Lagarde, D., Leonard, H., Williamson, S. L., Vasudevan, V., Christodoulou, J., Thompson, E., MacLeod, P., Ravine, D. <strong>Lost in translation: translational interference from a recurrent mutation in exon 1 of MECP2.</strong> J. Med. Genet. 43: 470-477, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16155192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16155192</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16155192[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2005.036244" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16155192">Saxena et al. (2006)</a> screened exon 1 among RNA samples from 20 females with classic or atypical RTT and detected the 11-bp deletion in exon 1 originally reported by <a href="#92" class="mim-tip-reference" title="Mnatzakanian, G. N., Lohi, H., Munteanu, I., Alfred, S. E., Yamada, T., MacLeod, P. J. M., Jones, J. R., Scherer, S. W., Schanen, N. C., Friez, M. J., Vincent, J. B., Minassian, B. A. <strong>A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome.</strong> Nature Genet. 36: 339-341, 2004. Note: Erratum: Nature Genet. 36: 540 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034579</a>] [<a href="https://doi.org/10.1038/ng1327" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15034579">Mnatzakanian et al. (2004)</a> in 1 subject with a milder phenotype. Although RNA expression for both protein isoforms was detected from the mutant allele, evaluation of MECP2 protein in uncultured patient lymphocytes by immunocytochemistry revealed that protein production was restricted to only 74 to 76% of lymphocytes. X chromosome inactivation studies of genomic DNA revealed similar X chromosome inactivation ratios at the HUMARA locus. <a href="#118" class="mim-tip-reference" title="Saxena, A., de Lagarde, D., Leonard, H., Williamson, S. L., Vasudevan, V., Christodoulou, J., Thompson, E., MacLeod, P., Ravine, D. <strong>Lost in translation: translational interference from a recurrent mutation in exon 1 of MECP2.</strong> J. Med. Genet. 43: 470-477, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16155192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16155192</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16155192[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2005.036244" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16155192">Saxena et al. (2006)</a> demonstrated that translation but not transcription of the isoform rising from exon 2 is ablated by the 11-nucleotide deletion, 103 nucleotides upstream of the translation start site of the exon 2 isoform. Thus, nucleotides within the deleted sequence in the 5-prime UTR of the exon 2 transcript, while not required for transcription, are essential for translation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15034579+16155192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs786205038 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205038;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs786205038" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs786205038" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a Danish patient with typical Rett syndrome (RTT; <a href="/entry/312750">312750</a>), <a href="#110" class="mim-tip-reference" title="Ravn, K., Nielsen, J. B., Schwartz, M. <strong>Mutations found within exon 1 of MECP2 in Danish patients with Rett syndrome. (Letter)</strong> Clin. Genet. 67: 532-533, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15857422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15857422</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2005.00444.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15857422">Ravn et al. (2005)</a> identified a 5-bp duplication (23dupCGCCG) in exon 1 of the MECP2 gene, resulting in a frameshift and premature termination of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15857422" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0030 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, LUBS-TYPE</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012611" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012611" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012611</a>
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<p>In a boy with Lubs-type X-linked intellectual developmental disorder (MRXSL; <a href="/entry/300260">300260</a>), <a href="#89" class="mim-tip-reference" title="Meins, M., Lehmann, J., Gerresheim, F., Herchenbach, J., Hagedorn, M., Hameister, K., Epplen, J. T. <strong>Submicroscopic duplication in Xq28 causes increased expression of the MECP2 gene in a boy with severe mental retardation and features of Rett syndrome. (Letter)</strong> J. Med. Genet. 42: e12, 2005. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15689435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15689435</a>] [<a href="https://doi.org/10.1136/jmg.2004.023804" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15689435">Meins et al. (2005)</a> found a submicroscopic duplication of Xq28, including the MECP2 gene. Dosage analysis of family members showed 2 gene copies in the boy and 3 copies in his healthy mother, who had severely skewed X inactivation. Quantification of transcript levels suggested a double dose of MECP2 in the boy, but not in his mother. Further analysis showed that the duplication included 12 genes, from AVPR2 (<a href="/entry/300538">300538</a>) to TKTL1 (<a href="/entry/300044">300044</a>); the L1CAM (<a href="/entry/308840">308840</a>) gene was excluded. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15689435" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By array comparative genomic hybridization (CGH) analysis, <a href="#134" class="mim-tip-reference" title="Van Esch, H., Bauters, M., Ignatius, J., Jansen, M., Raynaud, M., Hollanders, K., Lugtenberg, D., Bienvenu, T., Jensen, L. R., Gecz, J., Moraine, C., Marynen, P., Fryns, J.-P., Froyen, G. <strong>Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males.</strong> Am. J. Hum. Genet. 77: 442-453, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16080119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16080119</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16080119[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/444549" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16080119">Van Esch et al. (2005)</a> identified a small duplication at Xq28 in affected males from 4 families with a severe form of mental retardation associated with progressive spasticity and respiratory infections. The duplications in the 4 patients varied in size from 0.4 to 0.8 Mb and comprised the MECP2 and L1CAM genes in each case. Increased dosage of MECP2 appeared to be responsible for the mental retardation phenotype. The main features present in the affected males were severe to profound mental retardation with onset at birth, axial and facial hypotonia, progressive spasticity predominantly at the lower limbs, seizures, and recurrent infections leading to early death in 4 of the affected members of 1 family. The affected males also shared some mild dysmorphic features, including large ears and flat nasal bridge. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16080119" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#38" class="mim-tip-reference" title="del Gaudio, D., Fang, P., Scaglia, F., Ward, P. A., Craigen, W. J., Glaze, D. G., Neul, J. L., Patel, A., Lee, J. A., Irons, M., Berry, S. A., Pursley, A. A., and 12 others. <strong>Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males.</strong> Genet. Med. 8: 784-792, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17172942/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17172942</a>] [<a href="https://doi.org/10.1097/01.gim.0000250502.28516.3c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17172942">Del Gaudio et al. (2006)</a> reported 6 males with duplication and 1 male with triplication of MECP2. All had developmental delay and infantile hypotonia. All but 1 had absent speech. The spasticity reported by <a href="#134" class="mim-tip-reference" title="Van Esch, H., Bauters, M., Ignatius, J., Jansen, M., Raynaud, M., Hollanders, K., Lugtenberg, D., Bienvenu, T., Jensen, L. R., Gecz, J., Moraine, C., Marynen, P., Fryns, J.-P., Froyen, G. <strong>Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males.</strong> Am. J. Hum. Genet. 77: 442-453, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16080119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16080119</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16080119[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/444549" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16080119">Van Esch et al. (2005)</a> was not seen in the patients reported by <a href="#38" class="mim-tip-reference" title="del Gaudio, D., Fang, P., Scaglia, F., Ward, P. A., Craigen, W. J., Glaze, D. G., Neul, J. L., Patel, A., Lee, J. A., Irons, M., Berry, S. A., Pursley, A. A., and 12 others. <strong>Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males.</strong> Genet. Med. 8: 784-792, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17172942/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17172942</a>] [<a href="https://doi.org/10.1097/01.gim.0000250502.28516.3c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17172942">del Gaudio et al. (2006)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16080119+17172942" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Belligni, E. F., Palmer, R. W., Hennekam, R. C. M. <strong>MECP2 duplication in a patient with congenital central hypoventilation.</strong> Am. J. Med. Genet. 152A: 1591-1593, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20503343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20503343</a>] [<a href="https://doi.org/10.1002/ajmg.a.33311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20503343">Belligni et al. (2010)</a> reported a 5-year-old boy who demonstrated severe central hypotonia and central hypoventilation at birth, necessitating a tracheostomy. He showed severe developmental delay with poor head control. He also had a persistent ductus arteriosus and chronic constipation, without evidence of Hirschsprung disease. Brain MRI showed decreased white matter bulk and bilateral optic nerve hypoplasia. Genetic analysis identified a 0.5- to 0.8-Mb interstitial duplication of chromosome Xq28 including the MECP2 and L1CAM genes, which was inherited from his asymptomatic mother. <a href="#12" class="mim-tip-reference" title="Belligni, E. F., Palmer, R. W., Hennekam, R. C. M. <strong>MECP2 duplication in a patient with congenital central hypoventilation.</strong> Am. J. Med. Genet. 152A: 1591-1593, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20503343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20503343</a>] [<a href="https://doi.org/10.1002/ajmg.a.33311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20503343">Belligni et al. (2010)</a> suggested that MECP2 be evaluated in patients with features of the congenital hypoventilation syndrome (<a href="/entry/209880">209880</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20503343" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs786205040 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205040;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs786205040?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs786205040" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs786205040" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 1 of 20 girls with Rett syndrome (RTT; <a href="/entry/312750">312750</a>), <a href="#10" class="mim-tip-reference" title="Bartholdi, D., Klein, A., Weissert, M., Koenig, N., Baumer, A., Boltshauser, E., Schinzel, A., Berger, W., Matyas, G. <strong>Clinical profiles of four patients with Rett syndrome carrying a novel exon 1 mutation or genomic rearrangement in the MECP2 gene.</strong> Clin. Genet. 69: 319-326, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16630165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16630165</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00604.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16630165">Bartholdi et al. (2006)</a> identified a combination 1-bp deletion and 2-bp insertion (30delCinsGA) in exon 1 of the MECP2 gene, resulting in a frameshift and premature stop codon. She had a particularly severe form of the disorder, leading to death at age 19 years. <a href="#10" class="mim-tip-reference" title="Bartholdi, D., Klein, A., Weissert, M., Koenig, N., Baumer, A., Boltshauser, E., Schinzel, A., Berger, W., Matyas, G. <strong>Clinical profiles of four patients with Rett syndrome carrying a novel exon 1 mutation or genomic rearrangement in the MECP2 gene.</strong> Clin. Genet. 69: 319-326, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16630165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16630165</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00604.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16630165">Bartholdi et al. (2006)</a> postulated that patients with mutations involving exon 1 of the MECP2 gene are more severely affected than those with MECP2 mutations that do not affect exon 1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16630165" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267608488 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608488;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267608488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs267608488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000133140 OR RCV000170111" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000133140, RCV000170111" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000133140...</a>
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<p>In a girl with Rett syndrome (RTT; <a href="/entry/312750">312750</a>), <a href="#49" class="mim-tip-reference" title="Geerdink, N., Rotteveel, J. J., Lammens, M., Sistermans, E. A., Heikens, G. T., Gabreels, F. J. M., Mullaart, R. A., Hamel, B. C. J. <strong>MECP2 mutation in a boy with severe neonatal encephalopathy: clinical, neuropathological and molecular findings.</strong> Neuropediatrics 33: 33-36, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11930274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11930274</a>] [<a href="https://doi.org/10.1055/s-2002-23598" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11930274">Geerdink et al. (2002)</a> identified a 2-bp deletion (488delGG) in exon 3 of the MECP2 gene, resulting in a frameshift and premature termination. Her younger brother, who also carried the hemizygous mutation, had a severe neonatal encephalopathy (<a href="/entry/300673">300673</a>) with respiratory insufficiency with apnea, central hypoventilation, and poor feeding. He also had axial hypotonia with hyperextension and rigidity of the limbs, multifocal seizures, stereotypical rubbing of his hand over his face, and gastroesophageal reflux. He died at age 13 months of respiratory failure. Postmortem examination showed bilateral polymicrogyria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11930274" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0033 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC 13</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs61749715 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61749715;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs61749715" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs61749715" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012615 OR RCV000133194 OR RCV005089237" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012615, RCV000133194, RCV005089237" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012615...</a>
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<p>In a 21-year-old man with severely impaired intellectual disorder since infancy and spasticity (MRXS13; <a href="/entry/300055">300055</a>), <a href="#94" class="mim-tip-reference" title="Moog, U., Smeets, E. E. J., van Roozendaal, K. E. P., Schoenmakers, S., Herbergs, J., Schoonbrood-Lenssen, A. M. J., Schrander-Stumpel, C. T. R. M. <strong>Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2).</strong> Europ. J. Paediat. Neurol. 7: 5-12, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12615169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12615169</a>] [<a href="https://doi.org/10.1016/s1090-3798(02)00134-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12615169">Moog et al. (2003)</a> identified a de novo 674C-T transition in exon 3 of the MECP2 gene, resulting in a pro225-to-leu (P225L) substitution in the transcriptional repression domain of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12615169" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0034 ENCEPHALOPATHY, NEONATAL SEVERE, DUE TO MECP2 MUTATION</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1569548314 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1569548314;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1569548314" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1569548314" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012616" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012616" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012616</a>
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<p>In 2 brothers with severe neonatal encephalopathy and death in infancy (<a href="/entry/300673">300673</a>), <a href="#60" class="mim-tip-reference" title="Hoffbuhr, K., Devaney, J. M., LaFleur, B., Sirianni, N., Scacheri, C., Giron, J., Schuette, J., Innis, J., Marino, M., Philippart, M., Narayanan, V., Umansky, R., Kronn, D., Hoffman, E. P., Naidu, S. <strong>MeCP2 mutations in children with and without the phenotype of Rett syndrome.</strong> Neurology 56: 1486-1495, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11402105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11402105</a>] [<a href="https://doi.org/10.1212/wnl.56.11.1486" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11402105">Hoffbuhr et al. (2001)</a> identified a 32-bp deletion at nucleotide 1154 of the MECP2 gene, resulting in a truncation and absence of the methyl-binding and transcription repression domains. The unaffected carrier mother showed skewed X inactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11402105" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0035 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC 13</strong>
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MECP2, PRO322SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs61751449 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61751449;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs61751449" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs61751449" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012617 OR RCV000416315 OR RCV001090501 OR RCV005089238" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012617, RCV000416315, RCV001090501, RCV005089238" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012617...</a>
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<p>In a boy with delayed development, language delay, seizures, and ataxia (MRXS13; <a href="/entry/300055">300055</a>), <a href="#135" class="mim-tip-reference" title="Ventura, P., Galluzzi, R., Bacca, S. M., Giorda, R., Massagli, A. <strong>A novel familial MECP2 mutation in a young boy: clinical and molecular findings.</strong> Neurology 67: 867-868, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16966553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16966553</a>] [<a href="https://doi.org/10.1212/01.wnl.0000233990.87889.15" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16966553">Ventura et al. (2006)</a> identified a 964C-T transition in the MECP2 gene, resulting in a pro322-to-ser (P322S) substitution. He had frequent seizures, including myoclonic seizures, hypotonia, lower limb weakness, ataxia, dysmetria, and intention tremor. He also showed hyperactivity, irritability, and psychomotor restlessness. Mild dysmorphic features included frontal bossing, low-set ears, and irregular teeth placement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16966553" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0036 RETT SYNDROME, ZAPPELLA VARIANT</strong>
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MECP2, PRO152ALA
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs179363900 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs179363900;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs179363900?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs179363900" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs179363900" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012618 OR RCV000133115 OR RCV000492792 OR RCV000763200 OR RCV000991003 OR RCV001246099 OR RCV004734514" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012618, RCV000133115, RCV000492792, RCV000763200, RCV000991003, RCV001246099, RCV004734514" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012618...</a>
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<p>In a father and his 10-year-old daughter with neuropsychiatric features reminiscent of the mild phenotype of Zappella variant Rett syndrome (see <a href="/entry/312750">312750</a>), <a href="#2" class="mim-tip-reference" title="Adegbola, A. A., Gonzales, M. L., Chess, A., LaSalle, J. M., Cox, G. F. <strong>A novel hypomorphic MECP2 point mutation is associated with a neuropsychiatric phenotype.</strong> Hum. Genet. 124: 615-623, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18989701/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18989701</a>] [<a href="https://doi.org/10.1007/s00439-008-0585-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18989701">Adegbola et al. (2009)</a> identified a heterozygous 454C-G transversion in exon 4 of the MECP2 gene, resulting in a pro152-to-ala (P152A) substitution in the methyl-binding domain of the protein. The girl had purposeful hand movements with occasional hand-wringing stereotypes, was morbidly obese, was prone to aggressive outbursts, had mild autistic features, and IQ of 58. Her father had an IQ of 85, had special schooling, and showed behavioral dyscontrol and hyperactivity in childhood and adolescence. In vitro functional expression studies in mouse fibroblasts demonstrated that the mutant protein showed varying levels of diffuse nuclear staining outside of the heterochromatic foci compared to wildtype, which localizes exclusively to heterochromatic foci. Biochemical studies showed that mutant P152A had a 40% reduction in association with insoluble heterochromatin compared to wildtype. Classic Rett mutations showed an 70 to 80% decrease. The findings were consistent with a hypomorphic MECP2 allele contributing to a neuropsychiatric phenotype in this family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18989701" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs179363901 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs179363901;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs179363901?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs179363901" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs179363901" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012619 OR RCV001851806 OR RCV004760328" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012619, RCV001851806, RCV004760328" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012619...</a>
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<p>In a girl with Rett syndrome (RTT; <a href="/entry/312750">312750</a>), <a href="#44" class="mim-tip-reference" title="Fichou, Y., Nectoux, J., Bahi-Buisson, N., Rosas-Vargas, H., Girard, B., Chelly, J., Bienvenu, T. <strong>The first missense mutation causing Rett syndrome specifically affecting the MeCP2_e1 isoform.</strong> Neurogenetics 10: 127-133, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19034540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19034540</a>] [<a href="https://doi.org/10.1007/s10048-008-0161-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19034540">Fichou et al. (2009)</a> identified a de novo heterozygous 5T-C transition in exon 1 of the MECP2 gene, resulting in an ala2-to-val (A2V) substitution in the MeCP2_e1 isoform, which is more abundant in the brain than the MeCP2_e2 isoform. The mutation changed the first alanine of a well-conserved 7-residue polyalanine tract. In vitro studies of patient fibroblasts showed that the A2V mutation had no effect on the MeCP2_e2 isoform. The patient had severe developmental delay, microcephaly, no language, severe epilepsy, and cognitive impairment. <a href="#44" class="mim-tip-reference" title="Fichou, Y., Nectoux, J., Bahi-Buisson, N., Rosas-Vargas, H., Girard, B., Chelly, J., Bienvenu, T. <strong>The first missense mutation causing Rett syndrome specifically affecting the MeCP2_e1 isoform.</strong> Neurogenetics 10: 127-133, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19034540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19034540</a>] [<a href="https://doi.org/10.1007/s10048-008-0161-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19034540">Fichou et al. (2009)</a> concluded that disruption of the MeCP2_e1 isoform is sufficient to cause Rett syndrome, and that Rett syndrome can occur in the presence of a normal MeCP2_e2 isoform. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19034540" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0038 RETT SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs61749743 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61749743;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs61749743" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs61749743" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012620 OR RCV000506656 OR RCV001045878 OR RCV002362579" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012620, RCV000506656, RCV001045878, RCV002362579" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012620...</a>
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<p>In 1 of the original patients with Rett syndrome (RTT; <a href="/entry/312750">312750</a>) reported by <a href="#113" class="mim-tip-reference" title="Rett, A. <strong>Ueber ein eigenartiges hirnatrophisches Syndrom bei Hyperammoniamie in Kindesalter.</strong> Wien. Med. Wschr. 116: 723-738, 1966.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5300597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5300597</a>]" pmid="5300597">Rett (1966)</a>, <a href="#46" class="mim-tip-reference" title="Freilinger, M., Berndt, A., Haas, O. A. <strong>MECP2 mutation in one of Rett's original patients. (Letter)</strong> J. Med. Genet. 46: 647-648, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19724012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19724012</a>] [<a href="https://doi.org/10.1136/jmg.2008.063636" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19724012">Freilinger et al. (2009)</a> identified a 1-bp deletion (710delG) in exon 4 of the MECP2 gene, resulting in a frameshift and premature termination after amino acid 246. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19724012+5300597" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs587777421 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777421;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs587777421?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587777421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs587777421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000119842 OR RCV001507055 OR RCV001582589" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000119842, RCV001507055, RCV001582589" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000119842...</a>
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<p>In 2 brothers with autism (AUTSX3; <a href="/entry/300496">300496</a>), <a href="#153" class="mim-tip-reference" title="Yu, T. W., Chahrour, M. H., Coulter, M. E., Jiralerspong, S., Okamura-Ikeda, K., Ataman, B., Schmitz-Abe, K., Harmin, D. A., Adli, M., Malik, A. N., D'Gama, A. M., Lim, E. T., and 37 others. <strong>Using whole-exome sequencing to identify inherited causes of autism.</strong> Neuron 77: 259-273, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23352163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23352163</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23352163[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2012.11.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23352163">Yu et al. (2013)</a> identified a nonsense mutation in the MECP2 gene, glu483 to ter (E483X). The mutation was inherited from their unaffected mother. The mutation was predicted to result in removal of only the last 4 amino acids of the full-length protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23352163" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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Abuhatzira, L., Shemer, R., Razin, A.
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<strong>MeCP2 involvement in the regulation of neuronal alpha-tubulin production.</strong>
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Hum. Molec. Genet. 18: 1415-1423, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19174478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19174478</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19174478" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp048" target="_blank">Full Text</a>]
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Adegbola, A. A., Gonzales, M. L., Chess, A., LaSalle, J. M., Cox, G. F.
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<strong>A novel hypomorphic MECP2 point mutation is associated with a neuropsychiatric phenotype.</strong>
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Hum. Genet. 124: 615-623, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18989701/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18989701</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18989701" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00439-008-0585-6" target="_blank">Full Text</a>]
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Adler, D. A., Quaderi, N. A., Brown, S. D. M., Chapman, V. M., Moore, J., Tate, P., Disteche, C. M.
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<strong>The X-linked methylated DNA binding protein, Mecp2, is subject to X inactivation in the mouse.</strong>
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Mammalian Genome 6: 491-492, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8589515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8589515</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8589515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF00356163" target="_blank">Full Text</a>]
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Amano, K., Nomura, Y., Segawa, M., Yamakawa, K.
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<strong>Mutational analysis of the MECP2 gene in Japanese patients with Rett syndrome.</strong>
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J. Hum. Genet. 45: 231-236, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10944854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10944854</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10944854" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s100380070032" target="_blank">Full Text</a>]
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Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., Zoghbi, H. Y.
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<strong>Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.</strong>
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Nature Genet. 23: 185-188, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508514</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508514" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/13810" target="_blank">Full Text</a>]
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Archer, H. L., Whatley, S. D., Evans, J. C., Ravine, D., Huppke, P., Kerr, A., Bunyan, D., Kerr, B., Sweeney, E., Davies, S. J., Reardon, W., Horn, J., and 14 others.
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<strong>Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett syndrome patients. (Letter)</strong>
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J. Med. Genet. 43: 451-456, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16183801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16183801</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16183801[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16183801" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.2005.033464" target="_blank">Full Text</a>]
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Ashley-Koch, A. E., Carney, R. J., Wolpert, C. M., Cuccaro, M. L., Gilbert, J. R., Vance, J. M., Pericak-Vance, M. A.
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<strong>Screening for MECP2 mutations in females with autistic disorder. (Abstract)</strong>
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Am. J. Med. Genet. 105B: 632 only, 2001.
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Ballestar, E., Yusufzai, T. M., Wolffe, A. P.
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<strong>Effects of Rett syndrome mutations of the methyl-CpG binding domain of the transcriptional repressor MeCP2 on selectivity for association with methylated DNA.</strong>
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Biochemistry 39: 7100-7106, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10852707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10852707</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10852707" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1021/bi0001271" target="_blank">Full Text</a>]
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Balmer, D., Arredondo, J., Samaco, R. C., LaSalle, J. M.
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<strong>MECP2 mutations in Rett syndrome adversely affect lymphocyte growth, but do not affect imprinted gene expression in blood or brain.</strong>
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[<a href="https://doi.org/10.1007/s00439-002-0724-4" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2006.00604.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000304752.50773.ec" target="_blank">Full Text</a>]
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Belligni, E. F., Palmer, R. W., Hennekam, R. C. M.
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<strong>MECP2 duplication in a patient with congenital central hypoventilation.</strong>
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[<a href="https://doi.org/10.1002/ajmg.a.33311" target="_blank">Full Text</a>]
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<a id="Ben-Shachar2009" class="mim-anchor"></a>
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<div class="">
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<strong>Mouse models of MeCP2 disorders share gene expression changes in the cerebellum and hypothalamus.</strong>
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Hum. Molec. Genet. 18: 2431-2442, 2009.
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[<a href="https://doi.org/10.1093/hmg/ddp181" target="_blank">Full Text</a>]
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<a id="Beyer2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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<strong>Mutation analysis of the coding sequence of the MECP2 gene in infantile autism.</strong>
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Hum. Genet. 111: 305-309, 2002. Note: Erratum: Hum. Genet. 112: 437 only, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12384770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12384770</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12384770" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00439-002-0786-3" target="_blank">Full Text</a>]
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<a id="Bienvenu2000" class="mim-anchor"></a>
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<div class="">
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Bienvenu, T., Carrie, A., de Roux, N., Vinet, M.-C., Jonveaux, P., Couvert, P., Villard, L., Arzimanoglou, A., Beldjord, C., Fontes, M., Tardieu, M., Chelly, J.
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<strong>MECP2 mutations account for most cases of typical forms of Rett syndrome.</strong>
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Hum. Molec. Genet. 9: 1377-1384, 2000.
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[<a href="https://doi.org/10.1093/hmg/9.9.1377" target="_blank">Full Text</a>]
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<strong>A detailed analysis of the MECP2 gene: prevalence of recurrent mutations and gross DNA rearrangements in Rett syndrome patients.</strong>
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Hum. Genet. 108: 43-50, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11214906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11214906</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11214906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004390000422" target="_blank">Full Text</a>]
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<strong>X-chromosome inactivation ratios affect wild-type MeCP2 expression within mosaic Rett syndrome and Mecp2-/+ mouse brain.</strong>
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Hum. Molec. Genet. 13: 1275-1286, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15115765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15115765</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15115765" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddh142" target="_blank">Full Text</a>]
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<a id="Buchovecky2013" class="mim-anchor"></a>
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<div class="">
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Buchovecky, C. M., Turley, S. D., Brown, H. M., Kyle, S. M., McDonald, J. G., Liu, B., Pieper, A. A., Huang, W., Katz, D. M., Russell, D. W., Shendure, J., Justice, M. J.
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<strong>A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23892605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23892605</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23892605[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23892605" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.2714" target="_blank">Full Text</a>]
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<strong>Diagnostic testing for Rett syndrome by DHPLC and direct sequencing analysis of the MECP2 gene: identification of several novel mutations and polymorphisms.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11055898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11055898</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11055898[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11055898" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/316913" target="_blank">Full Text</a>]
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<a id="Caballero2005" class="mim-anchor"></a>
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<strong>MeCP2 in neurons: closing in on the causes of Rett syndrome.</strong>
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Hum. Molec. Genet. 14: R19-R26, 2005. Note: Erratum: Hum. Molec. Genet. 14: 2089 only, 2005.
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[<a href="https://doi.org/10.1093/hmg/ddi102" target="_blank">Full Text</a>]
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<strong>Identification of MeCP2 mutations in a series of females with autistic disorder.</strong>
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[<a href="https://doi.org/10.1016/s0887-8994(02)00624-0" target="_blank">Full Text</a>]
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<a id="Carvalho2011" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1038/ng.944" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp151" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1086446" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.20320" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5201911" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng1516" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.10633" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.56.11.1486" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng1491" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/9.9.1369" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M209923200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2004.023804" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/303078" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.10243" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng1327" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2007.049452" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/302690" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/10.10.1085" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1523/JNEUROSCI.1810-06.2006" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddi191" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11058114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11058114</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11058114[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11058114" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/nar/28.21.4172" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="155" class="mim-anchor"></a>
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<a id="Zhou2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhou, Z., Hong, E. J., Cohen, S., Zhao, W., Ho, H. H., Schmidt, L., Chen, W. G., Lin, Y., Savner, E., Griffith, E. C., Hu, L., Steen, J. A. J., Weitz, C. J., Greenberg, M. E.
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<strong>Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation.</strong>
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Neuron 52: 255-269, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17046689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17046689</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17046689[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17046689" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.neuron.2006.09.037" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 01/05/2021
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Ada Hamosh - updated : 02/22/2018<br>Matthew B. Gross - updated : 11/17/2017<br>Ada Hamosh - updated : 06/06/2017<br>Paul J. Converse - updated : 05/16/2017<br>Ada Hamosh - updated : 06/25/2015<br>Ada Hamosh - updated : 6/6/2014<br>Patricia A. Hartz - updated : 1/15/2014<br>Ada Hamosh - updated : 9/20/2013<br>Ada Hamosh - updated : 7/23/2012<br>Cassandra L. Kniffin - updated : 6/13/2012<br>Ada Hamosh - updated : 4/24/2012<br>Ada Hamosh - updated : 9/1/2011<br>Ada Hamosh - updated : 7/18/2011<br>Ada Hamosh - updated : 1/31/2011<br>Cassandra L. Kniffin - updated : 12/3/2010<br>Ada Hamosh - updated : 11/29/2010<br>Cassandra L. Kniffin - updated : 7/13/2010<br>George E. Tiller - updated : 3/30/2010<br>George E. Tiller - updated : 3/3/2010<br>Cassandra L. Kniffin - updated : 1/5/2010<br>George E. Tiller - updated : 11/25/2009<br>Cassandra L. Kniffin - updated : 10/16/2009<br>George E. Tiller - updated : 7/31/2009<br>Cassandra L. Kniffin - updated : 5/27/2009<br>Cassandra L. Kniffin - updated : 5/14/2009<br>Cassandra L. Kniffin - updated : 4/13/2009<br>Cassandra L. Kniffin - updated : 2/25/2009<br>Cassandra L. Kniffin - updated : 1/6/2009<br>George E. Tiller - updated : 11/21/2008<br>George E. Tiller - updated : 10/29/2008<br>Ada Hamosh - updated : 6/10/2008<br>George E. Tiller - updated : 4/25/2008<br>Cassandra L. Kniffin - updated : 3/6/2008<br>George E. Tiller - updated : 2/18/2008<br>George E. Tiller - updated : 2/7/2008<br>George E. Tiller - updated : 1/3/2008<br>George E. Tiller - updated : 11/8/2007<br>Patricia A. Hartz - updated : 10/16/2007<br>Cassandra L. Kniffin - updated : 9/18/2007<br>Victor A. McKusick - updated : 9/6/2007<br>Cassandra L. Kniffin - updated : 8/24/2007<br>Ada Hamosh - updated : 7/25/2007<br>George E. Tiller - updated : 6/13/2007<br>Cassandra L. Kniffin - updated : 4/27/2007<br>Ada Hamosh - updated : 4/17/2007<br>Cassandra L. Kniffin - updated : 1/4/2007<br>John Logan Black, III - updated : 8/4/2006<br>Victor A. McKusick - updated : 7/5/2006<br>Cassandra L. Kniffin - updated : 6/2/2006<br>Patricia A. Hartz - updated : 5/5/2006<br>Marla J. F. O'Neill - updated : 12/1/2005<br>Marla J. F. O'Neill - updated : 10/18/2005<br>Cassandra L. Kniffin - updated : 10/3/2005<br>George E. Tiller - updated : 9/30/2005<br>Patricia A. Hartz - updated : 9/21/2005<br>Victor A. McKusick - updated : 8/18/2005<br>Patricia A. Hartz - updated : 8/4/2005<br>Cassandra L. Kniffin - updated : 5/18/2005<br>Cassandra L. Kniffin - updated : 3/18/2005<br>Victor A. McKusick - updated : 3/8/2005<br>Marla J. F. O'Neill - updated : 1/28/2005<br>George E. Tiller - updated : 8/19/2004<br>Victor A. McKusick - updated : 7/2/2004<br>Victor A. McKusick - updated : 5/11/2004<br>Ada Hamosh - updated : 3/30/2004<br>Cassandra L. Kniffin - updated : 3/23/2004<br>Felicity Collins - updated : 12/10/2003<br>Ada Hamosh - updated : 12/3/2003<br>Cassandra L. Kniffin - updated : 11/10/2003<br>Cassandra L. Kniffin - reorganized : 11/7/2003<br>Cassandra L. Kniffin - updated : 10/23/2003<br>Victor A. McKusick - updated : 9/9/2003<br>Michael B. Petersen - updated : 6/16/2003<br>Michael B. Petersen - updated : 6/16/2003<br>Victor A. McKusick - updated : 6/11/2003<br>Cassandra L. Kniffin - updated : 1/28/2003<br>Victor A. McKusick - updated : 1/8/2003<br>Dawn Watkins-Chow - updated : 12/16/2002<br>Victor A. McKusick - updated : 11/13/2002<br>Victor A. McKusick - updated : 11/1/2002<br>Victor A. McKusick - updated : 9/19/2002<br>George E. Tiller - updated : 9/16/2002<br>Michael B. Petersen - updated : 9/10/2002<br>Michael B. Petersen - updated : 9/10/2002<br>Victor A. McKusick - updated : 8/27/2002<br>Victor A. McKusick - updated : 8/13/2002<br>Michael J. Wright - updated : 7/1/2002<br>Michael J. Wright - updated : 4/26/2002<br>Victor A. McKusick - updated : 4/12/2002<br>George E. Tiller - updated : 2/5/2002<br>Victor A. McKusick - updated : 1/17/2002<br>Michael B. Petersen - updated : 11/28/2001<br>Victor A. McKusick - updated : 11/7/2001<br>Michael B. Petersen - updated : 10/25/2001<br>George E. Tiller - updated : 10/11/2001<br>George E. Tiller - updated : 10/2/2001<br>Victor A. McKusick - updated : 9/20/2001<br>Victor A. McKusick - updated : 8/3/2001<br>Victor A. McKusick - updated : 6/13/2001<br>Stylianos E. Antonarakis - updated : 6/4/2001<br>Ada Hamosh - updated : 3/2/2001<br>Victor A. McKusick - updated : 1/31/2001<br>Victor A. McKusick - updated : 1/12/2001<br>Michael J. Wright - updated : 1/8/2001<br>Ada Hamosh - updated : 1/3/2001<br>Victor A. McKusick - updated : 12/13/2000<br>Victor A. McKusick - updated : 11/2/2000<br>Ada Hamosh - updated : 11/2/2000<br>Victor A. McKusick - updated : 10/20/2000<br>Victor A. McKusick - updated : 8/31/2000<br>Paul J. Converse - updated : 8/21/2000<br>George E. Tiller - updated : 8/8/2000<br>George E. Tiller - updated : 5/12/2000<br>Victor A. McKusick - updated : 12/20/1999<br>Victor A. McKusick - updated : 9/28/1999<br>Victor A. McKusick - updated : 9/14/1998<br>Victor A. McKusick - updated : 5/27/1998<br>Rebekah S. Rasooly - updated : 3/2/1998
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 1/29/1996
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<span class="mim-text-font">
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carol : 08/20/2021
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<div class="row collapse" id="mimCollapseEditHistory">
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carol : 08/19/2021<br>mgross : 01/05/2021<br>carol : 02/26/2018<br>carol : 02/23/2018<br>alopez : 02/22/2018<br>mgross : 11/17/2017<br>alopez : 06/06/2017<br>alopez : 06/06/2017<br>mgross : 05/16/2017<br>carol : 02/22/2017<br>carol : 02/01/2017<br>carol : 01/31/2017<br>joanna : 08/04/2016<br>alopez : 06/25/2015<br>mgross : 3/20/2015<br>alopez : 6/6/2014<br>alopez : 6/6/2014<br>mgross : 1/17/2014<br>mcolton : 1/15/2014<br>mcolton : 11/26/2013<br>alopez : 9/20/2013<br>carol : 9/6/2013<br>carol : 4/19/2013<br>alopez : 10/3/2012<br>alopez : 7/24/2012<br>terry : 7/23/2012<br>alopez : 6/19/2012<br>ckniffin : 6/13/2012<br>terry : 5/10/2012<br>alopez : 4/25/2012<br>terry : 4/24/2012<br>alopez : 9/6/2011<br>terry : 9/1/2011<br>alopez : 7/18/2011<br>carol : 7/6/2011<br>alopez : 2/4/2011<br>terry : 1/31/2011<br>carol : 1/21/2011<br>alopez : 1/10/2011<br>wwang : 12/3/2010<br>alopez : 12/1/2010<br>terry : 11/29/2010<br>wwang : 7/14/2010<br>ckniffin : 7/13/2010<br>wwang : 4/2/2010<br>terry : 3/30/2010<br>wwang : 3/12/2010<br>terry : 3/3/2010<br>wwang : 2/2/2010<br>wwang : 1/5/2010<br>ckniffin : 1/5/2010<br>wwang : 1/5/2010<br>terry : 11/25/2009<br>wwang : 11/6/2009<br>ckniffin : 10/16/2009<br>wwang : 9/1/2009<br>wwang : 8/14/2009<br>terry : 7/31/2009<br>wwang : 6/8/2009<br>ckniffin : 5/27/2009<br>wwang : 5/27/2009<br>ckniffin : 5/14/2009<br>wwang : 4/29/2009<br>ckniffin : 4/13/2009<br>wwang : 3/6/2009<br>ckniffin : 2/25/2009<br>wwang : 1/13/2009<br>ckniffin : 1/6/2009<br>wwang : 11/21/2008<br>wwang : 11/18/2008<br>wwang : 10/29/2008<br>terry : 9/26/2008<br>ckniffin : 7/10/2008<br>alopez : 6/12/2008<br>terry : 6/10/2008<br>wwang : 4/29/2008<br>terry : 4/25/2008<br>wwang : 4/10/2008<br>ckniffin : 3/6/2008<br>wwang : 2/18/2008<br>wwang : 2/13/2008<br>terry : 2/7/2008<br>wwang : 1/11/2008<br>terry : 1/3/2008<br>wwang : 11/30/2007<br>terry : 11/8/2007<br>mgross : 10/18/2007<br>terry : 10/16/2007<br>wwang : 9/18/2007<br>ckniffin : 9/18/2007<br>carol : 9/7/2007<br>carol : 9/7/2007<br>ckniffin : 9/7/2007<br>alopez : 9/6/2007<br>carol : 9/5/2007<br>ckniffin : 8/24/2007<br>alopez : 7/30/2007<br>terry : 7/25/2007<br>wwang : 6/15/2007<br>terry : 6/13/2007<br>wwang : 5/9/2007<br>ckniffin : 4/27/2007<br>alopez : 4/19/2007<br>terry : 4/17/2007<br>wwang : 1/26/2007<br>ckniffin : 1/4/2007<br>carol : 11/27/2006<br>carol : 8/29/2006<br>terry : 8/4/2006<br>alopez : 7/7/2006<br>terry : 7/5/2006<br>wwang : 6/16/2006<br>ckniffin : 6/13/2006<br>wwang : 6/5/2006<br>ckniffin : 6/2/2006<br>wwang : 5/11/2006<br>terry : 5/5/2006<br>terry : 12/20/2005<br>wwang : 12/1/2005<br>wwang : 10/18/2005<br>wwang : 10/18/2005<br>ckniffin : 10/3/2005<br>alopez : 9/30/2005<br>wwang : 9/26/2005<br>wwang : 9/21/2005<br>alopez : 8/24/2005<br>terry : 8/18/2005<br>mgross : 8/4/2005<br>tkritzer : 5/19/2005<br>ckniffin : 5/18/2005<br>tkritzer : 3/28/2005<br>ckniffin : 3/18/2005<br>terry : 3/16/2005<br>wwang : 3/14/2005<br>wwang : 3/10/2005<br>terry : 3/8/2005<br>carol : 2/3/2005<br>terry : 1/28/2005<br>alopez : 8/19/2004<br>tkritzer : 7/6/2004<br>terry : 7/2/2004<br>terry : 6/2/2004<br>tkritzer : 6/1/2004<br>ckniffin : 5/18/2004<br>carol : 5/17/2004<br>ckniffin : 5/17/2004<br>terry : 5/11/2004<br>alopez : 4/29/2004<br>alopez : 4/2/2004<br>alopez : 3/30/2004<br>terry : 3/30/2004<br>tkritzer : 3/23/2004<br>ckniffin : 3/23/2004<br>joanna : 3/17/2004<br>carol : 12/10/2003<br>alopez : 12/9/2003<br>alopez : 12/9/2003<br>terry : 12/3/2003<br>tkritzer : 11/18/2003<br>carol : 11/18/2003<br>ckniffin : 11/10/2003<br>carol : 11/7/2003<br>ckniffin : 11/7/2003<br>carol : 11/7/2003<br>ckniffin : 10/23/2003<br>tkritzer : 9/11/2003<br>tkritzer : 9/9/2003<br>cwells : 6/16/2003<br>cwells : 6/16/2003<br>carol : 6/12/2003<br>terry : 6/11/2003<br>mgross : 5/12/2003<br>terry : 2/26/2003<br>tkritzer : 2/3/2003<br>ckniffin : 1/28/2003<br>tkritzer : 1/16/2003<br>tkritzer : 1/9/2003<br>tkritzer : 1/9/2003<br>terry : 1/8/2003<br>carol : 12/19/2002<br>tkritzer : 12/16/2002<br>tkritzer : 12/16/2002<br>tkritzer : 11/22/2002<br>tkritzer : 11/14/2002<br>terry : 11/13/2002<br>tkritzer : 11/4/2002<br>terry : 11/1/2002<br>tkritzer : 9/19/2002<br>tkritzer : 9/19/2002<br>cwells : 9/16/2002<br>cwells : 9/10/2002<br>cwells : 9/10/2002<br>tkritzer : 9/10/2002<br>tkritzer : 8/29/2002<br>terry : 8/27/2002<br>tkritzer : 8/19/2002<br>tkritzer : 8/15/2002<br>terry : 8/13/2002<br>terry : 8/13/2002<br>alopez : 7/2/2002<br>terry : 7/1/2002<br>alopez : 4/26/2002<br>alopez : 4/26/2002<br>cwells : 4/19/2002<br>terry : 4/12/2002<br>cwells : 2/13/2002<br>cwells : 2/5/2002<br>carol : 1/31/2002<br>mcapotos : 1/22/2002<br>terry : 1/17/2002<br>mcapotos : 12/21/2001<br>cwells : 12/7/2001<br>cwells : 12/5/2001<br>cwells : 11/28/2001<br>carol : 11/12/2001<br>terry : 11/7/2001<br>cwells : 10/26/2001<br>cwells : 10/25/2001<br>cwells : 10/25/2001<br>cwells : 10/15/2001<br>cwells : 10/11/2001<br>cwells : 10/9/2001<br>cwells : 10/2/2001<br>mcapotos : 10/2/2001<br>mcapotos : 9/25/2001<br>mcapotos : 9/24/2001<br>terry : 9/20/2001<br>carol : 8/13/2001<br>cwells : 8/7/2001<br>terry : 8/3/2001<br>cwells : 6/19/2001<br>cwells : 6/14/2001<br>terry : 6/13/2001<br>mgross : 6/4/2001<br>alopez : 3/2/2001<br>mcapotos : 2/6/2001<br>mcapotos : 2/2/2001<br>terry : 1/31/2001<br>cwells : 1/18/2001<br>cwells : 1/18/2001<br>terry : 1/12/2001<br>alopez : 1/8/2001<br>carol : 1/7/2001<br>terry : 1/3/2001<br>carol : 12/14/2000<br>terry : 12/13/2000<br>terry : 12/4/2000<br>carol : 11/6/2000<br>mcapotos : 11/6/2000<br>carol : 11/3/2000<br>terry : 11/2/2000<br>mgross : 11/2/2000<br>carol : 11/2/2000<br>mcapotos : 10/31/2000<br>terry : 10/20/2000<br>terry : 8/31/2000<br>mgross : 8/21/2000<br>mgross : 8/21/2000<br>alopez : 8/8/2000<br>alopez : 5/12/2000<br>carol : 12/27/1999<br>terry : 12/20/1999<br>alopez : 9/30/1999<br>terry : 9/28/1999<br>psherman : 2/23/1999<br>alopez : 9/15/1998<br>alopez : 9/15/1998<br>terry : 9/14/1998<br>alopez : 6/1/1998<br>terry : 5/27/1998<br>carol : 3/2/1998<br>mark : 7/7/1997<br>mark : 9/11/1996<br>terry : 9/6/1996<br>mark : 1/29/1996
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<strong>*</strong> 300005
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<h3>
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<span class="mim-font">
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METHYL-CpG-BINDING PROTEIN 2; MECP2
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: MECP2</em></strong>
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<strong>SNOMEDCT:</strong> 68618008, 702356009, 702816000, 718393002, 771303004;
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<strong>ICD10CM:</strong> F84.2;
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: Xq28
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Genomic coordinates <span class="small">(GRCh38)</span> : X:154,021,573-154,097,717 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="7">
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<span class="mim-font">
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Xq28
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</span>
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</td>
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<td>
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<span class="mim-font">
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{Autism susceptibility, X-linked 3}
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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300496
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</span>
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
X-linked
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|
</span>
|
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</td>
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|
<td>
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|
<span class="mim-font">
|
|
3
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|
</span>
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</td>
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</tr>
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Encephalopathy, neonatal severe
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</span>
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
300673
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked recessive
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|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
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</tr>
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<tr>
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<td>
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|
<span class="mim-font">
|
|
Intellectual developmental disorder, X-linked syndromic 13
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
300055
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Intellectual developmental disorder, X-linked syndromic, Lubs type
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
300260
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
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</tr>
|
|
|
|
|
|
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<tr>
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<td>
|
|
<span class="mim-font">
|
|
Rett syndrome
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
312750
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Rett syndrome, atypical
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
312750
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Rett syndrome, preserved speech variant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
312750
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
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|
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</tbody>
|
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</table>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
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</h4>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<span class="mim-text-font">
|
|
<p>MECP2, which binds methylated CpGs, is a chromatin-associated protein that can both activate and repress transcription. It is required for maturation of neurons and is developmentally regulated (summary by Swanberg et al., 2009). </p>
|
|
</span>
|
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<div>
|
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<br />
|
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</div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
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|
|
<span class="mim-text-font">
|
|
<p>Lewis et al. (1992) identified and cloned Mecp2 from a rat brain cDNA library. The deduced 492-amino acid protein has a molecular mass of 53 kD and is rich in basic amino acids and potential phosphorylation sites. Immunofluorescent staining showed that the distribution of Mecp2 along chromosomes parallels that of methyl-CpG. In the mouse, Mecp2 is concentrated in pericentromeric heterochromatin, which contains about 40% of all genomic 5-methylcytosine. Unlike methyl-CpG-binding protein-1 (MBD1; 156535), MECP2 is able to bind a single methyl-CpG pair. Nan et al. (1993) cloned the rat Mecp2 gene and defined the methyl-CpG-binding domain (MBD). The MBD is 85 amino acids long and binds exclusively to DNA that contains one or more symmetrically methylated CpGs. </p><p>Using a rat MECP2 probe to screen a human skeletal muscle cDNA library, D'Esposito et al. (1996) isolated the human homolog, which encodes a deduced 485-amino acid protein. The human and rat proteins share 93% overall sequence identity and 100% identity in the MBD region. Northern blot analysis detected a 1.8-kb transcript in all tissues analyzed, with the highest level of expression in heart and skeletal muscle. </p><p>Mnatzakanian et al. (2004) identified a theretofore unknown isoform of MECP2 that they called MECP2B. They referred to the known isoform as MECP2A, which has a translation start site in exon 2 and uses full-length exons 3 and 4 to yield a 486-residue protein. In contrast, the MECP2B transcript uses exon 1 of MECP2, skips exon 2, and then uses full-length exons 3 and 4 to yield a 498-residue protein. Thus, the 2 isoforms differ at the N terminus. MECP2B is expressed in all tissues, including fetal and adult brain and brain subregions. In adult human brain, MECP2B expression is 10 times higher than that of MECP2A. MECP2A is expressed more abundantly in placenta, liver, and skeletal muscle. The MECP2A and MECP2B (or MECP2-beta) isoforms are also known, respectively, as MeCP2_e2 (encoded by exons 2, 3, and 4) and MeCP2_e1 (encoded by exons 1, 3, and 4) (Fichou et al., 2009). </p><p>In mice, Itoh et al. (2012) demonstrated a role for the Mecp2_e2 isoform in placenta development and embryo viability (see ANIMAL MODEL). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Reichwald et al. (2000) determined that the human MECP2 gene has 4 exons. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Quaderi et al. (1994) mapped the mouse Mecp2 gene to a 40-kb interval between L1cam and Rsvp in the central span of the mouse X chromosome, close to the microsatellite marker DXMit1. This region is known to be syntenically equivalent to human Xq28, and, with the exception of F8A, locus order is conserved between the 2 species. Therefore, D'Esposito et al. (1996) expected the human MECP2 gene to be located between L1CAM (308840) and the RCP/GCP color vision loci. A filter containing all YACs localized between these 2 points was hybridized with the rat Mecp2 probe, and 3 overlapping YACs were positive for MECP2, placing MECP2 about 70 kb centromeric to the RCP/GCP color vision cluster. By fluorescence in situ hybridization, Vilain et al. (1996) confirmed the Xq28 map position of MECP2. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Biochemical Features</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Solution Structure</em></strong></p><p>
|
|
Ohki et al. (2001) reported the solution structure of the conserved MBD of human MBD1 bound to methylated DNA. DNA binding causes a loop in MBD1 to fold into a major and novel DNA-binding interface. Recognition of the methyl groups and CG sequence at the methylation site is due to 5 highly conserved residues that form a hydrophobic patch. The authors concluded that the structure indicates how the MBD may access nucleosomal DNA without encountering steric interference from core histones. </p><p><strong><em>Electron Microscopy</em></strong></p><p>
|
|
Georgel et al. (2003) used electron cryomicroscopy and electron microscope tomography to characterize complexes formed between recombinant human MECP2 and 12-mer nucleasomal arrays. At molar ratios near 1 MECP2 per nucleosome, binding of MECP2 converted extended nucleosomal arrays into extensively compacted 60S ellipsoidal structures. At molar ratios at or above 1 MECP2 per nucleosome, the 60S particles assembled into morphologically defined oligomeric suprastructures. The ability of MECP2 to mediate chromatin compaction did not require its MBD. Georgel et al. (2003) concluded that MECP2 is a chromatin-condensing protein that mediates assembly of novel secondary chromatin structures. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
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</h4>
|
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</div>
|
|
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<span class="mim-text-font">
|
|
<p>Inactivation of X-linked genes is usually associated with methylation of the CpG island at the 5-prime end of the gene. Proteins that recognize and bind to methylated bases in DNA include the methylated DNA-binding protein MECP2. To determine whether this gene is expressed from the inactive X chromosome, Adler et al. (1995) used an X/autosome translocation system in the mouse in which expression from the Mecp2 allele on the inactive X chromosome could be assayed. Results from these experiments indicated that Mecp2 is subject to X inactivation in mouse. D'Esposito et al. (1996) demonstrated that the MECP2 gene in humans is subject to X inactivation. </p><p>To find out whether the heterochromatic localization of MECP2 depends on DNA methylation, Nan et al. (1996) transiently expressed rat Mecp2-LacZ fusion proteins in cultured cells. Intact protein was targeted to heterochromatin in wildtype cells but was insufficiently localized in mutant cells with low levels of genomic DNA methylation. Deletions within Mecp2 showed that localization to heterochromatin required the 85-amino acid methyl-CpG binding domain but not the remainder of the protein. Thus, Mecp2 is a methyl-CpG-binding protein in vivo and is likely to be a major mediator of downstream consequences of DNA methylation. </p><p>MECP2 is an abundant chromosomal protein that binds specifically to methylated DNA in vitro and depends upon methyl-CpG for its chromosomal distribution in vivo. To assess its functional significance, Tate et al. (1996) mutated the X-linked gene in male mouse embryonic stem (ES) cells using a promoterless gene-targeting construct containing a lacZ reporter gene. Mutant ES cells lacking MECP2 grew with the same vigor as the parental line and were capable of considerable differentiation. Chimeric embryos derived from several independent mutant lines, however, exhibited development defects with a severity that was positively correlated with the distribution of mutant cells. The results demonstrated to the authors that MECP2, like DNA methyltransferase (DNMT1; 126375), is dispensable in stem cells but is essential for embryonic development. </p><p>Nan et al. (1997) found that native and recombinant rat Mecp2 repressed transcription in vitro from methylated promoters but did not repress nonmethylated promoters. Moreover, Mecp2 was able to displace histone H1 (HIF1; 142709) from preassembled chromatin that contains methyl-CpG. These properties, together with the abundance of Mecp2 and the high frequency of its 2-bp binding site, suggested a role as a global transcriptional repressor in vertebrate genomes. Nan et al. (1998) studied the mechanism of repression by Mecp2. Mecp2 binds tightly to chromosomes in a methylation-dependent manner. It contains a transcriptional-repression domain (TRD) that can function at a distance in vitro and in vivo. Nan et al. (1998) showed that a region of Mecp2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases (see HDAC1; 601241). Transcriptional repression in vivo is relieved by the deacetylase inhibitor trichostatin A, indicating that deacetylation of histones (and/or of other proteins) is an essential component of this repression mechanism. The data suggested that 2 global mechanisms of gene regulation, DNA methylation and histone deacetylation, can be linked by Mecp2. In Xenopus oocytes, DNA methylation dominantly silences transcription through the assembly of a repressive nucleosomal array. Jones et al. (1998) found that silencing conferred by Mecp2 and methylated DNA can be relieved by inhibition of histone deacetylase, facilitating the remodeling of chromatin and transcriptional activation. These results established a direct causal relationship between DNA methylation-dependent transcriptional silencing and the modification of chromatin. </p><p>Shahbazian et al. (2002) investigated the spatial and temporal distribution of the Mecp2 protein during mouse and human development. By Western blot analysis, they found that Mecp2 in the adult mouse is high in the brain, lung, and spleen, lower in heart and kidney, and barely detectable in liver, stomach, and small intestine. There was no obvious correlation between protein levels and RNA levels, suggesting that translation may be posttranscriptionally regulated by tissue-specific factors. The timing of Mecp2 expression in mouse and human correlated with the maturation of the central nervous system, with the ontogenetically older structures such as the spinal cord and brainstem becoming positive before newer structures such as the hippocampus and cerebral cortex. In the cortex, Mecp2 first appeared in the Cajal-Retzius cells, then in the neurons of the deeper, more mature cortical layers, and finally in the neurons of the more superficial layers. The Mecp2 protein was eventually present in a majority of neurons but was absent from glial cells. Shahbazian et al. (2002) suggested that Mecp2 may become abundant only once a neuron has reached a certain degree of maturity. </p><p>Chen et al. (2003) found that MECP2 binds selectively to BDNF (113505) promoter III and functions to repress expression of the BDNF gene. Membrane depolarization triggers the calcium-dependent phosphorylation and release of MECP2 from BDNF promoter III, thereby facilitating transcription. Chen et al. (2003) concluded that MECP2 plays a key role in the control of neuronal activity-dependent gene regulation and that the deregulation of this process may underlie the pathology of Rett syndrome (RTT; 312750). </p><p>Martinowich et al. (2003) reported that increased synthesis of BDNF in mouse neurons after depolarization correlates with a decrease in CpG methylation within the regulatory region of the BDNF gene. Moreover, increased BDNF transcription involves dissociation of the MECP2-histone deacetylase-Sin3A (607776) repression complex from its promoter. Martinowich et al. (2003) concluded that DNA methylation-related chromatin remodeling is important for activity-dependent gene regulation that may be critical for neural plasticity. Martinowich et al. (2003) proposed a model in which DNA methylation and its related chromatin remodeling play critical roles in regulating gene transcription response to neuronal activity. CpG methylation at any critical site may increase the likelihood of MECP2 binding, which can recruit histone deacetylases and the H3-K9 methyltransferase to mediate inactive chromatin remodeling, or may directly induce chromatin compaction to repress gene expression. </p><p>In Xenopus embryos, Stancheva et al. (2003) found that Mecp2 with the R168X (300005.0020) truncation was unable to interact with the Smrt (NCOR2; 600848) complex or fully activate Hairy2a, a a Notch-regulated neuronal repressor, during primary neurogenesis. This disruption of Mecp2 activity resulted in abnormal patterning of primary neurons during neuronal differentiation. </p><p>By expressing rodent cDNAs in human embryonic kidney cells, Kimura and Shiota (2003) showed that Dnmt1 interacted directly with Mecp2. Dnmt1 formed complexes with HDACs as well as with Mecp2, but Mecp2-interacting Dnmt1 did not bind Hdac1. Mecp2 could form complexes with hemimethylated and fully methylated DNA. Immunoprecipitated Mecp2 complexes showed DNA methyltransferase activity to hemimethylated DNA. Kimura and Shiota (2003) concluded that DNMT1 associates with MECP2 in order to perform maintenance methylation during cell division. </p><p>Harikrishnan et al. (2005) found that BRM (SMARCA2; 600014) associated with MECP2 in mouse fibroblasts and human T-lymphoblastic leukemia cells, and the association was functionally linked with repression. Promoter methylation specified the recruitment of MECP2 and BRM, and inhibition of methylation caused their release. The MECP2-BRM corepressor complex was directly recruited to the FMR1 gene, and somatic knockdown in fragile X cells alleviated the repression. Harikrishnan et al. (2005) concluded that both MECP2 and components of the SWI/SNF complex are involved in gene repression. </p><p>Klose et al. (2005) found that genomic sites occupied by MECP2 and MBD2 (603547) were largely mutually exclusive. MBD2 was able to colonize sites vacated by MECP2 depletion, but the reverse was not true. Artificial selection of MECP2-binding sites in vitro demonstrated that MECP2 required an A/T run of 4 or more base pairs adjacent to the methyl-CpG for efficient DNA binding. Klose et al. (2005) concluded that methyl-CpG is necessary, but not sufficient, for MECP2 binding. </p><p>Nan et al. (2007) found that MECP2 interacts with ATRX (300032), a DNA helicase/ATPase that is mutated in the alpha-thalassemia/mental retardation syndrome (301040). Studies in cultured mouse cells showed that MECP2 targeted the C-terminal helicase domain of ATRX to heterochromatic foci. The heterochromatic localization of ATRX was disturbed in neurons from Mecp2-null mice. The findings suggested that disruption of MECP2-ATRX interaction leads to pathologic changes that contribute to mental retardation. </p><p>Schule et al. (2007) found that lymphoblastoid cells and brain cells from RTT patients with MECP2 mutations showed normal imprinting of the imprinted genes PEG3 (601483) and PEG10 (609810), indicating that the MECP2 protein is not necessary for normal imprinting to occur. </p><p>In rodent brain tissue, Deng et al. (2007) identified the FXYD1 (602359) promoter as an endogenous target of MECP2, which can cause transcriptional regulation of FXYD1. Transgenic Mecp2-null mice had increased Fxyd1 mRNA and protein levels in the frontal cortex, similar to that observed in patients with Rett syndrome. Increased Fxyd1 expression in Mecp2-null mice was associated with decreased Na,K-ATPase activity in the frontal cortex. In cultured mouse neurons, overexpression of Fxyd1 was associated with decreased neuronal dendritic tree and spine formation compared to controls, findings that have been observed in Rett syndrome. Overall, the results suggested that derepression of FXYD1, resulting from inactivation of MECP2, may contribute to the neuropathogenesis of Rett syndrome. </p><p>Chahrour et al. (2008) examined gene expression patterns in the hypothalamus of mice that either lack or overexpress MECP2. In both models, MECP2 dysfunction induced changes in the expression levels of thousands of genes, but expectedly, the majority of genes (about 85%) appeared to be activated by MECP2. Chahrour et al. (2008) then selected 6 genes, SST (182450), OPRK1 (165196), MEF2C (600662), GAMT (601240), GPRIN1 (611239), and A2BP1 (605104), and confirmed that MECP2 binds to their promoters. Furthermore, Chahrour et al. (2008) showed that MECP2 associates with the transcriptional activator CREB1 (123810) at the promoter of an activated target but not a repressed target. Chahrour et al. (2008) concluded that their study suggested that MECP2 regulates the expression of a wide range of genes in the hypothalamus and that it can function as both an activator and a repressor of transcription. </p><p>Swanberg et al. (2009) showed by chromatin immunoprecipitation analysis that EGR2 (129010) bound to the MECP2 promoter and that MeCP2 bound to the intron 1 enhancer region of EGR2. Reduction in EGR2 and MeCP2 levels in cultured human neuroblastoma cells by RNAi reciprocally reduced expression of both EGR2 and MECP2 and their protein products. Mecp2-deficient mouse cortex samples showed significantly reduced EGR2 by quantitative immunofluorescence. Furthermore, MeCP2 and EGR2 showed coordinately increased levels during postnatal development of both mouse and human cortex. In contrast to age-matched controls, Rett and autism (209850) postmortem cortex samples showed significant reduction in EGR2. Swanberg et al. (2009) proposed a role of dysregulation of an activity-dependent EGR2/MeCP2 pathway in Rett syndrome and autism. </p><p>Abuhatzira et al. (2009) conducted expression analysis of cytoskeleton-related genes in brain tissue from RTT and AS patients. Striking examples of genes with reduced expression were TUBA1B (602530) and TUBA3 (TUBA1A; 602529) that encode the ubiquitous alpha-tubulin and the neuronal specific alpha-tubulin, respectively. In accordance with downregulation of these genes, there was a reduction in the level of the corresponding protein product-tyrosinated alpha-tubulin. Low levels of alpha-tubulin and deteriorated cell morphology were also observed in Mecp2(-/y) mouse embryonic fibroblast cells. The effects of MeCP2 deficiency in these cells were completely reversed by introducing and expressing the human MECP2 gene. Abuhatzira et al. (2009) proposed that MECP2 is involved in the regulation of neuronal alpha-tubulin. </p><p>Muotri et al. (2010) showed that L1 neuronal transcription and retrotransposition in rodents are increased in the absence of Mecp2. Using neuronal progenitor cells derived from human induced pluripotent stem cells and human tissues, they revealed that patients with Rett syndrome, carrying MeCP2 mutations, have increased susceptibility for L1 retrotransposition. Muotri et al. (2010) concluded that L1 retrotransposition can be controlled in a tissue-specific manner and that disease-related genetic mutations can influence the frequency of neuronal L1 retrotransposition. </p><p>Forlani et al. (2010) demonstrated that MeCP2 interacts in vitro and in vivo with YY1 (600013). Forlani et al. (2010) showed that MeCP2 cooperates with YY1 in repressing the ANT1 (103220) gene, encoding a mitochondrial adenine nucleotide translocase. Importantly, ANT1 mRNA levels are increased in human and mouse cell lines devoid of MeCP2, in Rett patient fibroblast, and in the brain of MeCP2-null mice. Forlani et al. (2010) further demonstrated that ANT1 protein levels are upregulated in MeCP2-null mice. </p><p>Using phosphotryptic mapping, Ebert et al. (2013) identified 3 sites (S86, S274, and T308) of activity-dependent MeCP2 phosphorylation. Phosphorylation of these sites is differentially induced by neuronal activity, brain-derived neurotrophic factor (BDNF; 113505), or agents that elevate the intracellular level of cAMP, indicating that MeCP2 may function as an epigenetic regulator of gene expression that integrates diverse signals from the environment. Ebert et al. (2013) showed that the phosphorylation of T308 blocks the interaction of the repressor domain of MeCP2 with the nuclear receptor corepressor (NCoR) complex (see 600849) and suppresses the ability of MeCP2 to repress transcription. In knockin mice bearing the common human RTT missense mutation R306C (300005.0016), neuronal activity failed to induce MeCP2 T308 phosphorylation, suggesting that the loss of T308 phosphorylation might contribute to RTT. Consistent with this possibility, the mutation of MeCP2 T308A in mice led to a decrease in the induction of a subset of activity-regulated genes and to RTT-like symptoms. Ebert et al. (2013) concluded that the activity-dependent phosphorylation of MeCP2 at T308 regulates the interaction of MeCP2 with the NCoR complex, and that RTT in humans may be due, in part, to the loss of activity-dependent MeCP2 T308 phosphorylation and a disruption of the phosphorylation-regulated interaction of MeCP2 with the NCoR complex. </p><p>Using mouse and cellular models of Huntington disease (HD; 143100), McFarland et al. (2014) showed that mutant Htt (613004) protein interacted directly with Mecp2. Htt-Mecp2 interactions were enhanced in the presence of the expanded polyglutamine tract and were stronger in nucleus compared with cytoplasm. Binding of Mecp2 to the promoter of Bdnf increased in the presence of mutant Htt. Decreasing Mecp2 expression through small interfering RNA treatment in cells expressing mutant Htt increased Bdnf levels, suggesting that MECP2 downregulates BDNF expression in HD. McFarland et al. (2014) proposed that aberrant interactions between HTT and MECP2 contribute to transcriptional dysregulation in HD. </p><p>By expression profiling of discrete neuronal subtypes from Mecp2-knockout mice, Sugino et al. (2014) found that loss of Mecp2 primarily resulted in misregulation of genes involved in neuronal connectivity and communication. Genes upregulated were biased toward longer genes, whereas downregulated genes showed no such bias, suggesting that MECP2 selectively represses long genes. Since genes involved in neuronal connectivity and communication are enriched among longer genes, the authors proposed that their misregulation following loss of MECP2 suggests a possible etiology for altered circuit function in Rett syndrome. </p><p>By identifying a genomewide length-dependent increase in gene expression in Mecp2-mutant mouse models and human RTT brains, Gabel et al. (2015) presented evidence that MECP2 represses gene expression by binding to methylated CA sites within long genes, and that in neurons lacking MECP2, decreasing the expression of long genes attenuates RTT-associated cellular deficits. In addition, the authors found that long genes as a population are enriched for neuronal functions and are selectively expressed in the brain. Gabel et al. (2015) concluded that these findings suggested that mutations in MECP2 may cause neurologic dysfunction by specifically disrupting long gene expression in the brain. </p><p>Tillotson et al. (2017) tested the hypothesis that the single dominant function of MeCP2 is to physically connect DNA with the NCoR/SMRT complex, by removing almost all amino acid sequences except the methyl-CpG binding and NCoR/SMRT interaction domains. Tillotson et al. (2017) found that mice expressing truncated MeCP2 lacking both the N- and C-terminal regions (approximately half of the native protein) are phenotypically near-normal, and those expressing a minimal MeCP2 additionally lacking a central domain survive for over 1 year with only mild symptoms. This minimal protein was able to prevent or reverse neurologic symptoms when introduced into MeCP2-deficient mice by genetic activation or virus-mediated delivery to the brain. Tillotson et al. (2017) concluded that despite evolutionary conservation of the entire MeCP2 protein sequence, the DNA and corepressor binding domains alone are sufficient to avoid Rett syndrome-like defects and may therefore have therapeutic utility. </p><p>Li et al. (2020) showed that mouse Mecp2 was a dynamic component of heterochromatin condensates in cells and was stimulated by DNA to form liquid-like condensates. Several domains of Mecp2 contributed to formation of condensates, and mutations in human MECP2 associated with Rett syndrome disrupted the ability of MECP2 to form condensates. Condensates formed by Mecp2 selectively incorporated and concentrated heterochromatin cofactors rather than components of euchromatic transcriptionally active condensates. Li et al. (2020) proposed that MECP2 enhances separation of heterochromatin and euchromatin through its condensate partitioning properties, and that disruption of condensates may be a consequence of MECP2 mutations that cause Rett syndrome. </p>
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<p>Caballero and Hendrich (2005) provided a review of the role of MECP2 in the developing brain, the targets of MECP2-mediated repression, and the possible effect of misexpressed gene targets leading to clinical manifestations of RTT. </p><p><strong><em>Rett Syndrome</em></strong></p><p>
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Rett syndrome (RTT; 312750) is a progressive neurologic developmental disorder and one of the most common causes of mental retardation in females. Because RTT occurs almost exclusively in females, it had been proposed that RTT is caused by an X-linked dominant mutation with lethality in hemizygous males. Using a systematic mutation analysis of genes located in the Xq28 region containing the locus for Rett syndrome, Amir et al. (1999) identified mutations in the MECP2 gene as the cause of some cases of RTT. In 5 of 21 sporadic patients with RTT, Amir et al. (1999) found 3 de novo missense mutations in the region encoding the highly conserved methyl-binding domain of the MECP2 gene (300005.0001, 300005.0002, 300005.0007), as well as a de novo frameshift and a de novo nonsense mutation (300005.0021), both of which disrupted the transcription repression domain. Among 8 cases of familial Rett syndrome, Amir et al. (1999) found segregation of an additional missense mutation (300005.0008) in 1 family with 2 affected half sisters. The mutation was not detected in their obligate carrier mother, suggesting that the mother was a germline mosaic for this mutation. The authors suggested that the findings point to abnormal epigenetic regulation as a mechanism underlying the pathogenesis of Rett syndrome. </p><p>Wan et al. (1999) reviewed the mutations identified by Amir et al. (1999) and added 5 additional mutations (see, e.g., 300005.0003, 300005.0020). Of these, 5 were missense mutations, 5 were protein-truncating mutations, and 1 was a variant type of mutation. They found that missense mutations causing Rett syndrome were de novo and affected conserved domains of MECP2. All of the nucleotide substitutions involved C-T transitions at CpG hotspots. They presented evidence that some males with RTT-causing MECP2 mutations may survive to birth, and female heterozygotes with favorably skewed X-inactivation patterns may have little or no involvement. </p><p>Cheadle et al. (2000) identified mutations in 44 of 55 (80%) unrelated classic sporadic and familial RTT patients (see, e.g., 300005.0004), but in only 1 of 5 (20%) sporadic cases with suggestive, but nondiagnostic features of RTT. Twenty-one different mutations were identified (12 missense, 4 nonsense, and 5 frameshift mutations); 14 of these were novel. All missense mutations were located either in the methyl-CpG-binding domain or in the transcription repression domain. Nine recurrent mutations were characterized in a total of 33 unrelated cases (73% of all cases with MECP2 mutations). Significantly milder disease was noted in patients carrying missense mutations as compared with those with truncating mutations (P = 0.0023), and milder disease was associated with late as compared with early truncating mutations (P = 0.0190). Bienvenu et al. (2000) identified 30 mutations among 46 RTT patients, including 12 novel mutations (11 in exon 3 and 1 in exon 2). Mutations such as R270X (300005.0005) and frameshift deletions in a (CCACC)n-rich region were found with multiple recurrences; most of the mutations were de novo. Although mutations in noncoding regions could not be excluded for 35% of their cases, the authors proposed that a putative second X-linked gene may exist. Huppke et al. (2000) found mutations in 24 of 31 RTT patients; in at least 20 patients the mutation was de novo. Confirming 2 earlier studies, most mutations were truncating, and only a few were missense mutations. Several females carrying the same mutation displayed different phenotypes, suggesting that factors other than the type or position of mutations influence the severity of RTT. In 19 of 26 Japanese patients with sporadic Rett syndrome, Amano et al. (2000) identified 12 different mutations in the MECP2 gene, 8 of which were novel. </p><p>De Bona et al. (2000) explored the spectrum of mutations affecting the MECP2 gene in a group of 25 classic Rett syndrome girls and in 3 patients with the preserved speech variant (PVS) of Rett syndrome. They noted 2 hotspots: R270X (300005.0005) and R294X (300005.0011). Among the preserved speech variants, 2 patients carried deletions of 41 bp (300005.0012) and 44 bp (300005.0014), respectively, which were strikingly similar to deletions observed in classic Rett syndrome. Thus, the allelism of the variant form to the classic form was established. </p><p>Xiang et al. (2000) reported mutation analysis of the MECP2 gene in 59 sporadic cases of Rett syndrome and 9 families with a total of 19 affected individuals. Mutations were found in 27 of the sporadic cases but in none of the familial cases. Mutation analysis of the UBE1 (314370), UBE2I (601661), GDX (312070), SOX3 (313430), GABRA3 (305660), and CDR2 (117340) genes, which the authors regarded as candidate genes on the basis of clinical, pathologic, and genetic features, was also performed in 10 'classical' cases. No mutations were found in any of these genes in any individuals. Gene expression of MECP2, GDX, GABRA3, and L1CAM (308840) was investigated by in situ hybridization studies of postmortem brain tissue samples from 6 affected individuals and 7 controls. No gross differences were observed in the neurons of several brain regions between normal controls and Rett patients. Buyse et al. (2000) identified several novel mutations n the MECP2 gene. </p><p>Bourdon et al. (2001) achieved a mutation detection rate of 79% among 47 cases of classic RTT and 25% among 8 nonclassic RTT cases. Combining their findings with those previously reported, the spectrum of mutations in the MECP2 gene associated with RTT encompassed missense (34%), nonsense (46%), and frameshift (20%) mutations. The occurrence of mutations mainly in exon 3 (89%) and the multiple recurrence of specific mutations pointed to mutation hotspots that could propose diagnostic strategies for RTT. Three missense mutations, R106W (300005.0008), T158M (300005.0007), and R306C (300005.0016), represented about 23% of all mutations in their study and about 16 to 32% in the literature. Together with 4 nonsense mutations, a total of 7 mutations represented 64% of those found by Bourdon et al. (2001) and an even higher proportion (72%) in the patients studied by Amir et al. (1999). </p><p>In 26 of 30 Danish RTT patients, Nielsen et al. (2001) identified 15 different de novo mutations in the MECP2 gene, of which 5 were novel. Novel mutations included a 1-bp deletion (300005.0018) and a 14-bp duplication (300005.0019). The 30 patients were sporadic cases, chosen from 69 known RTT patients in Denmark because of availability of DNA samples. Twenty-seven of the patients were diagnosed with classic RTT and 3 as forme fruste variants with a milder phenotype. The authors performed direct sequencing of the coding region and parts of the 5-prime and 3-prime UTR. Nineteen of the 26 detected mutations were C-T transitions at CpG dinucleotides. Three of the 4 patients without identified mutations (all with classic RTT) were analyzed by FISH, and gross rearrangements of the MECP2 region were excluded. X-chromosome inactivation (XCI) was found to be random in 19 and skewed in 9 patients (2 were not informative); in 8 patients the paternal X chromosome was preferentially inactivated. The authors found no consistent correlation between the type (truncating or missense) or position of mutations and the severity of clinical presentation. Furthermore, the XCI pattern in peripheral blood did not seem to influence the score. The authors concluded that the clinical inclusion criteria are the most important factors in relation to the mutation detection rate. In a study of 116 patients, including 91 with classic and 25 with atypical RTT, Hoffbuhr et al. (2001) identified causative mutations in the MECP2 gene in 63% of the patients, representing a total of 30 different mutations. Mutations were identified in 72% of patients with classic RTT, but in only one-third of patients with atypical RTT. The authors found 17 novel mutations, including a complex gene rearrangement involving 2 deletions and a duplication in 1 individual. The duplication was identical to a region within the 3-prime UTR, and represented the first report of involvement of this region in RTT. Mutations in the N terminus were significantly correlated with a more severe clinical presentation compared with mutations closer to the C terminus of MECP2. Skewed X-inactivation patterns were found in 2 asymptomatic carriers of MECP2 mutations and in 6 girls diagnosed with either atypical or classic RTT. </p><p>In 35 of 50 Italian girls with classic Rett syndrome, Nicolao et al. (2001) identified 19 different de novo MECP2 mutations, 8 of which were novel. In a total of 22 unrelated cases, 7 recurrent mutations were characterized. Initial DHPLC screening allowed the identification of 17 of the 19 mutations (90%); after optimal conditions were established, this figure increased to 100%, with all recurrent MECP2 mutations generating a characteristic chromatographic profile. They found a tendency in this series for milder disease to be associated with nonsense mutations as compared to patients carrying missense mutations, although the difference was not statistically significant (p = 0.077). Pan et al. (2002) identified 12 different mutations in the MECP2 gene in 17 out of 31 (55%) sporadic Chinese classic RTT patients. The mutations (4 missense, 3 nonsense, and 5 frameshift) were all in the third exon and 2 were novel. Truncating mutations within or downstream of the TRD or deletions in the C-terminal region were consistent with reduced clinical severity when compared with truncating mutations N-terminal to this domain. </p><p>Trappe et al. (2001) analyzed the parental origin of MECP2 mutations in sporadic cases of RTT by analysis of linkage between the mutation in the MECP2 gene and intronic polymorphisms in 27 families with 15 different mutations, and found a high predominance of mutations of paternal origin (26 of 27 cases). The paternal origin was independent of type of mutation and was found for single-base exchanges as well as for deletions. Parents were not of especially advanced age. Trappe et al. (2001) concluded that de novo mutations in RTT occur almost exclusively on the paternally derived X chromosome and that this is probably the cause for the high female:male ratio observed in patients with RTT. Affected males have been described in a few cases of familial inheritance. Identification of the parental origin may be useful to distinguish between the sporadic form of RTT and a potentially familial form. </p><p>Miltenberger-Miltenyi and Laccone (2003) stated that 218 different mutations in the MECP2 gene had been reported in more than 2,100 patients. The mutations, which are responsible for up to 75% of classic RTT cases, are distributed along the whole gene and comprise all types of mutations. Almost all cases are sporadic. </p><p>Christodoulou et al. (2003) described RettBASE, a database for mutations in the MECP2 gene responsible for Rett syndrome and other abnormalities. </p><p>Mnatzakanian et al. (2004) screened the exon 1 sequence, which is used in the MECP2B isoform, in 19 girls with typical Rett syndrome in whom no mutations had been found in the other exons. In 1 affected individual, they identified an 11-bp deletion in exon 1 (300005.0028). This deletion does not affect the expression of MECP2A, indicating that inactivation of the MECP2B isoform is sufficient to cause Rett syndrome. Bartholdi et al. (2006) reported 2 unrelated girls with Rett syndrome caused by different mutations affecting exon 1 of the MECP2 gene (see, e.g., 300005.0031). </p><p>Li et al. (2007) analyzed the sequence of the MECP2 gene in 121 unrelated Chinese patients with classical or atypical RTT for deletions and mutations. They identified 45 different MECP2 mutations in 102 of these patients. The T158M mutation (300005.0007) was the most common (15.7%), followed in order of frequency by R168X (300005.0020) at 11.8%, R133C (300005.0001) at 6.9%, R270X (300005.0005) at 6.9%, G269fs (300005.0003) at 6.9%, R255X (300005.0021) at 4.9%, and R306C (300005.0016) at 3.9%. They identified 5 novel MECP2 mutations: 3 missense, 1 insertion, and a 22-bp deletion. Large deletions represented 10.5% of all identified MECP2 mutations. Mutations in exon 1 appeared to be rare. Cases without MECP2 mutations were screened for changes in the CDKL5 gene (300203). One synonymous mutation was found in exon 5. </p><p>Using multiplex ligation-dependent probe amplification (MLPA), Hardwick et al. (2007) identified multiexonic deletions in the MECP2 gene in 12 (8.1%) of 149 apparently mutation-negative patients with Rett syndrome. All of the deletions involved exon 3, exon 4, or both. There was no correlation between phenotypic severity and deletion size. </p><p>Thatcher et al. (2005) tested a potential role for MECP2 in the homologous pairing of imprinted 15q11-q13 alleles. FISH analysis of control cerebral tissue samples demonstrated a significant increase in homologous pairing specific to chromosome 15 from infant to juvenile brain samples. Significant and specific deficiencies in the percentage of paired chromosome 15 alleles were observed in Rett syndrome (312750), Angelman syndrome (105830), and autism (209850) brain samples when compared with normal controls. Human neuroblastoma cells also showed a significant and specific increase in the percentage of chromosome 15q11-q13 paired alleles following induced differentiation in vitro. Transfection with a methylated oligonucleotide decoy specifically blocked binding of MECP2 to the SNURF/SNRPN (182279) promoter within 15q11-q13 and significantly lowered the percentage of paired 15q11-q13 alleles in human neuroblastoma cells. Thatcher et al. (2005) suggested a role for MECP2 in chromosome organization in the developing brain and provided a potential mechanistic association between several related neurodevelopmental disorders. </p><p><strong><em>Males with Mutations in the MECP2 Gene</em></strong></p><p>
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Males with mutations in the MECP2 gene can be categorized into 4 main groups. Rarely, males with an extra X chromosome or somatic mosaicism harboring a classic RTT mutation phenotypically show classic Rett syndrome. A second group includes karyotypically normal 46,XY males with MECP2 mutations that cause classic Rett syndrome in females; these males show a severe congenital encephalopathy with early death (300673). In a third group, males with MECP2 mutations that have not been identified in females with Rett syndrome show a variable phenotype of impaired intellectual development with spasticity and other features (MRXS13; 300055). A fourth group of male patients has been reported with increased dosage of the MECP2 gene due to duplication; these patients have a severe form of impaired intellectual development, often with recurrent respiratory infections (MRXSL; 300260). The phenotypes associated with MECP2 mutations in males is highly variable, but usually severe (Gomot et al., 2003; Villard, 2007). </p><p>Meloni et al. (2000) stated that there had been no reports of males with Rett syndrome with a mutation in the MECP2 gene who survived beyond the age of 1 year. They studied a 3-generation family in which 2 affected males showed a severe syndromic form of X-linked impaired intellectual development with progressive spasticity (MRXS13) and 2 obligate carrier females showed either normal or borderline intelligence. This family had previously been reported by Claes et al. (1997), who mapped the disorder to Xq27.2-qter. Meloni et al. (2000) found that the affected males and the carrier females had a mutation (E406X; 300005.0009) in the MECP2 gene, demonstrating that, in males, MECP2 can be responsible for severe mental retardation associated with neurologic disorders. </p><p>Orrico et al. (2000) found a novel mutation (A140V; 300005.0015) in the MECP2 gene in a female with mild mental retardation, her similarly affected daughter, and her 4 adult sons with severe mental retardation with movement disorders, including tremor, bradykinesia, and pyramidal signs (MRXS13). The results indicated that not all MECP2 mutations are lethal in males and can result in a severe phenotype. </p><p>Couvert et al. (2001) identified 2 mutations, not found in RTT, in families with nonspecific X-linked intellectual developmental disorder (MRXS13) (see, e.g., E137F; 300005.0017). Upon screening a cohort of 185 mentally retarded males who were negative for the expansions across the FRAXA CGG repeat, 2 were found to carry A140V. Two other patients also carried mutations. The authors found the frequency of mutations in the MECP2 gene comparable to the frequency of the CGG expansions in the FMR1 gene (309550), which causes fragile X syndrome (300624) and suggested systematic screening of MECP2 in mentally retarded patients. </p><p>Ylisaukko-oja et al. (2005) screened the MECP2 gene in 118 unrelated mentally retarded Finnish patients (103 males, 15 females). They identified 2 known polymorphisms in the coding sequence and 4 variants in the intronic or 3-prime UTR regions, but stated that none of these was likely to be causal. Ylisaukko-oja et al. (2005) concluded that the evidence in their own and other mutation screening studies implies that MECP2 mutations do not represent a major cause of nonspecific mental retardation. </p><p>Moncla et al. (2002) reviewed a total of 13 MECP2 mutations reported in males. The first cases demonstrated a variant phenotype of Rett syndrome characterized by severe neonatal encephalopathy and lethality in early childhood (300673). In those cases, the carrier mothers had totally skewed X-chromosome inactivation. Further mutations were associated with nonspecific X-linked mental retardation, but also sporadic cases were described with a wide spectrum of mental retardation varying from a severe form with an Angelman syndrome (105830) phenotype to moderately mentally retarded males. In a series of 23 unrelated boys with severe mental retardation either with a variant phenotype of Rett syndrome or an Angelman-like phenotype, Moncla et al. (2002) identified 2 missense mutations in the C-terminal domain of the MECP2 gene. The first mutation was also detected in a healthy male cousin of the proband and the second mutation had been described previously as a polymorphism. The authors noted that the findings highlighted the need for extreme caution in the clinical interpretation of sequence variation in the MECP2 gene, before genetic counseling or prenatal diagnosis is proposed to the families involved. </p><p>Yntema et al. (2002) performed MECP2 mutation analysis in a cohort of 475 mentally retarded males who were negative for the FMR1 CGG repeat expansion. Fourteen different sequence changes were detected, 4 of which were previously reported as nonpathogenic variants and 5 that were novel silent changes. Five changes were possible novel mutations, including 4 amino acid changes and a deletion of 2 bases. For 3 of the 4 amino acid changes, segregation analysis revealed that the mutations could be traced in unaffected male family members. One missense mutation was inherited from the mother, but no other family members were available for further segregation analysis. This change, however, involved a nonconserved amino acid, making it unlikely that it had a dramatic effect on the MECP2 protein. The frequency of MECP2 mutations in the Dutch mentally retarded males was therefore 0.2% (1 of 475), and the study revealed the crucial importance of segregation analysis for low frequency mutations in order to distinguish them from rare polymorphisms. </p><p>Hoffbuhr et al. (2001) identified MECP2 mutations in 2 males: a Klinefelter male with classic RTT (300005.0007) and a hemizygous male infant with neonatal encephalopathy and early death and a novel 32-bp frameshift deletion (300005.0034). </p><p>Kleefstra et al. (2002) reported a 10-year-old boy with moderate mental retardation, emotional disturbances, hypotonia, obesity, and gynecomastia and a de novo 2-bp deletion in the MECP2 gene that resulted in a frameshift and premature stop codon. They pointed out that the clinical features were suggestive of Prader-Willi syndrome (176270). This was the first reported male with a de novo MECP2 mutation. Although most de novo MECP2 mutations in female patients with RTT are of paternal origin (Trappe et al., 2001), the example reported by Kleefstra et al. (2002) indicated that de novo mutations can appear on the maternal allele. </p><p>Laccone et al. (2002) commented that some reported MECP2 mutations, those associated with male phenotypes in particular, may actually be rare genetic variants, and they cautioned against hasty interpretation of the pathogenicity of these nucleotide changes (see, e.g., 300005.0023). </p><p>By array comparative genomic hybridization (array CGH), Van Esch et al. (2005) identified a small duplication at Xq28 (300005.0030) in a large family with a severe form of intellectual developmental disorder associated with progressive spasticity (MRXSL; 300260). Screening by real-time quantification of 17 additional patients with mental retardation who had similar phenotypes revealed 3 more duplications. The duplications in the 4 patients varied in size from 0.4 to 0.8 Mb and harbored several genes, which, for each duplication, included the mental retardation-related genes L1CAM (308840) and MECP2. The proximal breakpoints were located within a 250-kb region centromeric to L1CAM, whereas the distal breakpoints were located in a 300-kb interval telomeric of MECP2. The size and location of each duplication was different in the 4 patients. The duplications segregated with the disease in the families, and asymptomatic carrier females showed complete skewing of X inactivation. Comparison of the clinical features in these patients and in a previously reported patient enabled refinement of the genotype-phenotype correlation and strongly suggested that increased dosage of MECP2 results in the mental retardation phenotype. The findings demonstrated that, in humans, not only impaired or abolished gene function but also increased MECP2 dosage causes a distinct phenotype. Duplication of the MECP2 region occurs frequently in male patients with a severe form of mental retardation, which justifies quantitative screening of MECP2 in this group of patients. </p><p>Del Gaudio et al. (2006) reported 7 male patients with increased MECP2 gene copy number who manifested a progressive neurodevelopmental syndrome. </p><p>Carvalho et al. (2009) investigated the potential mechanisms for MECP2 duplication and examined whether genomic architectural features may play a role in their origin using a 4-Mb tiling-path oligonucleotide array CGH assay. The 30 male patients analyzed showed a unique duplication varying in size from 250 kb to 2.6 Mb. In 77% of these nonrecurrent duplications, the distal breakpoints grouped within a 215-kb genomic interval, located 47 kb telomeric to the MECP2 gene. The genomic architecture of this region contains both direct and inverted low-copy repeat (LCR) sequences; this same region undergoes polymorphic structural variation in the general population. Array CGH analysis revealed complex rearrangements in 8 patients; in 6 patients the duplication contained an embedded triplicated segment, and in the other 2, stretches of nonduplicated sequences occurred within the duplicated region. Breakpoint junction sequencing was achieved in 4 duplications and identified an inversion in 1 patient, demonstrating further complexity. Carvalho et al. (2009) proposed that the presence of LCRs in the vicinity of the MECP2 gene may generate an unstable DNA structure that can induce DNA strand lesions, such as a collapsed fork, and facilitate a fork stalling and template switching (FoSTeS) event producing the complex rearrangements involving the MECP2 gene. </p><p>Carvalho et al. (2011) identified complex genomic rearrangements consisting of intermixed duplications and triplications of genomic segments at the MECP2 and the PLP1 (300401) loci. These complex rearrangements were characterized by a triplicated segment embedded within a duplication in 11 unrelated subjects. Notably, only 2 breakpoint junctions were generated during each rearrangement formation. All the complex rearrangement products shared a common genomic organization, duplication-inverted triplication-duplication (DUP-TRP/INV-DUP), in which the triplicated segment is inverted and located between directly oriented duplicated genomic segments. Carvalho et al. (2011) provided evidence that the DUP-TRP/INV-DUP structures are mediated by inverted repeats that can be separated by more than 300 kb, a genomic architecture that apparently leads to susceptibility to such complex rearrangements. </p><p><strong><em>Atypical Rett Syndrome or Angelman-like Phenotype</em></strong></p><p>
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Watson et al. (2001) identified MECP2 mutations in 5 of 47 patients with a clinical diagnosis of an Angelman-like syndrome (see 105830) and no cytogenetic or molecular abnormality of chromosome 15q11-q13. Four of these patients were female and 1 male. By the time of diagnosis, 3 of the patients were showing signs of regression and had features suggestive of Rett syndrome; in the remaining 2, the clinical phenotype was still considered to be Angelman-like. </p><p>Imessaoudene et al. (2001) identified MECP2 mutations in 6 of 78 patients with possible Angelman syndrome but with normal methylation pattern at the UBE3A locus (601623). Of these, 4 were females with a phenotype consistent with Rett syndrome, one was a female with progressive encephalopathy of neonatal onset, and one was a male with a nonprogressive encephalopathy of neonatal onset. This boy had a gly428-to-ser mutation (300005.0023). </p><p><strong><em>Autism</em></strong></p><p>
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As there is a resemblance between the phenotypes for autism (209850) and Rett syndrome, and 70% of individuals with autism show some degree of mental retardation, some questioned whether specific mutations within the coding region of MECP2 are involved in the etiology of infantile autism. Lam et al. (2000) and Ashley-Koch et al. (2001) identified mutations in the MECP2 gene in sporadic cases of autism, whereas no mutations were found in a sample of 59 autistic individuals by Vourc'h et al. (2001). </p><p>Beyer et al. (2002) systematically screened for MECP2 mutations in 152 autistic patients from 134 German families and 50 unrelated patients from the affected relative-pair sample of the International Molecular Genetic Study of Autism Consortium (IMGSAC), and identified 14 sequence variants. Eleven variants were excluded from having an etiologic role as they were either silent mutations, did not cosegregate with autism in the pedigrees of the patients, or represented known polymorphisms. The etiologic relevance of the 3 remaining mutations could not be ruled out, although they were not localized within functional domains of MECP2 and may be rare polymorphisms. Given the large size of the sample, Beyer et al. (2002) concluded that mutations in the coding region of MECP2 do not play a major role in autism susceptibility. </p><p>Carney et al. (2003) analyzed 69 females clinically diagnosed with autistic disorder for the presence of mutations in the MECP2 gene. Two autistic disorder females were found to have de novo mutations in the MECP2 gene, one a 41-bp deletion beginning at nucleotide 1157 (300005.0012), the other an arg294-to-ter mutation (300005.0011), which is one of the most common RTT mutations in MECP2. </p><p>Rett syndrome and Angelman syndrome, an imprinted disorder caused by maternal 15q11-q13 or UBE3A deficiency, have phenotypic and genetic overlap with autism. Samaco et al. (2005) tested the hypothesis that MECP2 deficiency may affect the level of expression of UBE3A and neighboring autism candidate gene GABRB3 (137192) without necessarily affecting imprinted expression. Multiple quantitative methods revealed significant defects in UBE3A expression in 2 different Mecp2-deficient mouse strains, as well as Rett, Angelman, and autism brain samples compared with control samples. Although no difference was observed in the allelic expression of several imprinted transcripts in Mecp2-null mouse brain, Ube3a sense expression was significantly reduced, consistent with the decrease in protein. The nonimprinted GABRB3 gene also showed significantly reduced expression in multiple Rett, Angelman, and autism brain samples, as well as Mecp2-deficient mice. Samaco et al. (2005) proposed an overlapping pathway of gene dysregulation within chromosome 15q11-q13 in Rett syndrome, Angelman syndrome, and autism, and implicated MECP2 in the regulation of UBE3A and GABRB3 expression in the postnatal mammalian brain. </p><p>Makedonski et al. (2005) showed that UBE3A mRNA and protein were significantly reduced in human and mouse MECP2-deficient brains. Reduced UBE3A level was associated with biallelic production of the UBE3A antisense RNA (SNHG14; 616259). In addition, MECP2 deficiency resulted in elevated histone H3 acetylation and H3(K4) methylation and reduced H3(K9) methylation at the PWS/AS imprinting center, with no effect on DNA methylation or SNRPN (182279) expression. Makedonski et al. (2005) concluded that MECP2 deficiency causes epigenetic aberrations at the PWS imprinting center. These changes in histone modifications may result in loss of imprinting of the UBE3A antisense gene in the brain, increase in UBE3A antisense RNA level, and, consequently, reduction in UBE3A production. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between variation in the MECP2 gene and susceptibility to systemic lupus erythematosus, see SLEB15 (300809).</p><p><strong><em>Effects of Mutations on Protein Function</em></strong></p><p>
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Dragich et al. (2000) reviewed the structure, function, and effect of mutations on the activity of MECP2. </p><p>By Southwestern and gel shift binding analyses of MECP2 proteins with RTT-causing mutations in conserved residues of the MBD, Ballestar et al. (2000) determined that arg106-to-trp (300005.0008), arg133- to-cys (300005.0001), and phe155-to-ser (300005.0002) had dramatically reduced (100-fold) capacities to bind mono- and polymethylated DNA compared with wildtype MECP2. Another mutation, thr158-to-met (T158M; 300005.0007), which occurs at a nonconserved MBD residue near the C-terminal side of the MBD, bound methylated DNA only 2-fold less well than wildtype. Ballestar et al. (2000) noted that T158M is one of the most common mutations in RTT patients. Although the T158 residue is located in the MBD, the authors suggested that it may have other roles related to the function of MECP2, possibly involving interactions with the TRD. </p><p>Yusufzai and Wolffe (2000) studied the consequences of MECP2 mutations on the ability of MECP2 protein to bind specifically to methylated DNA and its transcription repression capabilities in Xenopus oocytes. Yusufzai and Wolffe (2000) found that all missense mutations within the methyl-binding domain impaired selectivity for methylated DNA, and that all nonsense mutations that truncate all or some of the transcriptional repression domain affected the ability to repress transcription and had decreased levels of stability in vivo. Two missense mutations, one in the TRD (arg306-to-cys) and one in the C terminus (glu397-to-lys), had no noticeable effects on MECP2 function. </p><p>Wan et al. (2001) examined mutant MECP2 expression and global histone acetylation levels in clonal cell cultures from a female RTT patient with one mutant allele on the active X chromosome, as well as in cells from a male hemizygous for a 1-bp deletion mutation (300005.0003). Both mutant alleles generated stable RNA transcripts, but no intact MECP2 protein was detected by Western blot analysis. Western blot analysis further revealed that histone H4, but not H3, was hyperacetylated, specifically at lysine-16. The authors hypothesized that subsequent overexpression of MECP2 target genes may play a role in the pathogenesis of RTT. </p><p>LaSalle et al. (2001) quantitated the level and distribution of wildtype and mutant MECP2 protein in situ by immunofluorescence and laser scanning cytometry of brain biopsies and tissue arrays. Cellular heterogeneity in MECP2 expression level was observed in normal brain with a subpopulation of cells exhibiting high expression and the remainder exhibiting low expression. MECP2 expression was significantly higher in CNS compared with non-CNS tissues; MECP2 neurons exhibiting high expression were more numerous in layer IV of the cerebrum, and MECP2 neurons exhibiting low expression were more numerous in the granular layer of the cerebellum. MECP2 mutant-expressing cells were randomly localized in Rett cerebrum and cerebellum and showed normal MECP2 expression with N-terminal-specific anti-MECP2. The authors suggested that mutations in the MECP2 gene in RTT are only manifested in cells highly expressing in the MECP2 protein. Shahbazian and Zoghbi (2002) reviewed the manner in which the linking of epigenetics and neuronal function is revealed by studies of the MECP2 gene in Rett syndrome. Originally thought to be a protein that functions as a global transcriptional repressor, MECP2 is actually specialized for a function in neurons of the CNS. Mouse models reproduce virtually every aspect of RTT, including highly specialized hand-wringing behaviors, which suggests that the pathways leading from dysfunctional MECP2 to each of these features are conserved between humans and mice. Given that, in humans, the phenotypic outcome of MECP2 truncation mutations depends on the position of the truncation, different regions of the protein may interact with particular proteins or complexes. </p><p>Balmer et al. (2002) performed single cell cloning of T lymphocytes from 4 RTT patients with MECP2 mutations to isolate cells expressing mutant MECP2. Mutant-expressing clones were present at a significantly lower frequency (P less than 0.0001) than wildtype clones. These results demonstrated that although MECP2 is not essential for lymphocyte growth, expression of the MECP2 mutation causes a growth disadvantage in cultured clonal T cells by reducing the response to mitogenic stimulation. Mutant MECP2 was expressed at normal transcript and protein levels, and exhibited no significant effect on acetylated histones or methyl-binding protein-3 (MBD3; 603573) levels. Examination of the expression of 5 imprinted genes suggested that MECP2 does not have an essential role in the silencing of these genes. </p><p>Kudo et al. (2002) noted that 2 MECP2 mutations, A140V (300005.0015) and E137G (300005.0017), had been found in male patients with nonspecific X-linked mental retardation. Using mouse L929 cells, Kudo et al. (2002) found that expression of these mutant proteins showed clear focal heterochromatin staining patterns indistinguishable from that of wildtype protein, indicating that the 2 mutants retained their ability to bind methyl-CpG. Another mutant, R106W (300005.0008), which had been identified in Rett syndrome, had impaired heterochromatin staining. Using a Drosophila cell line, the authors showed that the A140V mutant retained transcriptional repression activity, whereas the Rett mutant R106W did not. The E137G mutant had impaired transcriptional repression activity. Kudo et al. (2002) concluded that the A140V and E137G Mecp2 mutants exhibited mild impairment of protein function compared to the mutants identified in Rett syndrome. </p>
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<p>Weaving et al. (2003) reported a large MECP2 screening project in patients diagnosed with Rett syndrome. Composite phenotype severity scores did not correlate with mutation type, domain affected, or X inactivation. Other correlations, including head circumference, height, presence of speech, and age at development of hand stereotypies, suggested that truncating mutations and mutations affecting the MBD tend to lead to a more severe phenotype. Skewed X inactivation was found in 31 (43%) of 72 patients tested, primarily in those with truncating mutations and mutations affecting the MBD. Weaving et al. (2003) concluded that it is likely that X inactivation modulates the phenotype in RTT. </p><p>In a study of genotype/phenotype correlations, Schanen et al. (2004) analyzed 85 Rett syndrome patients with mutation in the MECP2 gene. Sixty-five (76%) carried 1 of the 8 common mutations. Patients with missense mutations had lower total severity scores and better language performance than those with nonsense mutations. No difference was noted between severity scores for mutations in the MBD and the TRD. However, patients with missense mutations in TRD had the best overall scores and better preservation of head growth and language skills. Analysis of specific mutation groups demonstrated a striking difference for patients with the R306C mutation (300005.0016), including better overall score, later regression, and better language with less motor impairment. Indeed, these patients as a group accounted for the differences in overall scores between the missense and nonsense groups. </p><p>Bartholdi et al. (2006) reported 2 unrelated girls with Rett syndrome caused by different mutations affecting exon 1 of the MECP2 gene (see, e.g., 300005.0031). The phenotype of both girls was more severe than that of 2 additional unrelated girls with Rett syndrome caused by MECP2 mutations not affecting exon 1. The authors speculated that MECP2 mutations involving exon 1 result in a more severe phenotype because MECP2B is more abundantly expressed in the brain than MECP2A. </p><p>Among 110 patients with Rett syndrome in whom an MECP2 mutation was not identified, Archer et al. (2006) used dosage analysis to detect large deletions in 37.8% (14 of 37) patients with classic Rett syndrome and 7.5% (4 of 53) patients with atypical Rett syndrome. Most large deletions contained a breakpoint in the deletion prone region of exon 4. Five patients with large MECP2 deletions had additional congenital anomalies, which was significantly more than in RTT patients with other MECP2 mutations. </p><p>Robertson et al. (2006) compared the behavioral profile of cases in the Australian Rett Syndrome Database with those of a British study using the Rett Syndrome Behavioral Questionnaire (Mount et al., 2002). Behavioral patterns were compared to MECP2 gene findings in the probands. Fear/anxiety was more commonly reported in those individuals with R133C and R306C. The R294X mutation (300005.0011) was more likely to be associated with mood difficulties and body rocking but less likely to have hand behaviors and to display repetitive face movements. Hand behaviors were more commonly reported in those with R270X (300005.0005) or R255X (300005.0021). </p><p>Bebbington et al. (2008) investigated genotype/phenotype correlations of 276 cases of Rett syndrome reported in a large global database. Among the most common mutations, R270X and R255X were associated with the most severe phenotype, and R133C (300005.0001) and R294X were associated with the mildest phenotype. </p><p>Saunders et al. (2009) identified 4 patients with classic Rett syndrome associated with mutations in exon 1 of the MECP2 gene, affecting the MeCP2_e1 isoform. Three of the mutations were predicted to result in absent translation of the isoform. Three of the mutations were proven to be de novo; the fourth was likely de novo, but the unaffected father was not available for DNA analysis. Two of the patients had previously tested negative for MECP2 mutation, which at the time only included sequencing of exons 2 to 4 of the gene (MeCP2_e2 isoform). The findings suggested that mutations affecting exon 1 of MECP2 is important in the etiology of RTT. </p>
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<p>Willard and Hendrich (1999) pointed out that the finding that MECP2 is mutated in Rett syndrome (312750) fits well with what is known about Mecp2 deficiency in mice (Tate et al., 1996). Male mouse embryonic stem (ES) cells in which Mecp2 is disrupted cannot support development, consistent with the possible male lethality of RTT. In contrast, chimeric mice, in which a small proportion of cells are derived from Mecp2-deficient ES cells, are viable. These animals might provide a model for RTT, as female RTT patients are also mosaic for MECP2-expressing and MECP2-deficient cells because of random X-chromosome inactivation. They also pointed out that Rett syndrome is one of a number of human diseases involving abnormal chromatin assembly or remodeling, with consequent epigenetic effects on expression of one or more genes that are themselves not mutated. Other examples include the imprinting defects and the discovery of a defect in phosphorylation of histone H3 by ribosomal protein S6 kinase (RPS6KA3; 300075) in Coffin-Lowry syndrome (303600). </p><p>Chen et al. (2001) generated mice deficient in MECP2. Contrary to the conclusion of Tate et al. (1996), Chen et al. (2001) demonstrated that disruption of Mecp2 does not lead to embryonic lethality. Mecp2-null mice were normal until 5 weeks of age, when they began to develop disease, leading to death between 6 and 12 weeks. The initial manifestations of abnormal behavior included nervousness, body trembling, pila erection, and occasional hard respiration at 5 weeks of age. A significant portion of mutant mice became overweight, and most exhibited signs of physical deterioration by 8 weeks of age. At late stages of the disease, mutants were hypoactive, trembled when handled, and often began to lose weight. Most mutants died at approximately 10 weeks of age. Heterozygous mutant females seemed normal for the first 4 months but began to show symptoms such as weight gain, reduced activity, and ataxic gait at a later age. Autopsy showed a substantial reduction in both brain weight and neuronal cell size but no obvious structural defects or signs of neurodegeneration. Brain-specific deletion of Mecp2 at embryonic day 12 resulted in a phenotype identical to that of the null mutation, indicating that the phenotype is caused by Mecp2 deficiency in the central nervous system (CNS) rather than in peripheral tissues. Deletion of Mecp2 in postnatal CNS neurons led to a similar neuronal phenotype, although at a later age. Chen et al. (2001) concluded that the role of MECP2 is not restricted to the immature brain but becomes critical in mature neurons. MECP2 deficiency in these neurons is sufficient to cause neuronal dysfunction with symptomatic manifestation similar to Rett syndrome. </p><p>Using similar methods, Guy et al. (2001) replaced exons 3 and 4 of MECP2. They also found that mice homozygous or hemizygous for the replacement were viable and fertile. Guy et al. (2001) found that body weight varied depending upon genetic background. The Mecp2-null mutation on a C57BL/6 background gave rise to animals that were substantially underweight from 4 weeks of age with full penetrance. After crossing to a 129 strain, F1 animals showed a reverse effect. Instead of losing weight, male Mecp2-null mice were the same weight as wildtype littermates until 8 weeks, when survivors became significantly heavier than sibs with an obvious increase in deposited fat. Other aspects of the phenotype including behavioral defects were not affected by altered genetic background. Mecp2-null male and female mice showed no initial phenotype, but both developed a stiff uncoordinated gait and reduced spontaneous movement between 3 and 8 weeks of age. Most animals subsequently developed hindlimb clasping and irregular breathing. Pathologic analysis of symptomatic animals revealed no obvious histologic abnormalities in a range of organs. In particular, the brain showed no unusual features of cortical lamination, ectopias, or other abnormalities. Variable progression of symptoms led ultimately to rapid weight loss and death at approximately 54 days. After several months heterozygous female mice also showed behavioral symptoms. The overlapping delay before symptom onset in humans and mice, despite the profoundly different rates of development, raises the possibility that stability of brain function, not brain development per se, is compromised by the absence of MECP2. </p><p>Shahbazian et al. (2002) generated mice expressing a truncated Mecp2 protein similar to those found in RTT. They showed that although the truncated Mecp2 protein in these mice localized normally to heterochromatic domains in vivo, histone H3 (142780) was hyperacetylated. Shahbazian et al. (2002) suggested that the elevated levels of histone H3 acetylation provided in vivo evidence for the role of MECP2 in the modification of chromatin architecture. </p><p>Kriaucionis and Bird (2003) reviewed the basic properties of Mecp2 in the context of a mouse model of Rett syndrome. </p><p>By binding to methylated CpG dinucleotide promoter regions, MECP2 acts as a transcriptional repressor; its absence might therefore result in widespread aberrant gene transcription, leading to the phenotype of Rett syndrome. Considering this potentially broad action of MECP2 on expression and the complexity of the brain, especially during development, Matarazzo and Ronnett (2004) approached the consequences of MECP2 deficiency in a mouse model by using a temporal and regional proteomic strategy. They used the olfactory system (olfactory epithelium and bulb) because its attributes make it an excellent developmental model system. They found evidence of temporal and regional proteomic pattern differences between wildtype and Mecp2 deficient mice. These changes in protein expression were segregated into 5 groups based on biologic function: cytoskeleton arrangement, chromatin modeling, energy metabolism, cell signaling, and neuroprotection. By combining the proteomic results with the RNA levels of the identified proteins, the authors showed that protein expression changes are the consequence of differences in mRNA level or posttranslational modifications. Matarazzo and Ronnett (2004) concluded that brain regions and ages must be carefully considered when investigating MECP2 deficiency, and that not only transcription should be taken into account as a source of these changes, but also posttranslational protein modifications. </p><p>Collins et al. (2004) generated transgenic mice that overexpressed wildtype human MECP2 as a model of MECP2 duplication syndrome (MRXSL; 300260). Detailed neurobehavioral and electrophysiologic studies in these mice, which express MECP2 at 2-fold wildtype levels, demonstrated onset of phenotypes around 10 weeks of age. Mice displayed enhanced motor and contextual learning and enhanced synaptic plasticity in the hippocampus. After 20 weeks of age, mice developed seizures, hypoactivity, and spasticity, and 30% of mice died by 1 year of age. Collins et al. (2004) concluded that MECP2 levels must be tightly regulated in vivo and that even mild overexpression of this protein may be detrimental. </p><p>To search for Mecp2 target genes in mouse brain that might be dysregulated in individuals with Rett syndrome, Horike et al. (2005) used a modified chromatin immunoprecipitation-based cloning strategy. The strategy was based on the assumption that Mecp2 target genes were located close to the binding sites of Mecp2 in vivo. They identified Dlx5 (600028) as a direct target gene of Mecp2 and found that human DLX5 had lost its maternal-specific imprinted status in lymphoblastoid cells of patients with RTT. They also found that Mecp2-mediated histone modification and formation of a higher-order chromatin-loop structure specifically associated with silent chromatin at the Dlx5-Dlx6 locus. In contrast to the findings of Horike et al. (2005), Schule et al. (2007) found no increased expression of Dlx5 or Dlx6 (600030) in mutant Mecp2 mice and disputed the 'chromatin-loop structure' hypothesis suggested by Horike et al. (2005). Furthermore, Schule et al. (2007) found no evidence that Dlx5 or Dlx6 are imprinted in mouse or human cells and indicated that Mecp2 does not play a role in imprinting. </p><p>Moretti et al. (2005) studied home cage behavior and social interactions in a mouse model of RTT. Young adult mutant mice showed abnormal home cage diurnal activity in the absence of motor skill deficits. Mutant mice showed deficits in nest building, decreased nest use, and impaired social interaction. They also took less initiative and were less decisive approaching unfamiliar males and spent less time in close vicinity to them in several social interaction paradigms. Abnormalities of diurnal activity and social behavior in Mecp2-mutant mice were reminiscent of the sleep/wake dysfunction and autistic features of RTT. Moretti et al. (2005) suggested that MECP2 may regulate expression and/or function of genes involved in social behavior. </p><p>Using cDNA microarrays, Nuber et al. (2005) found that Mecp2-null mice differentially expressed several genes that are induced during the stress response by glucocorticoids. Increased levels of mRNAs for SGK1 (602958) and FK506-binding protein-51 (FKBP5; 602623) were observed before and after onset of neurologic symptoms, but plasma glucocorticoid was not significantly elevated in Mecp2-null mice. MeCP2 binds to Fkbp5 and Sgk1 in brain and may function as a modulator of glucocorticoid-inducible gene expression. Given the known deleterious effect of glucocorticoid exposure on brain development, Nuber et al. (2005) proposed that disruption of MeCP2-dependent regulation of stress-responsive genes may contribute to the symptoms of Rett syndrome. </p><p>McGill et al. (2006) found that male mice with a truncated Mecp2 allele displayed increased anxiety-like behavior and an abnormal stress response, similar to patients with RTT. The changes were associated with increased serum corticosterone levels, suggesting an enhanced physiologic response to stress. Further studies showed that the mutant mice overexpressed Crh (122560) in the paraventricular nucleus of the hypothalamus, the central amygdala, and the stria terminalis. Mutant Mecp2 did not bind the Crh promoter, whereas wildtype Mecp2 preferentially bound a repressed form of the Crh promoter, The findings suggested that Mecp2 regulates Crh expression and that Crh overexpression may underlie certain features of mouse models of Rett syndrome. </p><p>Chang et al. (2006) found that Mecp2-mutant mice had decreased levels of Bdnf (113505) in the brain, at about 70% of wildtype levels. Bdnf expression depended on neuronal activity, and the authors hypothesized that Mecp2 deficiency reduces neuronal activity, thereby indirectly causing decreased BDNF protein levels. Mice with conditional deletion of Bdnf showed some anatomic similarities to Mecp2-mutant mice, including smaller brain size, smaller CA2 neurons, smaller glomerulus size, and a characteristic hindlimb-clasping phenotype. Furthermore, deletion of Bdnf in Mecp2 mutants caused an earlier onset of RTT-like symptoms. Overexpression of human BDNF in Mecp2 mutant mice extended the life span, rescued a locomotor defect, and reversed an electrophysiologic deficit observed in Mecp2 mutants. The results provided in vivo evidence for a functional interaction between Mecp2 and Bdnf and showed the physiologic significance of altered BDNF expression/signaling in RTT disease progression. </p><p>In cultured rat neurons, Zhou et al. (2006) found that neuronal activity and subsequent calcium influx triggered the de novo phosphorylation of Mecp2 at serine-421. Mecp2 ser421 phosphorylation was induced selectively in the rat brain in vivo in response to physiologic stimuli, including pharmacologically induced seizures and light. The phosphorylation of Mecp2 appeared to relieve transcriptional repression of Bdnf, and overall controlled the ability of Mecp2 to regulate dendritic patterning and spine morphogenesis, Phosphorylation of Mecp2 was not observed in other tissues besides brain. These findings suggested that, by triggering MECP2 phosphorylation, neuronal activity regulates a program of gene expression that mediates nervous system maturation. Disruption of this process in individuals with mutations in MECP2 may underlie the neural-specific pathology of RTT. </p><p>Wang et al. (2006) observed that although Mecp2-deficient mouse neurons released increased amounts of Bdnf, the overall levels of Bdnf were decreased compared to controls. These findings suggested that loss of Mecp2 function disrupts transynaptic Bdnf signaling. Mecp2-null adrenal chromaffin cells also showed increased exocytic function compared to wildtype cells. Thus, other features of RTT, such as autonomic dysfunction, may be associated with abnormal neuropeptide and catecholamine secretion. </p><p>The persistent viability of mutant neurons in patients with Rett syndrome raised the possibility that reexpression of MECP2 might restore full function and thereby reverse RTT. Alternatively, MECP2 may be essential for neuronal development during a specific time window, after which damage caused by its absence is irreversible. To distinguish these possibilities, Guy et al. (2007) created a mouse model in which the endogenous Mecp2 gene was silenced by insertion of a lox-Stop cassette, but could be conditionally activated under the control of its own promoter and regulatory elements by cassette deletion. Using this method they demonstrated robust phenotypic reversal, as activation of Mecp2 expression led to striking loss of advanced neurologic symptoms in both the immature and mature adult animals. Guy et al. (2007) concluded that developmental absence of MECP2 does not irreversibly damage neurons, which suggested that Rett syndrome is not strictly a neurodevelopmental disorder. The delayed onset of behavioral and long-term potentiation phenotypes in Mecp2 heterozygous females emphasized the initial functional integrity of Mecp2-deficient neurons and fit with the proposal that MECP2 is required to stabilize and maintain the mature neuronal state. The restoration of neuronal function by late expression of Mecp2 suggested that the molecular preconditions for normal MECP2 activity are preserved in its absence. </p><p>Fyffe et al. (2008) generated conditional transgenic mice with loss of Mecp2 expression in Sim1 (603128)-expressing neurons in the hypothalamus. The mutant animals showed increased anxiety-like behavior and abnormal physiologic responses to stress, including increased serum cortisol, that was similar to that observed when Mecp2 is inactivated in the entire brain. In addition, these mice were aggressive, hyperphagic, and obese, indicating dysfunction of the regulation of social and feeding behaviors. Other behaviors observed in humans with MECP2 mutations, such as motor coordination problems and learning and memory deficits, were not observed, suggesting a specific role for MECP2 in the hypothalamus. Fyffe et al. (2008) noted that the experimental protocol used in this study could enable mapping of the neuroanatomic origins of complex behaviors seen in MECP2-related disorders. </p><p>Kerr et al. (2008) generated mice with conditional expression of a hypomorphic Mecp2 allele (about 50% of wildtype) in the brain, caused by a disruption of the 3-prime noncoding region of the gene. Male mutant mice had increased body weight, increased fat, and subtle paw clasping at about 6 weeks of age. Behavioral studies showed that male mutant mice had similar spontaneous exploration and novelty-induced locomotor activity as wildtype mice, but showed defects in fine motor control as well as decreased social behavior. Expression of Mecp2 in the mutant mice was particularly decreased in the hypothalamus, which controls energy homeostasis. Overall, the hypomorphic Mecp2 mouse phenotype was much less severe than the phenotype caused by lack of functional Mecp2. </p><p>Similar studies by Samaco et al. (2008) found that male mice carrying a Mecp2 hypomorphic (50% of wildtype) allele had a mild increase in body weight and decreased motor coordination. Behavioral abnormalities included decreased pain recognition, decreased acoustic startle response and prepulse inhibition, decreased social interactions, and decreased nest-building behavior compared to wildtype mice. Hypomorphic mice also showed decreased hippocampal- and amygdala-dependent learning, decreased anxiety, and altered breathing patterns. Samaco et al. (2008) suggested that there is tight regulation of MECP2 levels in the brain, suggesting a dynamic role for MECP2 in neuronal function, and they predicted that changes in MECP2 dosage may result in human neurodevelopmental disorders. </p><p>Ben-Shachar et al. (2009) studied gene expression patterns in the cerebellum of Mecp2-null and MECP2-Tg mice, modeling RTT and MECP2 duplication syndrome (300260), respectively. Abnormal MECP2 dosage caused alterations in the expression of hundreds of genes in the cerebellum. The majority of genes were upregulated in MECP2-Tg mice and downregulated in Mecp2-null mice, consistent with a role for MECP2 as a modulator that can both increase and decrease gene expression. Many of the genes altered in the cerebellum, particularly those increased by the presence of MECP2 and decreased in its absence, were similarly altered in the hypothalamus. Ben-Shachar et al. (2009) suggested that either gain or loss of MeCP2 may result in gene expression changes in multiple brain regions and that some of these changes may be global. </p><p>Tropea et al. (2009) found that systemic treatment of Mecp2 mutant mice with an active peptide fragment of IGF1 (147440) extended their life span, improved locomotor function, ameliorated breathing patterns, and reduced heart rate irregularity. Postmortem brains of treated mice showed increased weight, improved neuron spine density in the motor cortex, increased synaptic amplitude, and increased staining for PSD95 (602887) compared to untreated mice. The findings suggested that IGF1 treatment can improve synaptic maturation and transmission. </p><p>Chao et al. (2010) generated mice lacking Mecp2 from GABA-releasing neurons, designated Viaat-Mecp2(-/y), and showed that they recapitulate numerous Rett syndrome and autistic features, including repetitive behaviors. Viaat-Mecp2(-/y) mice were indistinguishable from controls until approximately 5 weeks of age, when they began to exhibit repetitive behavior such as forelimb stereotypies reminiscent of midline hand-wringing that characterizes Rett syndrome and hindlimb clasping. Viaat-Mecp2(-/y) mice spent 300% more time grooming than wildtype mice, leading to fur loss and epidermal lesions in group- and single-housed mice. Viaat-Mecp2(-/y) mice showed progressive motor dysfunction. The mice also developed motor weakness and by 12 weeks showed a trend toward reduced activity, becoming clearly hypoactive by 19 weeks. MeCP2 deficiency in GABAergic neurons also impaired hippocampal learning and memory. Roughly one-half of Viaat-Mecp2(-/y) mice died by 26 weeks of age after a period of marked weight loss. Coinciding with the weight loss, mice developed severe respiratory dysfunction. Next, Chao et al. (2010) generated male conditional deletion mice, designed Dlx5/6-Mecp2(-/y), missing MeCP2 from a subset of forebrain GABAergic neurons. These mice showed repetitive behavior, impaired motor coordination, increased social interaction preference, reduced acoustic startle response, and enhanced prepulse inhibition. In contrast to Viaat-Mecp2(-/y) mice, Dlx5/6-Mecp2(-/y) mice survived at least 80 weeks without apparent alterations in respiratory function. MeCP2-deficient GABAergic neurons showed reduced inhibitory quantal size, consistent with a presynaptic reduction in glutamic acid decarboxylase-1 (GAD1; 605363) and -2 (GAD2; 138275) levels. Chao et al. (2010) concluded that MeCP2 is critical for normal function of GABA-releasing neurons and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes. </p><p>McGraw et al. (2011) developed an adult-onset model of Rett syndrome by crossing mice harboring a floxed Mecp2 allele and tamoxifen-inducible CreER allele to delete Mecp2 when animals were fully mature. Thus, Mecp2 expression was eliminated only during adult life. Mice lacking Mecp2 as adults (AKO) developed symptoms of disease and behavioral deficits similar to germline-null (KO) mice. By 10 weeks after dosing, AKO mice were less active, had abnormal gait, and developed hindlimb clasping, similar to 10- to 11-week-old knockout mice. AKO mice also developed motor abnormalities and impaired nesting ability, as observed in knockout mice. In addition, both AKO and KO mice showed impaired learning and memory. Adult deletion of Mecp2 also demonstrated that some genes whose expression levels are sensitive to Mecp2 abundance are altered in its absence. In total, McGraw et al. (2011) tested 10 genes whose expression levels were known to be altered in knockout mice, and 60% were significantly altered in AKO mice compared with wildtype controls. However, 4 of these altered genes (Htr1a, 109760; Oprk1, 165196; Tac1, 162320; and Nxph4, 604637) were also significantly altered in control Mecp2(flox) mice, suggesting increased sensitivity of these loci to Mecp2 function. Finally, both AKO and KO mice died prematurely with similar median time to death (13 weeks after dosing period (n = 20) vs 13.3 weeks of life (n = 13), respectively). McGraw et al. (2011) argued that their results suggested that the temporal association of disease with the postnatal period of neurodevelopment may be unrelated to any developmental or stage-restricted function of MeCP2, at least in mouse models. They also suggested that the mature brain is dependent on Mecp2 function and that any therapies for Rett syndrome would be required to be continuously maintained. </p><p>Derecki et al. (2012) examined the role of microglia in a murine model of Rett syndrome and showed that transplantation of wildtype bone marrow into irradiation-conditioned Mecp2-null hosts resulted in engraftment of brain parenchyma by bone marrow-derived myeloid cells of microglial phenotype and arrest of disease development. However, when cranial irradiation was blocked by lead shield and microglial engraftment was prevented, disease was not arrested. Similarly, targeted expression of MECP2 in myeloid cells, driven by Lysm(cre) on an Mecp2-null background, markedly attenuated disease symptoms. Thus, through multiple approaches, wildtype Mecp2-expressing microglia within the context of an Mecp2-null male mouse arrested numerous facets of disease pathology: life span was increased, breathing patterns were normalized, apneas were reduced, body weight was increased to near that of wildtype, and locomotor activity was improved. Mecp2 +/- females also showed significant improvements as a result of wildtype microglial engraftment. These benefits mediated by wildtype microglia, however, were diminished when phagocytic activity was inhibited pharmacologically by using annexin V to block phosphatidylserine residues on apoptotic targets, thus preventing recognition and engulfment by tissue-resident phagocytes. Derecki et al. (2012) concluded that their results suggested the importance of microglial activity in Rett syndrome, implicated microglia as major players in the pathophysiology of Rett syndrome, and suggested bone marrow transplantation as a possible therapy. </p><p>Mutations in exon 2 of the MECP2 gene (isoform Mecp2_e2 only) have never been reported in Rett syndrome. Itoh et al. (2012) generated mice with selective loss of the Mecp2_e2 isoform due to excision of exon 2. Mutant mice were indistinguishable from wildtype mice and showed no neurologic deficits or morphologic brain anomalies, indicating that isoform Mecp2_e1 is sufficient to carry out normal protein function in the brain. However, there were reduced births of progeny that carried a Mecp_e2-null allele of maternal origin. Specifically, there was a 76% reduction in Xe2-/Y males and a 44% reduction in Xe2-/X females born to X/Xe2- females and wildtype males. In Xe2-/X and Xe2-/Y pairings, Xe2-/Y and Xe2-/Xe2- births were reduced by 50 and 60%, respectively. Placentas of embryos carrying a maternal e2-null allele showed increased apoptosis and had increased expression of Peg1 (MEST; 601029), indicating impaired silencing of Peg1 due to lack of Mecp2_e2. Itoh et al. (2012) concluded that Mecp2_e2 is dispensable for RTT-associated neurologic phenotypes, and that Mecp2_e2 is required for placenta and embryonic viability. </p><p>Buchovecky et al. (2013) found that 2 different strains of Mecp2-null mice showed abnormal brain cholesterol metabolism and perturbed liver lipid profiles. Pharmacologic inhibition of cholesterol synthesis via statin drugs or inactivation of the Sqle gene (602019) at least partly improved health, motor symptoms, and life span of Mecp2-null mice. </p><p>Liu et al. (2016) reported that lentivirus-based transgenic cynomolgus monkeys (Macaca fascicularis) expressing human MeCP2 in the brain exhibit autism-like behaviors and show germline transmission of the transgene. Expression of the MECP2 transgene was confirmed by Western blotting and immunostaining of brain tissues of transgenic monkeys. Genomic integration sites of the transgenes were characterized by a deep-sequencing-based method. As compared to wildtype monkeys, MECP2 transgenic monkeys exhibited a higher frequency of repetitive circular locomotion and increased stress responses, as measured by the threat-related anxiety and defensive test. The transgenic monkeys showed less interaction with wildtype monkeys within the same group, and also a reduced interaction time when paired with other transgenic monkeys in social interaction tests. The cognitive functions of the transgenic monkeys were largely normal in the Wisconsin general test apparatus, although some showed signs of stereotypic cognitive behaviors. Liu et al. (2016) generated 5 F1 offspring of MECP2 transgenic monkeys by intracytoplasmic sperm injection with sperm from 1 F0 transgenic monkey, showing germline transmission and Mendelian segregation of several MECP2 transgenes in the F1 progeny. Moreover, F1 transgenic monkeys also showed reduced social interactions when tested in pairs, as compared to wildtype monkeys of similar age. </p><p><strong><em>X-Chromosome Inactivation Studies</em></strong></p><p>
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Using quantitative laser scanning cytometry, Braunschweig et al. (2004) showed that Mecp2 -/+ female mice exhibited uniform regional distribution of Mecp2 mutant-expressing cells in brain, but unbalanced X-chromosome inactivation (XCI) in the population, thus favoring expression of the Mecp2 wildtype allele. In addition, the level of Mecp2 expression in Mecp2 wildtype-expressing cells from Mecp2 -/+ mice was significantly lower than those from Mecp2 +/+ age-matched controls. The negative effect of Mecp2 mutation on wildtype Mecp2 expression correlated with the percentage of Mecp2 mutant-expressing cells in the cortex. Similar results were observed in 2 RTT females with identical MECP2 mutations but different XCI ratios. Braunschweig et al. (2004) concluded that Mecp2-mutant neurons affect the development of surrounding neurons in a non-cell-autonomous manner, and that environmental influences may affect the level of Mecp2 expression in wildtype neurons. </p><p>In transgenic female mice heterozygous for a truncating Mecp2(308) mutation Young and Zoghbi (2004) found that XCI patterns were unbalanced in more than 60% of the animals, favoring expression of the wildtype allele. None of the animals had nonrandom XCI favoring the mutant allele. Primary neuronal cell cultures from the mutant mice showed selective survival of neurons in which the wildtype X chromosome was active. Phenotypic manifestations, including tremor, grooming, and stereotypic forepaw movements, were highly variable in the mutant female mice. There was a correlation between the pattern of XCI, expressed as the percentage of neurons with the wildtype allele active, and phenotype; significantly fewer abnormal phenotypes were observed when a large percentage of neurons had skewing toward expression of the wildtype X chromosome. Young and Zoghbi (2004) noted that previous reports had suggested that the majority of human patients with Rett syndrome have balanced translocations (Shahbazian et al., 2002), and suggested that this finding may be due to ascertainment bias; there may be females with MECP2 mutations who are asymptomatic or unrecognized due to skewed XCI. </p><p>Watson et al. (2005) assessed patterns of XCI in embryos and adult brains of mice heterozygous for the Mecp2(308) allele. There was no difference in the staining patterns of wildtype and heterozygous mutant embryos at embryonic day 9.5, suggesting that Mecp2 has no effect on the primary pattern of XCI. At 20 weeks of age, there was no significant difference between XCI patterns in the Purkinje cells in the cerebellum of heterozygous mutant and wildtype mice when the mutant allele was inherited from the mother. However, when the mutant allele was paternally inherited, a significant difference was detected. An estimation of the Purkinje cell precursor number based on XCI mosaicism revealed that, when the mutation was paternally inherited, the precursor number was less than that in wildtype mice. Therefore, the number of precursor cells allocated to the Purkinje cell lineage may be affected by a paternally inherited mutation in Mecp2. The pattern of XCI in cultured fibroblasts significantly correlated with patterns in the Purkinje cells in mutant animals but not in wildtype mice. </p>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>39 Selected Examples):</strong>
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<span class="mim-font">
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<strong>.0001 RETT SYNDROME, ZAPPELLA VARIANT</strong>
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<span class="mim-text-font">
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RETT SYNDROME, INCLUDED
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MECP2, ARG133CYS
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SNP: rs28934904,
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ClinVar: RCV000012578, RCV000030666, RCV000081202, RCV000169934, RCV000170107, RCV000445570, RCV000460141, RCV000624907, RCV001257757, RCV002273925, RCV003984804, RCV004734512
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<p>In a sporadic case of Rett syndrome (RTT; 312750), Amir et al. (1999) found a 471C-T transition in the MECP2 gene, resulting in an arg133-to-cys (R133C) amino acid substitution. </p><p>By analysis of genotype/phenotype correlations of Rett syndrome cases reported in a large global database, Bebbington et al. (2008) found that R133C and R294X (300005.0011) were associated with the mildest phenotype. </p><p>Renieri et al. (2009) identified the R133C mutation in 7 patients with a milder form called Zappella variant Rett syndrome (see 312750). </p>
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<span class="mim-font">
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<strong>.0002 RETT SYNDROME</strong>
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MECP2, PHE155SER
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SNP: rs28934905,
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ClinVar: RCV000012579
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<p>In a sporadic case of Rett syndrome (RTT; 312750), Amir et al. (1999) identified a 538T-C transition in the MECP2 gene, resulting in a phe155-to-ser (F155S) amino acid substitution. </p>
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<span class="mim-font">
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<strong>.0003 RETT SYNDROME</strong>
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<span class="mim-text-font">
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ENCEPHALOPATHY, NEONATAL SEVERE, DUE TO MECP2 MUTATION, INCLUDED
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MECP2, 1-BP DEL, 806G
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SNP: rs61750241,
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ClinVar: RCV000081211, RCV000168691, RCV000169939, RCV000170113, RCV000624370, RCV000850572, RCV001000009, RCV002251971, RCV003227637, RCV003333025
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<p>In a woman with motor coordination problems, mild learning disability, and skewed X inactivation, Wan et al. (1999) identified a 1-bp deletion (806delG) in the MECP2 gene, resulting in a val288-to-ter (V288X) substitution in the transcription repression domain. The same mutation was found in her sister and daughter, who were affected with classic Rett syndrome (RTT; 312750), and in her hemizygous son, who died from congenital encephalopathy (300673). </p><p>Leuzzi et al. (2004) reported a 28-month-old boy with the 806delG mutation. The patient's mother did not carry the mutation, suggesting germline mosaicism or a de novo mutation. After a normal pregnancy and cesarean section, the patient was markedly hypotonic with weak suction and vomiting. He showed chaotic ocular movements, masticatory automatisms, and brief seizure-like episodes. Brain MRI was normal. Examination at age 10 months showed microcephaly, severe developmental delay, axial hypotonia, limb rigidity, hyperreflexia, lack of purposeful hand movements, and poor eye contact. In addition, he had paroxysmal myoclonic movements of the upper limbs that were unresponsive to conventional antiepileptic drugs. Neurophysiologic investigations showed arrhythmic multifocal myoclonus that was of cortical origin, although not associated with cortical hyperexcitability. The findings were similar to those observed in patients with Rett syndrome and believed to result from reduced dendritic branching and circuitry derangement (Guerrini et al., 1998). </p><p>Li et al. (2007) referred to this mutation as G269fs. </p>
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<span class="mim-font">
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<strong>.0004 RETT SYNDROME</strong>
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</h4>
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<span class="mim-text-font">
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MECP2, 44-BP DEL, NT1152
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SNP: rs267608372,
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ClinVar: RCV000132880, RCV005089652
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<p>In a patient with classic Rett syndrome (RTT; 312750), Cheadle et al. (2000) identified a de novo 44-bp deletion in exon 3 of the MECP2 gene. The deletion begins at base 1152, 3-prime to the transcription repression domain, and is predicted to produce a truncated protein of 388 amino acids. </p>
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<h4>
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<span class="mim-font">
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<strong>.0005 RETT SYNDROME</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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MECP2, ARG270TER
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SNP: rs61750240,
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gnomAD: rs61750240,
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ClinVar: RCV000012586, RCV000081212, RCV000146359, RCV000169940, RCV000515283, RCV000624100, RCV001196907, RCV001705588, RCV004540996
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<span class="mim-text-font">
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<p>In 3 of 31 patients with Rett syndrome (RTT; 312750), Huppke et al. (2000) identified an 808C-T transition in the MECP2 gene, resulting in a premature stop codon (arg270-to-ter; R270X) in exon 3. Bienvenu et al. (2000) found the same mutation in 5 of 46 Rett syndrome patients studied. De Bona et al. (2000) identified the R270X mutation in 4 unrelated individuals with Rett syndrome, indicating that it represents a hotspot. </p><p>Topcu et al. (2002) reported a boy with features of classic Rett syndrome and a normal karyotype, with somatic mosaicism for the truncating R270X mutation. The mutation abolished an NlaIV restriction site, and densitometric scanning of the restriction fragments revealed that the allele ratio was approximately 36 to 64 for the mutant-to-normal allele. Topcu et al. (2002) speculated that the somatic mosaicism could be the result of an early postzygotic mutation or chimerism. </p><p>In 524 females with Rett syndrome and an identified MECP2 mutation, Jian et al. (2005) prospectively analyzed mortality data and found significant differences in survival among the 8 most common mutations; survival among cases with the R270X mutation was reduced compared to all the other mutations (p = 0.01). </p><p>By analysis of genotype/phenotype correlations of Rett syndrome cases reported in a large global database, Bebbington et al. (2008) found that R270X and R255X (300005.0021) were associated with the most severe phenotype. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>.0006 RETT SYNDROME</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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MECP2, IVS2AS, A-G, -2
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SNP: rs267608464,
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ClinVar: RCV000144113, RCV000170199
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<span class="mim-text-font">
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<p>In a patient with classic Rett syndrome (RTT; 312750), Huppke et al. (2000) found a 378A-2G transition in the splice acceptor site 5-prime to exon 3 of the MECP2 gene. The mutation was predicted to affect all 4 domains of the protein: the nuclear localization signal (NLS), transcription repression domain (TRD), methyl-CpG-binding domain (MBD), and C-terminal segment (CTS). </p>
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<h4>
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<span class="mim-font">
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<strong>.0007 RETT SYNDROME</strong>
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</span>
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<span class="mim-text-font">
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ENCEPHALOPATHY, NEONATAL SEVERE, DUE TO MECP2 MUTATION, INCLUDED
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MECP2, THR158MET
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SNP: rs28934906,
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ClinVar: RCV000012580, RCV000133129, RCV000169935, RCV000170109, RCV000170110, RCV000623451, RCV000763199, RCV001813975, RCV002247328, RCV002273926, RCV003984805, RCV004540995
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<span class="mim-text-font">
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<p>In a sporadic patient with Rett syndrome (RTT; 312750), Amir et al. (1999) identified a 547C-T transition in the MECP2 gene, resulting in a thr158-to-met (T148M) substitution. </p><p>Villard et al. (2000) reported a family in which a daughter had classic Rett syndrome and her 2 brothers died in infancy from severe encephalopathy (300673). The affected girl and 1 brother tested showed the T158M mutation. The unaffected carrier mother had a completely biased pattern of X-chromosome inactivation that favored expression of the normal allele. One of the affected boys showed severe mental retardation and hypotonia soon after birth and died at age 11 months. </p>
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<strong>.0008 RETT SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
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|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MECP2, ARG106TRP
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|
|
|
|
<br />
|
|
|
|
SNP: rs28934907,
|
|
|
|
|
|
|
|
ClinVar: RCV000012585, RCV000255874, RCV000552837, RCV001000318, RCV001195924, RCV002247329, RCV002311513, RCV003224092, RCV004794330
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 affected half sisters of a family with Rett syndrome (RTT; 312750), Amir et al. (1999) identified a 390C-T transition in the MECP2 gene, resulting in an arg106-to-trp (R106W) substitution. </p>
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
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|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC 13</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MECP2, GLU406TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs61753965, rs63094662,
|
|
|
|
|
|
gnomAD: rs61753965, rs63094662,
|
|
|
|
|
|
ClinVar: RCV000012588, RCV000146349
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected males in a family reported by Claes et al. (1997) as having syndromic X-linked intellectual developmental disorder with progressive spasticity (MRXS13; 300055), Meloni et al. (2000) found a 1216C-T transition in exon 3 of the MECP2 gene, resulting in a glu406ter (E406X) nonsense mutation. The authors suggested that the position of the mutation near the end of the protein may explain the nonlethal male phenotype. Males showed delayed development (first steps at 2 to 5.5 years) and were never able to speak. They had facial hypotonia, sialorrhea, and a habitus suggesting complicated spastic paraplegia; their head circumferences were at the 75th to 90th percentile. One of them had choreoathetotic movements in the right arm, and global bradyarrhythmia as indicated by electroencephalogram, and bilateral juvenile cataract; he was confined to a wheelchair and died from pneumonia at age 39 years. Meloni et al. (2000) compared the phenotypic findings with those of Rett syndrome (312750). Similarities included absence of language, ataxic gait, seizures, grinding of teeth, and sialorrhea. Moreover, spastic paraparesis is a frequent end-stage finding in Rett syndrome. Salient differences included absence of growth retardation, of loss of acquired purposeful hand skills, and of acquired microcephaly. Microcephaly is one of the major diagnostic criteria of Rett syndrome, in contrast with the macrocephaly in the family studied by Meloni et al. (2000). </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 RETT SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MECP2, 2-BP DEL, 211CC
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267608434,
|
|
|
|
|
|
|
|
ClinVar: RCV000012589, RCV000133026
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male with a progressive neurologic disorder (see Rett syndrome; 312750), Clayton-Smith et al. (2000) identified a 2-bp deletion at nucleotide 211 of the MECP2 gene, resulting in a frameshift. This change created a novel restriction site for Cfo1. The mutation was not identified in either parent or in any of 100 normal X chromosomes. The patient was found to be somatic mosaic for the mutation, which explained the lack of embryonic lethality. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 RETT SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
AUTISM, SUSCEPTIBILITY TO, X-LINKED 3, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MECP2, ARG294TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs61751362,
|
|
|
|
|
|
gnomAD: rs61751362,
|
|
|
|
|
|
ClinVar: RCV000012590, RCV000012591, RCV000081215, RCV000474366, RCV000515413, RCV000624805, RCV001420261, RCV003984806, RCV004545726
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Rett Syndrome</em></strong></p><p>
|
|
De Bona et al. (2000) identified an 880C-T transition in the MECP2 gene, leading to an arg294-to-ter (R294X) nonsense mutation in 4 unrelated patients with Rett syndrome (RTT; 312750), thus indicating that this represents a hotspot. </p><p>By analysis of genotype/phenotype correlations of Rett syndrome cases reported in a large global database, Bebbington et al. (2008) found that R133C (300005.0001) and R294X were associated with the mildest phenotype. </p><p><strong><em>Autism, Susceptibility to, X-Linked 3</em></strong></p><p>
|
|
Carney et al. (2003) identified this mutation in a female with classic autism disorder (AUTSX3; 300496) who had most of the diagnostic features of RTT. Analysis for skewed X chromosome inactivation in blood leukocytes showed that she had a 29% pattern. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 RETT SYNDROME, ZAPPELLA VARIANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
AUTISM, SUSCEPTIBILITY TO, X-LINKED 3, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MECP2, 41-BP DEL, NT1157
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267608327,
|
|
|
|
|
|
|
|
ClinVar: RCV000012592, RCV000132895, RCV000168701, RCV000169930, RCV000170099, RCV000645107, RCV002251999
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Rett Syndrome, Zappella Variant</em></strong></p><p>
|
|
In a patient with Zappella variant, also known as preserved speech variant, Rett syndrome (see 312750), De Bona et al. (2000) found a 41-bp deletion in the MECP2 gene beginning at nucleotide 1157. The DNA deletion resulted in a deletion of 14 amino acids beginning with codon 386 with a frameshift and stop codon at 404. </p><p><strong><em>Autism, Susceptibility to, X-Linked 3</em></strong></p><p>
|
|
Carney et al. (2003) identified a female with classic autism disorder (AUTSX3; 300496) who had this mutation in MECP2. She had virtually none of the diagnostic criteria for Rett syndrome. Analysis of X chromosome inactivation in blood leukocytes showed borderline skewing, with a 31% pattern. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 RETT SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MECP2, 41-BP DEL, NT1159
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267608592,
|
|
|
|
|
|
|
|
ClinVar: RCV000132913, RCV000486453
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with classic Rett syndrome (RTT; 312750), De Bona et al. (2000) found a 41-bp deletion beginning at nucleotide 1159 of the MECP2 gene. The DNA deletion resulted in deletion of 14 amino acids beginning with codon 387 as well as a frameshift with a stop codon at codon 404. Remarkably, the 1157del41 mutation (300005.0012) also has a 41-bp deletion with loss of 14 amino acids and a stop at 404; however, that mutation caused the preserved speech variant, whereas the 1159del41 mutation caused classic Rett syndrome. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 RETT SYNDROME, ZAPPELLA VARIANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MECP2, 44-BP DEL, NT1159
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs61752992,
|
|
|
|
|
|
|
|
ClinVar: RCV000012595, RCV000132932, RCV000169931, RCV000169932, RCV000170102, RCV000170103, RCV000415090, RCV000491803, RCV000624849, RCV000768267, RCV001002125, RCV001420272, RCV003989323, RCV004528867
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Zappella variant Rett syndrome, also known as preserved speech variant (see 312750), De Bona et al. (2000) found a 44-bp deletion beginning at nucleotide 1159 of the MECP2 gene, and resulting in deletion of 15 amino acids beginning with codon 387 and stopping with a frameshift and a stop codon at 404. Remarkably, the deletion began at the same nucleotide as in the 1159del41 mutation (300005.0013) and led to a stop at the same codon, 404, but in this case caused the preserved speech variant rather than classic Rett syndrome. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC 13</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MECP2, ALA140VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28934908,
|
|
|
|
|
|
gnomAD: rs28934908,
|
|
|
|
|
|
ClinVar: RCV000012596, RCV000020628, RCV000224266, RCV000414791, RCV000544176, RCV001004016, RCV001197458, RCV001249626, RCV001257756, RCV001374894, RCV002326676, RCV002466399, RCV004734513, RCV004819207
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an adult mother and daughter with mildly impaired intellectual development, speech difficulties, and gait disturbances, Orrico et al. (2000) identified a 493C-T transition in the MECP2 gene, resulting in an ala140-to-val (A140V) substitution in a highly conserved region in the alpha helix of the methyl-CpG binding domain. Four of the mother's adult sons who inherited the mutation had severe mental retardation, impaired language development, and movement disorders with tremor and bradykinesia (MRXS13; 300055). The mutation was not present in the normal father or in 300 X chromosomes from normal individuals. The pattern of X-chromosome inactivation in the mother and daughter were close to random. The authors suggested that missense mutations such as A140V may correlate with milder disease than those resulting from truncating mutations, possibly through the presence of residual protein function. Dotti et al. (2002) reviewed the clinical findings of the family reported by Orrico et al. (2000) and noted that although the mental retardation and neurologic signs were more pronounced in the men than in the women, the women did demonstrate abnormalities. Features present in all 6 family members included slowly progressive spastic paraparesis/pyramidal signs, distal atrophy of the legs, and mild dysmorphic features. </p><p>In 2 males with nonspecific sporadic mental retardation, Couvert et al. (2001) identified the A140V mutation. No other clinical details were provided. </p><p>Winnepenninckx et al. (2002) identified the A140V mutation in 5 affected males from a large kindred with X-linked mental retardation, which the authors designated MRX79 (300055). Variable clinical features included delayed psychomotor development, tremor, mood instability, and hyperkinetic behavior. Four carrier females in the family appeared to be unaffected. Winnepenninckx et al. (2002) referred to several other reports of the A140V mutation and estimated that this mutation occurs in approximately 1% of all X-linked mental retardation families. </p><p>Klauck et al. (2002) identified the A140V mutation in affected members of a pedigree with mental retardation associated with psychosis, pyramidal signs, and macroorchidism, designated PPMX, and consistent with MRXS13. They pointed out that there had been independent reports of 2 patients with familial mental retardation and 2 patients with sporadic mental retardation caused by this mutation in the MECP2 gene. They suggested that A140V is a hotspot for mutation, resulting in moderate to severe mental retardation in males. They designed a simple and reliable PCR approach for detection of the A140V mutation as a prescreen in unexplained cases of mental retardation before further extensive mutation analyses. </p><p>Cohen et al. (2002) identified the A140V mutation in a boy with a developmental language disorder and onset of psychosis and childhood schizophrenia (see 300055) at age 12 years. His unaffected mother also carried the mutation. The report expanded the phenotypic spectrum of males with the A140V mutation. </p><p>Villard (2007) stated that the A140V mutation had never been reported in a girl with classic Rett syndrome (312750), suggesting that it results in serious disorders only when present in male patients. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 RETT SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MECP2, ARG306CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28935468,
|
|
|
|
|
|
|
|
ClinVar: RCV000012597, RCV000081218, RCV000202468, RCV000224156, RCV000466020, RCV001841244, RCV002273927, RCV002287332, RCV002444428, RCV003224093, RCV004532325
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated patients with Rett syndrome (RTT; 312750), Bourdon et al. (2001) found a 916C-T transition in exon 3 of the MECP2 gene resulting in an arg306-to-cys (R306C) amino acid change. </p><p>The R306C mutation was also found in heterozygous state by Heilstedt et al. (2002) in a girl with atypical Rett syndrome manifested by developmental delay and hypotonia without evidence of an initial period of normal development. The mother did not carry the mutation. </p><p>In a study of patients with mutations in the MECP2 gene, Schanen et al. (2004) found that the group of patients with the R306C mutation had a better prognosis, including better overall phenotype severity scores, later regression, and better speech with less motor impairment, than other mutation groups. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC 13</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MECP2, GLU137GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs61748392,
|
|
|
|
|
|
|
|
ClinVar: RCV000012598, RCV001230698, RCV001566839
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a 4-generation family with syndromic intellectual developmental disorder (MRXS13; 300055) described by Gendrot et al. (1999), Couvert et al. (2001) found an A-G transition in the MECP2 gene, resulting in a glu137-to-gly (E137G) substitution in the methyl-CpG-binding domain. Gomot et al. (2003) noted that some affected male patients in the family reported by Gendrot et al. (1999) had features seen in classic Rett syndrome, including regression of written and oral language, verbal and motor stereopathies, clumsiness, and spasticity. Female carriers of the mutation were unaffected but did not show remarkable X-inactivation patterns. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 RETT SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MECP2, 1-BP DEL, 76C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs61754426,
|
|
|
|
|
|
|
|
ClinVar: RCV000133236, RCV001808401
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a sporadic patient with classic Rett syndrome (RTT; 312750), Nielsen et al. (2001) detected a 1-bp deletion at nucleotide 76 of the MECP2 gene, which resulted in a truncated protein of 31 amino acids. X-chromosome inactivation was random and the phenotype was no more severe than that of patients with a deletion in the 3-prime end of the gene. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 RETT SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MECP2, 14-BP DUP, NT766
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<br />
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SNP: rs267608524,
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ClinVar: RCV000133235
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a sporadic patient with classic Rett syndrome (RTT; 312750), Nielsen et al. (2001) detected a 14-bp duplication beginning at nucleotide 766 of the MECP2 gene. The mutation was predicted to introduce a stop codon downstream after 32 missense amino acids, leading to a truncated protein of 292 amino acids missing part of the TRD domain. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0020 RETT SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MECP2, ARG168TER
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<br />
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SNP: rs61748421,
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ClinVar: RCV000012601, RCV000133143, RCV000224869, RCV000545521, RCV000626872, RCV002311514, RCV003984807, RCV004532326
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Wan et al. (1999) identified an arg168-to-ter (R168X) mutation in the MECP2 gene in 6 unrelated sporadic cases of Rett syndrome (RTT; 312750), as well as in 2 affected sisters and their normal mother. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0021 RETT SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MECP2, ARG255TER
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<br />
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SNP: rs61749721,
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ClinVar: RCV000012602, RCV000081209, RCV000169938, RCV000515183, RCV000553858, RCV001813976, RCV002273928, RCV002313706, RCV003989103, RCV004545727, RCV004698464
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with sporadic Rett syndrome (RTT; 312750), Amir et al. (1999) identified an 837C-T transition in the MECP2 gene, resulting in a nonsense mutation arg255-to-ter (R255X). Cheadle et al. (2000), Bienvenu et al. (2000), and Huppke et al. (2000) each found an R255X mutation in the methyl-CpG-binding protein in multiple patients with Rett syndrome. </p><p>By analysis of genotype/phenotype correlations of Rett syndrome cases reported in a large global database, Bebbington et al. (2008) found that R270X (300005.0005) and R255X were associated with the most severe phenotype. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0022 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC 13</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MECP2, 240-BP DEL, NT1161
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<br />
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SNP: rs1557134946,
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ClinVar: RCV000170257, RCV002472329
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family in which 3 males in 2 generations had mildly impaired intellectual development (MRXS13; 300055), Yntema et al. (2002) found an in-frame deletion of 240 basepairs (1161_1400del) from the MECP2 gene, resulting in the loss of 80 amino acids at the C-terminal end of the protein downstream of the transcription repression domain. There were no morphologic or neurologic anomalies. Gomot et al. (2003) provided follow-up of the family reported by Yntema et al. (2002). One obligate female carrier had markedly skewed X inactivation (0:100%). Affected males had various mood or behavioral problems, including emotional disturbance and aggression. Two had verbal stereotypies. Mental regression did not occur. Gomot et al. (2003) suggested that the relatively pure mental retardation phenotype in this family without severe motor abnormalities may be explained by the distal localization of the in-frame deletion in MECP2. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0023 ENCEPHALOPATHY, NEONATAL SEVERE, DUE TO MECP2 MUTATION</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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|
MECP2, GLY428SER
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<br />
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|
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SNP: rs61753971,
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gnomAD: rs61753971,
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ClinVar: RCV000012604, RCV000132982, RCV001719695, RCV002260597, RCV002371770, RCV004540997
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|
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|
|
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</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male with nonprogressive encephalopathy of neonatal onset (300673), Imessaoudene et al. (2001) identified a 1282G-A transition in the MECP2 gene, resulting in a gly428-to-ser (G428S) substitution. They suggested that the patient's grandfather, whose DNA was unavailable, was mosaic for the G428S mutation. </p><p>Laccone et al. (2002) questioned the validity of the G428S substitution as the disease-causing mutation. They identified the G428S substitution in a boy with severe encephalopathy and untreatable seizures who died at 18 months of age. They noted that the patient with the G428S mutation described by Imessaoudene et al. (2001) had a less severe phenotype and that the G428S change was more consistent with a rare genetic variant, as the grandpaternal mosaicism could not be proven. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 RETT SYNDROME, ATYPICAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MECP2, 52-BP DEL
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|
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|
|
<br />
|
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|
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SNP: rs1557135251,
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|
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ClinVar: RCV000012605, RCV000170146, RCV002508196, RCV003638635, RCV003991021
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|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Watson et al. (2001) reported a 52-bp deletion in the MECP2 gene in a girl with an Angelman-like phenotype (105830) who had some features of Rett syndrome (RTT; 312750). </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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|
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<div>
|
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0025 RETT SYNDROME, ATYPICAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MECP2, TYR141TER
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs61748396,
|
|
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|
|
|
|
|
ClinVar: RCV000012606, RCV000133106, RCV000170108, RCV000623504, RCV000729616, RCV001049210
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a girl with an Angelman-like phenotype (105830) with some features of Rett syndrome (RTT; 312750), Watson et al. (2001) reported a 497C-G transition in the MECP2 gene, resulting in premature termination of the protein at residue 141 (Y141X). This mutation had been reported in girls with Rett syndrome (Amir et al., 1999). </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0026 RETT SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MECP2, GLU455TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894864,
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|
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|
|
|
|
|
ClinVar: RCV000012607, RCV000132997
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Maiwald et al. (2002) described a 46,XX male with Rett syndrome (RTT; 312750) caused by a glu455-to-ter (E455X) mutation in exon 4 of the MECP2 gene. The boy was heterozygous for the mutation, which was of paternal origin and led to a premature termination of the protein downstream of the transcriptional repression domain. Upon amniocentesis performed because of advanced maternal age, a female karyotype was detected in the sonographically male fetus. Both the phenotype and the karyotype were confirmed after birth, and the absence of mullerian structures was demonstrated by ultrasonography. Motor development was delayed; he was able to sit only at 14 months of age. He was still not able to walk and there was no speech at the age of 24 months. At the age of 2 years, he showed truncal muscular hypotonia, microcephaly, spasticity, and convergent strabismus of the left eye. There was a loss of purposeful hand skills at approximately 6 months of age, and a deceleration of head growth at approximately 7 months. The clinical appearance of the boy resembled female Rett cases, which was explained by the karyotype. In addition, preferential expression of the normal allele may have contributed to the rather mild phenotype. Similar features had been described in male patients with MECP2 mutations and a Klinefelter karyotype (46,XXY). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0027 RETT SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MECP2, LEU100VAL
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs28935168,
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|
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|
|
|
ClinVar: RCV000012608, RCV000498874
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Rett syndrome (RTT; 312750), Buyse et al. (2000) identified a 298C-G change in the MECP2 gene, resulting in a leu100-to-val (L100V) substitution. </p><p>Hammer et al. (2003) reported a 5-year-old girl with a 47,XXX karyotype who had relatively mild atypical Rett syndrome leading initially to a diagnosis of infantile autism with regression. Mutation analysis identified a de novo L100V mutation in the MECP2 gene. The supernumerary X chromosome was maternally derived. X-inactivation patterns indicated preferential inactivation of the paternal allele. The authors suggested that the patient illustrated the importance of allele dosage on phenotypic expression. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0028 RETT SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MECP2, 11-BP DEL, EX1
|
|
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|
|
<br />
|
|
|
|
SNP: rs786205042,
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|
|
|
|
|
|
|
ClinVar: RCV000170288, RCV001245569
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with typical Rett syndrome (RTT; 312750), Mnatzakanian et al. (2004) identified an 11-bp deletion in exon 1 of the MECP2 gene. This mutation was not found in either of the patient's parents, in her brother, or in 200 control individuals. This mutation eliminates expression of the MECP2B isoform (which uses exons 1, 3, and 4) but does not affect the expression of MECP2A, the previously described isoform of MECP2. </p><p>Ravn et al. (2005) identified the 11-bp deletion in exon 1 of the MECP2 gene in a Danish patient with typical Rett syndrome. The authors emphasized the importance of mutation screening of MECP2 exon 1. </p><p>Saxena et al. (2006) screened exon 1 among RNA samples from 20 females with classic or atypical RTT and detected the 11-bp deletion in exon 1 originally reported by Mnatzakanian et al. (2004) in 1 subject with a milder phenotype. Although RNA expression for both protein isoforms was detected from the mutant allele, evaluation of MECP2 protein in uncultured patient lymphocytes by immunocytochemistry revealed that protein production was restricted to only 74 to 76% of lymphocytes. X chromosome inactivation studies of genomic DNA revealed similar X chromosome inactivation ratios at the HUMARA locus. Saxena et al. (2006) demonstrated that translation but not transcription of the isoform rising from exon 2 is ablated by the 11-nucleotide deletion, 103 nucleotides upstream of the translation start site of the exon 2 isoform. Thus, nucleotides within the deleted sequence in the 5-prime UTR of the exon 2 transcript, while not required for transcription, are essential for translation. </p>
|
|
</span>
|
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</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0029 RETT SYNDROME</strong>
|
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</span>
|
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</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
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MECP2, 5-BP DUP, 23CGCCG
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<br />
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SNP: rs786205038,
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ClinVar: RCV000170282
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a Danish patient with typical Rett syndrome (RTT; 312750), Ravn et al. (2005) identified a 5-bp duplication (23dupCGCCG) in exon 1 of the MECP2 gene, resulting in a frameshift and premature termination of the protein. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0030 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, LUBS-TYPE</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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|
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MECP2, DUP
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<br />
|
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ClinVar: RCV000012611
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a boy with Lubs-type X-linked intellectual developmental disorder (MRXSL; 300260), Meins et al. (2005) found a submicroscopic duplication of Xq28, including the MECP2 gene. Dosage analysis of family members showed 2 gene copies in the boy and 3 copies in his healthy mother, who had severely skewed X inactivation. Quantification of transcript levels suggested a double dose of MECP2 in the boy, but not in his mother. Further analysis showed that the duplication included 12 genes, from AVPR2 (300538) to TKTL1 (300044); the L1CAM (308840) gene was excluded. </p><p>By array comparative genomic hybridization (CGH) analysis, Van Esch et al. (2005) identified a small duplication at Xq28 in affected males from 4 families with a severe form of mental retardation associated with progressive spasticity and respiratory infections. The duplications in the 4 patients varied in size from 0.4 to 0.8 Mb and comprised the MECP2 and L1CAM genes in each case. Increased dosage of MECP2 appeared to be responsible for the mental retardation phenotype. The main features present in the affected males were severe to profound mental retardation with onset at birth, axial and facial hypotonia, progressive spasticity predominantly at the lower limbs, seizures, and recurrent infections leading to early death in 4 of the affected members of 1 family. The affected males also shared some mild dysmorphic features, including large ears and flat nasal bridge. </p><p>Del Gaudio et al. (2006) reported 6 males with duplication and 1 male with triplication of MECP2. All had developmental delay and infantile hypotonia. All but 1 had absent speech. The spasticity reported by Van Esch et al. (2005) was not seen in the patients reported by del Gaudio et al. (2006). </p><p>Belligni et al. (2010) reported a 5-year-old boy who demonstrated severe central hypotonia and central hypoventilation at birth, necessitating a tracheostomy. He showed severe developmental delay with poor head control. He also had a persistent ductus arteriosus and chronic constipation, without evidence of Hirschsprung disease. Brain MRI showed decreased white matter bulk and bilateral optic nerve hypoplasia. Genetic analysis identified a 0.5- to 0.8-Mb interstitial duplication of chromosome Xq28 including the MECP2 and L1CAM genes, which was inherited from his asymptomatic mother. Belligni et al. (2010) suggested that MECP2 be evaluated in patients with features of the congenital hypoventilation syndrome (209880). </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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|
|
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</div>
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<div>
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0031 RETT SYNDROME</strong>
|
|
</span>
|
|
</h4>
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</div>
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<div>
|
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<span class="mim-text-font">
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|
MECP2, 1-BP DEL AND 2-BP INS, NT30
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<br />
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SNP: rs786205040,
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gnomAD: rs786205040,
|
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|
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ClinVar: RCV000170285
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|
|
|
|
|
</span>
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|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 1 of 20 girls with Rett syndrome (RTT; 312750), Bartholdi et al. (2006) identified a combination 1-bp deletion and 2-bp insertion (30delCinsGA) in exon 1 of the MECP2 gene, resulting in a frameshift and premature stop codon. She had a particularly severe form of the disorder, leading to death at age 19 years. Bartholdi et al. (2006) postulated that patients with mutations involving exon 1 of the MECP2 gene are more severely affected than those with MECP2 mutations that do not affect exon 1. </p>
|
|
</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0032 RETT SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
ENCEPHALOPATHY, NEONATAL SEVERE, DUE TO MECP2 MUTATION, INCLUDED
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
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MECP2, 2-BP DEL, 488GG
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<br />
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SNP: rs267608488,
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|
ClinVar: RCV000133140, RCV000170111
|
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|
|
|
|
</span>
|
|
</div>
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|
<div>
|
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<span class="mim-text-font">
|
|
<p>In a girl with Rett syndrome (RTT; 312750), Geerdink et al. (2002) identified a 2-bp deletion (488delGG) in exon 3 of the MECP2 gene, resulting in a frameshift and premature termination. Her younger brother, who also carried the hemizygous mutation, had a severe neonatal encephalopathy (300673) with respiratory insufficiency with apnea, central hypoventilation, and poor feeding. He also had axial hypotonia with hyperextension and rigidity of the limbs, multifocal seizures, stereotypical rubbing of his hand over his face, and gastroesophageal reflux. He died at age 13 months of respiratory failure. Postmortem examination showed bilateral polymicrogyria. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0033 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC 13</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MECP2, PRO225LEU
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<br />
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|
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SNP: rs61749715,
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|
|
|
|
ClinVar: RCV000012615, RCV000133194, RCV005089237
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 21-year-old man with severely impaired intellectual disorder since infancy and spasticity (MRXS13; 300055), Moog et al. (2003) identified a de novo 674C-T transition in exon 3 of the MECP2 gene, resulting in a pro225-to-leu (P225L) substitution in the transcriptional repression domain of the protein. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0034 ENCEPHALOPATHY, NEONATAL SEVERE, DUE TO MECP2 MUTATION</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MECP2, 32-BP DEL, NT1154
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|
|
|
<br />
|
|
|
|
SNP: rs1569548314,
|
|
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|
|
|
|
|
ClinVar: RCV000012616
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 brothers with severe neonatal encephalopathy and death in infancy (300673), Hoffbuhr et al. (2001) identified a 32-bp deletion at nucleotide 1154 of the MECP2 gene, resulting in a truncation and absence of the methyl-binding and transcription repression domains. The unaffected carrier mother showed skewed X inactivation. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
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|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0035 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC 13</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MECP2, PRO322SER
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|
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<br />
|
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|
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SNP: rs61751449,
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|
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|
|
|
|
ClinVar: RCV000012617, RCV000416315, RCV001090501, RCV005089238
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a boy with delayed development, language delay, seizures, and ataxia (MRXS13; 300055), Ventura et al. (2006) identified a 964C-T transition in the MECP2 gene, resulting in a pro322-to-ser (P322S) substitution. He had frequent seizures, including myoclonic seizures, hypotonia, lower limb weakness, ataxia, dysmetria, and intention tremor. He also showed hyperactivity, irritability, and psychomotor restlessness. Mild dysmorphic features included frontal bossing, low-set ears, and irregular teeth placement. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0036 RETT SYNDROME, ZAPPELLA VARIANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MECP2, PRO152ALA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs179363900,
|
|
|
|
|
|
gnomAD: rs179363900,
|
|
|
|
|
|
ClinVar: RCV000012618, RCV000133115, RCV000492792, RCV000763200, RCV000991003, RCV001246099, RCV004734514
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a father and his 10-year-old daughter with neuropsychiatric features reminiscent of the mild phenotype of Zappella variant Rett syndrome (see 312750), Adegbola et al. (2009) identified a heterozygous 454C-G transversion in exon 4 of the MECP2 gene, resulting in a pro152-to-ala (P152A) substitution in the methyl-binding domain of the protein. The girl had purposeful hand movements with occasional hand-wringing stereotypes, was morbidly obese, was prone to aggressive outbursts, had mild autistic features, and IQ of 58. Her father had an IQ of 85, had special schooling, and showed behavioral dyscontrol and hyperactivity in childhood and adolescence. In vitro functional expression studies in mouse fibroblasts demonstrated that the mutant protein showed varying levels of diffuse nuclear staining outside of the heterochromatic foci compared to wildtype, which localizes exclusively to heterochromatic foci. Biochemical studies showed that mutant P152A had a 40% reduction in association with insoluble heterochromatin compared to wildtype. Classic Rett mutations showed an 70 to 80% decrease. The findings were consistent with a hypomorphic MECP2 allele contributing to a neuropsychiatric phenotype in this family. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0037 RETT SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MECP2, ALA2VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs179363901,
|
|
|
|
|
|
gnomAD: rs179363901,
|
|
|
|
|
|
ClinVar: RCV000012619, RCV001851806, RCV004760328
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a girl with Rett syndrome (RTT; 312750), Fichou et al. (2009) identified a de novo heterozygous 5T-C transition in exon 1 of the MECP2 gene, resulting in an ala2-to-val (A2V) substitution in the MeCP2_e1 isoform, which is more abundant in the brain than the MeCP2_e2 isoform. The mutation changed the first alanine of a well-conserved 7-residue polyalanine tract. In vitro studies of patient fibroblasts showed that the A2V mutation had no effect on the MeCP2_e2 isoform. The patient had severe developmental delay, microcephaly, no language, severe epilepsy, and cognitive impairment. Fichou et al. (2009) concluded that disruption of the MeCP2_e1 isoform is sufficient to cause Rett syndrome, and that Rett syndrome can occur in the presence of a normal MeCP2_e2 isoform. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0038 RETT SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MECP2, 1-BP DEL, 710G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs61749743,
|
|
|
|
|
|
|
|
ClinVar: RCV000012620, RCV000506656, RCV001045878, RCV002362579
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 1 of the original patients with Rett syndrome (RTT; 312750) reported by Rett (1966), Freilinger et al. (2009) identified a 1-bp deletion (710delG) in exon 4 of the MECP2 gene, resulting in a frameshift and premature termination after amino acid 246. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0039 AUTISM, SUSCEPTIBILITY TO, X-LINKED 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MECP2, GLU483TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587777421,
|
|
|
|
|
|
gnomAD: rs587777421,
|
|
|
|
|
|
ClinVar: RCV000119842, RCV001507055, RCV001582589
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 brothers with autism (AUTSX3; 300496), Yu et al. (2013) identified a nonsense mutation in the MECP2 gene, glu483 to ter (E483X). The mutation was inherited from their unaffected mother. The mutation was predicted to result in removal of only the last 4 amino acids of the full-length protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Abuhatzira, L., Shemer, R., Razin, A.
|
|
<strong>MeCP2 involvement in the regulation of neuronal alpha-tubulin production.</strong>
|
|
Hum. Molec. Genet. 18: 1415-1423, 2009.
|
|
|
|
|
|
[PubMed: 19174478]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddp048]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Adegbola, A. A., Gonzales, M. L., Chess, A., LaSalle, J. M., Cox, G. F.
|
|
<strong>A novel hypomorphic MECP2 point mutation is associated with a neuropsychiatric phenotype.</strong>
|
|
Hum. Genet. 124: 615-623, 2009.
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|
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|
|
[PubMed: 18989701]
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|
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|
|
[Full Text: https://doi.org/10.1007/s00439-008-0585-6]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Adler, D. A., Quaderi, N. A., Brown, S. D. M., Chapman, V. M., Moore, J., Tate, P., Disteche, C. M.
|
|
<strong>The X-linked methylated DNA binding protein, Mecp2, is subject to X inactivation in the mouse.</strong>
|
|
Mammalian Genome 6: 491-492, 1995.
|
|
|
|
|
|
[PubMed: 8589515]
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|
|
|
|
|
[Full Text: https://doi.org/10.1007/BF00356163]
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Amano, K., Nomura, Y., Segawa, M., Yamakawa, K.
|
|
<strong>Mutational analysis of the MECP2 gene in Japanese patients with Rett syndrome.</strong>
|
|
J. Hum. Genet. 45: 231-236, 2000.
|
|
|
|
|
|
[PubMed: 10944854]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s100380070032]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., Zoghbi, H. Y.
|
|
<strong>Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.</strong>
|
|
Nature Genet. 23: 185-188, 1999.
|
|
|
|
|
|
[PubMed: 10508514]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/13810]
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Archer, H. L., Whatley, S. D., Evans, J. C., Ravine, D., Huppke, P., Kerr, A., Bunyan, D., Kerr, B., Sweeney, E., Davies, S. J., Reardon, W., Horn, J., and 14 others.
|
|
<strong>Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett syndrome patients. (Letter)</strong>
|
|
J. Med. Genet. 43: 451-456, 2006.
|
|
|
|
|
|
[PubMed: 16183801]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1136/jmg.2005.033464]
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ashley-Koch, A. E., Carney, R. J., Wolpert, C. M., Cuccaro, M. L., Gilbert, J. R., Vance, J. M., Pericak-Vance, M. A.
|
|
<strong>Screening for MECP2 mutations in females with autistic disorder. (Abstract)</strong>
|
|
Am. J. Med. Genet. 105B: 632 only, 2001.
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ballestar, E., Yusufzai, T. M., Wolffe, A. P.
|
|
<strong>Effects of Rett syndrome mutations of the methyl-CpG binding domain of the transcriptional repressor MeCP2 on selectivity for association with methylated DNA.</strong>
|
|
Biochemistry 39: 7100-7106, 2000.
|
|
|
|
|
|
[PubMed: 10852707]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1021/bi0001271]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Balmer, D., Arredondo, J., Samaco, R. C., LaSalle, J. M.
|
|
<strong>MECP2 mutations in Rett syndrome adversely affect lymphocyte growth, but do not affect imprinted gene expression in blood or brain.</strong>
|
|
Hum. Genet. 110: 545-552, 2002.
|
|
|
|
|
|
[PubMed: 12107440]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s00439-002-0724-4]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bartholdi, D., Klein, A., Weissert, M., Koenig, N., Baumer, A., Boltshauser, E., Schinzel, A., Berger, W., Matyas, G.
|
|
<strong>Clinical profiles of four patients with Rett syndrome carrying a novel exon 1 mutation or genomic rearrangement in the MECP2 gene.</strong>
|
|
Clin. Genet. 69: 319-326, 2006.
|
|
|
|
|
|
[PubMed: 16630165]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1111/j.1399-0004.2006.00604.x]
|
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Wan, M., Zhao, K., Lee, S. S. J., Francke, U.
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Wang, H., Chan, S., Ogier, M., Hellard, D., Wang, Q., Smith, C., Katz, D. M.
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Ada Hamosh - updated : 01/05/2021<br>Ada Hamosh - updated : 02/22/2018<br>Matthew B. Gross - updated : 11/17/2017<br>Ada Hamosh - updated : 06/06/2017<br>Paul J. Converse - updated : 05/16/2017<br>Ada Hamosh - updated : 06/25/2015<br>Ada Hamosh - updated : 6/6/2014<br>Patricia A. Hartz - updated : 1/15/2014<br>Ada Hamosh - updated : 9/20/2013<br>Ada Hamosh - updated : 7/23/2012<br>Cassandra L. Kniffin - updated : 6/13/2012<br>Ada Hamosh - updated : 4/24/2012<br>Ada Hamosh - updated : 9/1/2011<br>Ada Hamosh - updated : 7/18/2011<br>Ada Hamosh - updated : 1/31/2011<br>Cassandra L. Kniffin - updated : 12/3/2010<br>Ada Hamosh - updated : 11/29/2010<br>Cassandra L. Kniffin - updated : 7/13/2010<br>George E. Tiller - updated : 3/30/2010<br>George E. Tiller - updated : 3/3/2010<br>Cassandra L. Kniffin - updated : 1/5/2010<br>George E. Tiller - updated : 11/25/2009<br>Cassandra L. Kniffin - updated : 10/16/2009<br>George E. Tiller - updated : 7/31/2009<br>Cassandra L. Kniffin - updated : 5/27/2009<br>Cassandra L. Kniffin - updated : 5/14/2009<br>Cassandra L. Kniffin - updated : 4/13/2009<br>Cassandra L. Kniffin - updated : 2/25/2009<br>Cassandra L. Kniffin - updated : 1/6/2009<br>George E. Tiller - updated : 11/21/2008<br>George E. Tiller - updated : 10/29/2008<br>Ada Hamosh - updated : 6/10/2008<br>George E. Tiller - updated : 4/25/2008<br>Cassandra L. Kniffin - updated : 3/6/2008<br>George E. Tiller - updated : 2/18/2008<br>George E. Tiller - updated : 2/7/2008<br>George E. Tiller - updated : 1/3/2008<br>George E. Tiller - updated : 11/8/2007<br>Patricia A. Hartz - updated : 10/16/2007<br>Cassandra L. Kniffin - updated : 9/18/2007<br>Victor A. McKusick - updated : 9/6/2007<br>Cassandra L. Kniffin - updated : 8/24/2007<br>Ada Hamosh - updated : 7/25/2007<br>George E. Tiller - updated : 6/13/2007<br>Cassandra L. Kniffin - updated : 4/27/2007<br>Ada Hamosh - updated : 4/17/2007<br>Cassandra L. Kniffin - updated : 1/4/2007<br>John Logan Black, III - updated : 8/4/2006<br>Victor A. McKusick - updated : 7/5/2006<br>Cassandra L. Kniffin - updated : 6/2/2006<br>Patricia A. Hartz - updated : 5/5/2006<br>Marla J. F. O'Neill - updated : 12/1/2005<br>Marla J. F. O'Neill - updated : 10/18/2005<br>Cassandra L. Kniffin - updated : 10/3/2005<br>George E. Tiller - updated : 9/30/2005<br>Patricia A. Hartz - updated : 9/21/2005<br>Victor A. McKusick - updated : 8/18/2005<br>Patricia A. Hartz - updated : 8/4/2005<br>Cassandra L. Kniffin - updated : 5/18/2005<br>Cassandra L. Kniffin - updated : 3/18/2005<br>Victor A. McKusick - updated : 3/8/2005<br>Marla J. F. O'Neill - updated : 1/28/2005<br>George E. Tiller - updated : 8/19/2004<br>Victor A. McKusick - updated : 7/2/2004<br>Victor A. McKusick - updated : 5/11/2004<br>Ada Hamosh - updated : 3/30/2004<br>Cassandra L. Kniffin - updated : 3/23/2004<br>Felicity Collins - updated : 12/10/2003<br>Ada Hamosh - updated : 12/3/2003<br>Cassandra L. Kniffin - updated : 11/10/2003<br>Cassandra L. Kniffin - reorganized : 11/7/2003<br>Cassandra L. Kniffin - updated : 10/23/2003<br>Victor A. McKusick - updated : 9/9/2003<br>Michael B. Petersen - updated : 6/16/2003<br>Michael B. Petersen - updated : 6/16/2003<br>Victor A. McKusick - updated : 6/11/2003<br>Cassandra L. Kniffin - updated : 1/28/2003<br>Victor A. McKusick - updated : 1/8/2003<br>Dawn Watkins-Chow - updated : 12/16/2002<br>Victor A. McKusick - updated : 11/13/2002<br>Victor A. McKusick - updated : 11/1/2002<br>Victor A. McKusick - updated : 9/19/2002<br>George E. Tiller - updated : 9/16/2002<br>Michael B. Petersen - updated : 9/10/2002<br>Michael B. Petersen - updated : 9/10/2002<br>Victor A. McKusick - updated : 8/27/2002<br>Victor A. McKusick - updated : 8/13/2002<br>Michael J. Wright - updated : 7/1/2002<br>Michael J. Wright - updated : 4/26/2002<br>Victor A. McKusick - updated : 4/12/2002<br>George E. Tiller - updated : 2/5/2002<br>Victor A. McKusick - updated : 1/17/2002<br>Michael B. Petersen - updated : 11/28/2001<br>Victor A. McKusick - updated : 11/7/2001<br>Michael B. Petersen - updated : 10/25/2001<br>George E. Tiller - updated : 10/11/2001<br>George E. Tiller - updated : 10/2/2001<br>Victor A. McKusick - updated : 9/20/2001<br>Victor A. McKusick - updated : 8/3/2001<br>Victor A. McKusick - updated : 6/13/2001<br>Stylianos E. Antonarakis - updated : 6/4/2001<br>Ada Hamosh - updated : 3/2/2001<br>Victor A. McKusick - updated : 1/31/2001<br>Victor A. McKusick - updated : 1/12/2001<br>Michael J. Wright - updated : 1/8/2001<br>Ada Hamosh - updated : 1/3/2001<br>Victor A. McKusick - updated : 12/13/2000<br>Victor A. McKusick - updated : 11/2/2000<br>Ada Hamosh - updated : 11/2/2000<br>Victor A. McKusick - updated : 10/20/2000<br>Victor A. McKusick - updated : 8/31/2000<br>Paul J. Converse - updated : 8/21/2000<br>George E. Tiller - updated : 8/8/2000<br>George E. Tiller - updated : 5/12/2000<br>Victor A. McKusick - updated : 12/20/1999<br>Victor A. McKusick - updated : 9/28/1999<br>Victor A. McKusick - updated : 9/14/1998<br>Victor A. McKusick - updated : 5/27/1998<br>Rebekah S. Rasooly - updated : 3/2/1998
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Creation Date:
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Victor A. McKusick : 1/29/1996
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carol : 08/20/2021<br>carol : 08/19/2021<br>mgross : 01/05/2021<br>carol : 02/26/2018<br>carol : 02/23/2018<br>alopez : 02/22/2018<br>mgross : 11/17/2017<br>alopez : 06/06/2017<br>alopez : 06/06/2017<br>mgross : 05/16/2017<br>carol : 02/22/2017<br>carol : 02/01/2017<br>carol : 01/31/2017<br>joanna : 08/04/2016<br>alopez : 06/25/2015<br>mgross : 3/20/2015<br>alopez : 6/6/2014<br>alopez : 6/6/2014<br>mgross : 1/17/2014<br>mcolton : 1/15/2014<br>mcolton : 11/26/2013<br>alopez : 9/20/2013<br>carol : 9/6/2013<br>carol : 4/19/2013<br>alopez : 10/3/2012<br>alopez : 7/24/2012<br>terry : 7/23/2012<br>alopez : 6/19/2012<br>ckniffin : 6/13/2012<br>terry : 5/10/2012<br>alopez : 4/25/2012<br>terry : 4/24/2012<br>alopez : 9/6/2011<br>terry : 9/1/2011<br>alopez : 7/18/2011<br>carol : 7/6/2011<br>alopez : 2/4/2011<br>terry : 1/31/2011<br>carol : 1/21/2011<br>alopez : 1/10/2011<br>wwang : 12/3/2010<br>alopez : 12/1/2010<br>terry : 11/29/2010<br>wwang : 7/14/2010<br>ckniffin : 7/13/2010<br>wwang : 4/2/2010<br>terry : 3/30/2010<br>wwang : 3/12/2010<br>terry : 3/3/2010<br>wwang : 2/2/2010<br>wwang : 1/5/2010<br>ckniffin : 1/5/2010<br>wwang : 1/5/2010<br>terry : 11/25/2009<br>wwang : 11/6/2009<br>ckniffin : 10/16/2009<br>wwang : 9/1/2009<br>wwang : 8/14/2009<br>terry : 7/31/2009<br>wwang : 6/8/2009<br>ckniffin : 5/27/2009<br>wwang : 5/27/2009<br>ckniffin : 5/14/2009<br>wwang : 4/29/2009<br>ckniffin : 4/13/2009<br>wwang : 3/6/2009<br>ckniffin : 2/25/2009<br>wwang : 1/13/2009<br>ckniffin : 1/6/2009<br>wwang : 11/21/2008<br>wwang : 11/18/2008<br>wwang : 10/29/2008<br>terry : 9/26/2008<br>ckniffin : 7/10/2008<br>alopez : 6/12/2008<br>terry : 6/10/2008<br>wwang : 4/29/2008<br>terry : 4/25/2008<br>wwang : 4/10/2008<br>ckniffin : 3/6/2008<br>wwang : 2/18/2008<br>wwang : 2/13/2008<br>terry : 2/7/2008<br>wwang : 1/11/2008<br>terry : 1/3/2008<br>wwang : 11/30/2007<br>terry : 11/8/2007<br>mgross : 10/18/2007<br>terry : 10/16/2007<br>wwang : 9/18/2007<br>ckniffin : 9/18/2007<br>carol : 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9/25/2001<br>mcapotos : 9/24/2001<br>terry : 9/20/2001<br>carol : 8/13/2001<br>cwells : 8/7/2001<br>terry : 8/3/2001<br>cwells : 6/19/2001<br>cwells : 6/14/2001<br>terry : 6/13/2001<br>mgross : 6/4/2001<br>alopez : 3/2/2001<br>mcapotos : 2/6/2001<br>mcapotos : 2/2/2001<br>terry : 1/31/2001<br>cwells : 1/18/2001<br>cwells : 1/18/2001<br>terry : 1/12/2001<br>alopez : 1/8/2001<br>carol : 1/7/2001<br>terry : 1/3/2001<br>carol : 12/14/2000<br>terry : 12/13/2000<br>terry : 12/4/2000<br>carol : 11/6/2000<br>mcapotos : 11/6/2000<br>carol : 11/3/2000<br>terry : 11/2/2000<br>mgross : 11/2/2000<br>carol : 11/2/2000<br>mcapotos : 10/31/2000<br>terry : 10/20/2000<br>terry : 8/31/2000<br>mgross : 8/21/2000<br>mgross : 8/21/2000<br>alopez : 8/8/2000<br>alopez : 5/12/2000<br>carol : 12/27/1999<br>terry : 12/20/1999<br>alopez : 9/30/1999<br>terry : 9/28/1999<br>psherman : 2/23/1999<br>alopez : 9/15/1998<br>alopez : 9/15/1998<br>terry : 9/14/1998<br>alopez : 6/1/1998<br>terry : 5/27/1998<br>carol : 3/2/1998<br>mark : 7/7/1997<br>mark : 9/11/1996<br>terry : 9/6/1996<br>mark : 1/29/1996
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