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<title>
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Entry
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- *607117 - MICROCEPHALIN 1; MCPH1
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- OMIM
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<div id="mimSearch" class="hidden-print">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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Advanced Search
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<a href="/search/advanced/entry"> OMIM </a>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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</form>
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<p />
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</div>
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<div class="row">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*607117</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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<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="#geneFunction">Gene Function</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="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#evolution">Evolution</a>
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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/607117">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 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=ENSG00000147316;t=ENST00000344683" 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=79648" 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=607117" 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=ENSG00000147316;t=ENST00000344683" 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_001172574,NM_001172575,NM_001322042,NM_001322043,NM_001322045,NM_001363979,NM_001363980,NM_001410916,NM_001410917,NM_024596,NR_136159,XM_011534756,XM_011534757,XM_011534758,XM_017013829,XM_017013832,XM_017013833,XM_047422233,XM_047422234" 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_024596" 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=607117" 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=06174&isoform_id=06174_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/MCPH1" 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/10434574,13396864,37529502,37529504,37529506,37529508,37529510,37529512,37529514,37529516,37529518,37529520,37529522,37529524,37529526,37529528,37529530,37529532,37529534,37529536,37529538,37529540,37529590,37529592,37529594,37529596,37529598,37529600,37529602,37529604,37529606,37529608,37529610,37529612,37529614,37529616,37529618,37529620,37529622,37529624,37529626,37529628,46276467,46276469,46276471,46276473,46276475,46276477,46276479,46276481,46276483,46276485,46276487,46276489,46276491,46276493,46276495,46276497,46276499,46276501,46276503,46276505,46276507,46276509,46276511,46276513,46276515,46276517,46276519,46276521,46276523,46276525,46276527,46276529,46276531,46276533,46276535,46276537,46276539,46276541,46276543,46276545,46276547,46276599,46276601,46276603,46276605,46276607,46276609,46276611,46276613,46276615,46276617,46276619,46276621,46276623,46276625,46276627,46276629,46276631,46276633,46276635,46276637,46276639,46276641,46276643,46276645,46276647,46276649,46276651,46276653,46276655,46276657,46276659,46276661,46276663,46276665,46276667,46276669,46276671,46276673,46276675,46276677,46276679,46276731,46276733,46276735,46276737,46276739,46276741,46276743,46276745,46276747,46276749,46276751,46276753,46276755,46276757,46276759,46276761,46276763,46276765,46276767,46276769,46276771,46276773,46276775,46276777,46276779,46276781,46276783,46276785,46276787,46276789,46276791,46276793,46276795,46276797,46276799,46276801,46276803,46276805,46276807,46276809,46276811,46324841,46324843,46324845,46324847,46324849,46324851,46324853,46324855,46324857,46324859,46324861,46324863,46324865,46324867,46324869,46324871,46324873,46324875,46324877,46324879,46324881,46324883,46324885,46324887,46324889,46324891,46324893,46324895,46324897,46324899,46324901,46324903,46324905,46324907,46324909,46324911,46324913,46324915,46324917,46324919,46324921,46324973,46324975,46324977,46324979,46324981,46324983,46324985,46324987,46324989,46324991,46324993,46324995,46324997,46324999,46325001,46325003,46325005,46325007,46325009,46325011,46325013,46325015,46325017,46325019,46325021,46325023,46325025,46325027,46325029,46325031,46325033,46325035,46325037,46325039,46325041,46325043,46325045,46325047,46325049,46325051,46325053,46325105,46325107,46325109,46325111,46325113,46325115,46325117,46325119,46325121,46325123,46325125,46325127,46325129,46325131,46325133,46325135,46325137,46325139,46325141,46325143,46325145,46325147,46325149,46325151,46325153,46325155,46325157,46325159,46325161,46325163,46325165,46325167,46325169,46325171,46325173,46325175,46325177,46325179,46325181,46325183,46325185,46325237,46325239,46325241,46325243,46325245,46325247,46325249,46325251,46325253,46325255,46325257,46325259,46325261,46325263,46325265,46325267,46325269,46325271,46325273,46325275,46325277,46325279,46325281,46325283,46325285,46325287,46325297,46325299,46325301,46325303,46325305,46325307,46325309,46325311,46325313,46325315,46325317,46325319,46325321,46325323,46325325,46325327,46325329,46325331,46325333,46325335,46325337,46325339,46325341,46325343,46325345,46325347,46325349,46325351,46325353,46325355,46325357,46325359,46325361,46325363,46325365,46325367,46325369,46325371,46325373,46325375,46325377,46325429,46325431,46325433,46325435,46325437,46325439,46325441,46325443,46325445,46325447,46325449,46325451,46325453,46325455,46325457,46325459,46325461,46325463,46325465,46325467,46325469,46325471,46325473,46325475,46325477,46325479,46325481,46325483,46325485,46325487,46325489,46325491,46325493,46325495,46325497,46325499,46325501,46325503,46325505,46325507,46325509,46325561,46325563,46325565,46325567,46325569,46325571,46325573,46325575,46325577,46325579,46325581,46325583,46325585,46325587,46325589,46325591,46325593,46325595,46325597,46325599,46325601,46325603,46325605,46325607,46325609,46325611,46325613,46325615,46325617,46325619,46325621,46325623,46325625,46325627,46325629,46325631,46325633,46325635,46325637,46325639,46325641,46325693,46325695,46325697,46325699,46325701,46325703,46325705,46325707,46325709,46325711,46325713,46325715,46325717,46325719,46325721,46325723,46325725,46325727,46325729,46325731,46325733,46325735,46325737,46325739,46325741,46325743,46325745,46325747,46325749,46325751,46325753,46325755,46325757,46325759,46325761,46325763,46325765,46325767,46325769,46325771,46325773,46358719,46358721,46358723,46358725,46358727,46358729,46358731,46358733,46358735,46358737,46358739,46358741,46358743,46358745,46358747,46358749,46358751,46358753,46358755,46358757,46358759,46358761,46358763,46358765,46358767,46358769,46358779,46358781,46358783,46358785,46358787,46358789,46358791,46358793,46358795,46358797,46358799,46358801,46358803,46358805,46358807,46358809,46358811,46358813,46358815,46358817,46358819,46358821,46358823,46358825,46358827,46358829,46358831,46358833,46358835,46358837,46358839,46358841,46358843,46358845,46358847,46358849,46358851,46358853,46358855,46358857,46358859,51536410,71051970,119600874,119600875,119600876,194377226,289191318,361073023,767950162,767950164,767950166,1027926617,1034661521,1034661529,1034661533,1051356712,1191186545,1394533646,1394533648,1519316290,1676344100,1890252436,1890321396,1890335888,2217373220,2217373224,2287478829,2287478833,2462621049,2462621051,2462621053,2462621055,2462621057,2462621059,2462621061,2462621063" 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/Q8NEM0" 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=79648" 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=ENSG00000147316;t=ENST00000344683" 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=MCPH1" 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=MCPH1" 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+79648" 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/MCPH1" 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:79648" 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/79648" 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=chr8&hgg_gene=ENST00000344683.10&hgg_start=6406627&hgg_end=6648508&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:6954" 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:6954" 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=607117[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=607117[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/MCPH1/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/ENSG00000147316" 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=MCPH1" 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=MCPH1" 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=MCPH1" 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="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=MCPH1&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/PA30701" 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:6954" 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://flybase.org/reports/FBgn0260959.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:2443308" 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/MCPH1#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:2443308" 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/79648/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://www.orthodb.org/?ncbi=79648" 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://wormbase.org/db/gene/gene?name=WBGene00012236;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-060421-6122" 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 class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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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 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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</a>
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<div><a href="https://reactome.org/content/query?q=MCPH1&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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<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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<a id="title" class="mim-anchor"></a>
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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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607117
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<a id="preferredTitle" class="mim-anchor"></a>
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<span class="mim-font">
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MICROCEPHALIN 1; MCPH1
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<em>Alternative titles; symbols</em>
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<span class="mim-font">
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MCPH1 GENE<br />
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MICROCEPHALIN<br />
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BRCT-REPEAT INHIBITOR OF TERT EXPRESSION 1; BRIT1
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=MCPH1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MCPH1</a></em></strong>
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Cytogenetic location: <a href="/geneMap/8/16?start=-3&limit=10&highlight=16">8p23.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr8:6406627-6648508&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'})">8:6,406,627-6,648,508</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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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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</th>
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<td rowspan="1">
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<span class="mim-font">
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<a href="/geneMap/8/16?start=-3&limit=10&highlight=16">
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8p23.1
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<span class="mim-font">
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Microcephaly 1, primary, autosomal recessive
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<td>
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<span class="mim-font">
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<a href="/entry/251200"> 251200 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/607117" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/607117" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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<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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<h4>
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<span class="mim-font">
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<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.">
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<strong>TEXT</strong>
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</span>
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<div>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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<p>The MCPH1 gene encodes a regulator of chromosome condensation (<a href="#16" class="mim-tip-reference" title="Trimborn, M., Bell, S. M., Felix, C., Rashid, Y., Jafri, H., Griffiths, P. D., Neumann, L. M., Krebs, A., Reis, A., Sperling, K., Neitzel, H., Jackson, A. P. <strong>Mutations in microcephalin cause aberrant regulation of chromosome condensation.</strong> Am. J. Hum. Genet. 75: 261-266, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15199523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15199523</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15199523[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/10.1086/422855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15199523">Trimborn et al., 2004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15199523" 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 id="cloning" class="mim-anchor"></a>
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Cloning and Expression</strong>
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<p>To identify the causative gene in a form of primary microcephaly linked to chromosome 8p23 (MCPH1; <a href="/entry/251200">251200</a>), <a href="#9" class="mim-tip-reference" title="Jackson, A. P., Eastwood, H., Bell, S. M., Adu, J., Toomes, C., Carr, I. M., Roberts, E., Hampshire, D. J., Crow, Y. J., Mighell, A. J., Karbani, G., Jafri, H., Rashid, Y., Mueller, R. F., Markham, A. F., Woods, C. G. <strong>Identification of microcephalin, a protein implicated in determining the size of the human brain.</strong> Am. J. Hum. Genet. 71: 136-142, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12046007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12046007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12046007[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/10.1086/341283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12046007">Jackson et al. (2002)</a> sought a founder effect in 2 linked families and then sequenced positional candidates. Of 2 genes identified in the MCPH1 interval, angiopoietin-2 (ANGPT2; <a href="/entry/601922">601922</a>) showed no changes. However, the other gene, which was previously uncharacterized, showed a nonsense mutation (<a href="#0001">607117.0001</a>) in both families sharing the ancestral 8p23 haplotype. <a href="#9" class="mim-tip-reference" title="Jackson, A. P., Eastwood, H., Bell, S. M., Adu, J., Toomes, C., Carr, I. M., Roberts, E., Hampshire, D. J., Crow, Y. J., Mighell, A. J., Karbani, G., Jafri, H., Rashid, Y., Mueller, R. F., Markham, A. F., Woods, C. G. <strong>Identification of microcephalin, a protein implicated in determining the size of the human brain.</strong> Am. J. Hum. Genet. 71: 136-142, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12046007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12046007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12046007[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/10.1086/341283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12046007">Jackson et al. (2002)</a> termed the predicted 835-amino acid protein encoded by this gene microcephalin. Microcephalin contains 3 BRCA1 (<a href="/entry/113705">113705</a>) C-terminal (BRCT) domains. It shares only 57% identity with its mouse ortholog, with the most conserved regions being the BRCT domains, where there is 80% identity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12046007" 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 RT-PCR of fetal tissues, <a href="#9" class="mim-tip-reference" title="Jackson, A. P., Eastwood, H., Bell, S. M., Adu, J., Toomes, C., Carr, I. M., Roberts, E., Hampshire, D. J., Crow, Y. J., Mighell, A. J., Karbani, G., Jafri, H., Rashid, Y., Mueller, R. F., Markham, A. F., Woods, C. G. <strong>Identification of microcephalin, a protein implicated in determining the size of the human brain.</strong> Am. J. Hum. Genet. 71: 136-142, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12046007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12046007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12046007[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/10.1086/341283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12046007">Jackson et al. (2002)</a> confirmed that microcephalin is expressed in fetal brain. A similar level of expression was present in fetal liver and kidney, and transcripts were detectable at low levels in a range of other fetal tissues, as well as in a number of adult tissues. In situ hybridization experiments on fetal mouse sections showed that microcephalin is expressed during neurogenesis. In fetal brain, high levels of gene expression localized to the developing forebrain and, in particular, to the walls of the lateral ventricles. Progenitor cells in this region divide to produce neurons that migrate to form the cerebral cortex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12046007" 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 Western blot analysis, <a href="#18" class="mim-tip-reference" title="Xu, X., Lee, J., Stern, D. F. <strong>Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1.</strong> J. Biol. Chem. 279: 34091-34094, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15220350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15220350</a>] [<a href="https://doi.org/10.1074/jbc.C400139200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15220350">Xu et al. (2004)</a> detected a 100-kD MCPH1 protein in human cell lines. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15220350" 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 id="mimGeneFunctionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Gene Function</strong>
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<p><a href="#10" class="mim-tip-reference" title="Lin, S.-Y., Rai, R., Li, K., Xu, Z.-X., Elledge, S. J. <strong>BRIT1/MCPH1 is a DNA damage responsive protein that regulates the Brca1-Chk1 pathway, implicating checkpoint dysfunction in microcephaly.</strong> Proc. Nat. Acad. Sci. 102: 15105-15109, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16217032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16217032</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16217032[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.0507722102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16217032">Lin et al. (2005)</a> examined the role of BRIT1 in DNA damage response and found that it was required for intra-S and G2/M checkpoints after irradiation damage in a human osteosarcoma cell line. These BRIT1 activities appeared to result from regulation or activation of at least 3 other checkpoint regulators, CHK1 (CHEK1; <a href="/entry/603078">603078</a>), BRCA1, and NBS1 (<a href="/entry/602667">602667</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16217032" 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 immunofluorescence, <a href="#18" class="mim-tip-reference" title="Xu, X., Lee, J., Stern, D. F. <strong>Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1.</strong> J. Biol. Chem. 279: 34091-34094, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15220350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15220350</a>] [<a href="https://doi.org/10.1074/jbc.C400139200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15220350">Xu et al. (2004)</a> showed MCPH1 colocalized in ionizing irradiation (IR)-induced foci with NFBD1 (MDC1; <a href="/entry/607593">607593</a>) and other DNA damage checkpoint proteins in human embryonic kidney cells following IR exposure. Inhibition of MCPH1 expression by small interfering RNA led to defective IR-induced intra-S-phase and G2/M checkpoints and was associated with decreased BRCA1 and CHK1 mRNA and protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15220350" 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="Alderton, G. K., Galbiati, L., Griffith, E., Surinya, K. H., Neitzel, H., Jackson, A. P., Jeggo, P. A., O'Driscoll, M. <strong>Regulation of mitotic entry by microcephalin and its overlap with ATR signalling.</strong> Nature Cell Biol. 8: 725-733, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16783362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16783362</a>] [<a href="https://doi.org/10.1038/ncb1431" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16783362">Alderton et al. (2006)</a> found defective G2/M checkpoint arrest, nuclear fragmentation after DNA damage, and supernumerary mitotic centrosomes in human lymphoblastoid cell lines with different truncating mutations in MCPH1. Mutant cells failed to inhibit CDC45 (<a href="/entry/603465">603465</a>) loading onto chromatin after replication arrest. They also showed low levels of tyr15-phosphorylated CDK1 (CDC2; <a href="/entry/116940">116940</a>) in S and G2 phase, which correlated with elevated frequency of G2-like cells displaying premature chromosome condensation. <a href="#1" class="mim-tip-reference" title="Alderton, G. K., Galbiati, L., Griffith, E., Surinya, K. H., Neitzel, H., Jackson, A. P., Jeggo, P. A., O'Driscoll, M. <strong>Regulation of mitotic entry by microcephalin and its overlap with ATR signalling.</strong> Nature Cell Biol. 8: 725-733, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16783362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16783362</a>] [<a href="https://doi.org/10.1038/ncb1431" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16783362">Alderton et al. (2006)</a> concluded that MCPH1 has a role in maintaining inhibitory CDK1 phosphorylation, which prevents premature entry into mitosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16783362" 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>By genomic sequence analysis, <a href="#9" class="mim-tip-reference" title="Jackson, A. P., Eastwood, H., Bell, S. M., Adu, J., Toomes, C., Carr, I. M., Roberts, E., Hampshire, D. J., Crow, Y. J., Mighell, A. J., Karbani, G., Jafri, H., Rashid, Y., Mueller, R. F., Markham, A. F., Woods, C. G. <strong>Identification of microcephalin, a protein implicated in determining the size of the human brain.</strong> Am. J. Hum. Genet. 71: 136-142, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12046007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12046007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12046007[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/10.1086/341283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12046007">Jackson et al. (2002)</a> determined that the MCPH1 gene contains 14 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12046007" 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>By positional cloning, <a href="#9" class="mim-tip-reference" title="Jackson, A. P., Eastwood, H., Bell, S. M., Adu, J., Toomes, C., Carr, I. M., Roberts, E., Hampshire, D. J., Crow, Y. J., Mighell, A. J., Karbani, G., Jafri, H., Rashid, Y., Mueller, R. F., Markham, A. F., Woods, C. G. <strong>Identification of microcephalin, a protein implicated in determining the size of the human brain.</strong> Am. J. Hum. Genet. 71: 136-142, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12046007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12046007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12046007[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/10.1086/341283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12046007">Jackson et al. (2002)</a> mapped the MCPH1 gene to the primary microcephaly-1 critical region on chromosome 8p23. <a href="#9" class="mim-tip-reference" title="Jackson, A. P., Eastwood, H., Bell, S. M., Adu, J., Toomes, C., Carr, I. M., Roberts, E., Hampshire, D. J., Crow, Y. J., Mighell, A. J., Karbani, G., Jafri, H., Rashid, Y., Mueller, R. F., Markham, A. F., Woods, C. G. <strong>Identification of microcephalin, a protein implicated in determining the size of the human brain.</strong> Am. J. Hum. Genet. 71: 136-142, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12046007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12046007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12046007[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/10.1086/341283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12046007">Jackson et al. (2002)</a> mapped the mouse Mcph1 gene to chromosome 8A2, a region that also contains the Angpt2 gene and thus shows homology of synteny to human chromosome 8p23. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12046007" 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="#9" class="mim-tip-reference" title="Jackson, A. P., Eastwood, H., Bell, S. M., Adu, J., Toomes, C., Carr, I. M., Roberts, E., Hampshire, D. J., Crow, Y. J., Mighell, A. J., Karbani, G., Jafri, H., Rashid, Y., Mueller, R. F., Markham, A. F., Woods, C. G. <strong>Identification of microcephalin, a protein implicated in determining the size of the human brain.</strong> Am. J. Hum. Genet. 71: 136-142, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12046007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12046007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12046007[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/10.1086/341283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12046007">Jackson et al. (2002)</a> identified a homozygous mutation in the microcephalin gene (S25X; <a href="#0001">607117.0001</a>) in 2 families with primary microcephaly-1 (MCPH1; <a href="/entry/251200">251200</a>) sharing an ancestral 8p23 haplotype. All 7 affected individuals were homozygous for the mutation, and their 8 parents (obligate carriers) were heterozygous for this mutation. The S25X mutation occurred in the first BRCT domain and considerably truncated the microcephalin protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12046007" 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 sibs, born of consanguineous parents, with microcephaly and premature chromosome condensation syndrome originally reported by <a href="#14" class="mim-tip-reference" title="Neitzel, H., Neumann, L. M., Schindler, D., Wirges, A., Tonnies, H., Trimborn, M., Krebsova, A., Richter, R., Sperling, K. <strong>Premature chromosome condensation in humans associated with microcephaly and mental retardation: a novel autosomal recessive condition.</strong> Am. J. Hum. Genet. 70: 1015-1022, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11857108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11857108</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11857108[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/10.1086/339518" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11857108">Neitzel et al. (2002)</a>, <a href="#16" class="mim-tip-reference" title="Trimborn, M., Bell, S. M., Felix, C., Rashid, Y., Jafri, H., Griffiths, P. D., Neumann, L. M., Krebs, A., Reis, A., Sperling, K., Neitzel, H., Jackson, A. P. <strong>Mutations in microcephalin cause aberrant regulation of chromosome condensation.</strong> Am. J. Hum. Genet. 75: 261-266, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15199523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15199523</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15199523[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/10.1086/422855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15199523">Trimborn et al. (2004)</a> identified a homozygous 1-bp insertion (427insA; <a href="#0002">607117.0002</a>) in exon 5 of the MCPH1 gene. The cellular phenotype showed premature chromosome condensation in the early G2 phase of the cell cycle, which may be a useful diagnostic marker for individuals with mutation in the MCPH1 gene. <a href="#16" class="mim-tip-reference" title="Trimborn, M., Bell, S. M., Felix, C., Rashid, Y., Jafri, H., Griffiths, P. D., Neumann, L. M., Krebs, A., Reis, A., Sperling, K., Neitzel, H., Jackson, A. P. <strong>Mutations in microcephalin cause aberrant regulation of chromosome condensation.</strong> Am. J. Hum. Genet. 75: 261-266, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15199523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15199523</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15199523[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/10.1086/422855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15199523">Trimborn et al. (2004)</a> demonstrated that siRNA-mediated depletion of MCPH1 is sufficient to reproduce this cellular phenotype, and also showed that MCPH1-deficient cells exhibit delayed decondensation postmitosis. These findings implicated microcephalin as a regulator of chromosome condensation and linked the apparently disparate fields of neurogenesis and chromosome biology. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15199523+11857108" 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="#3" class="mim-tip-reference" title="Darvish, H., Esmaeeli-Nieh, S., Monajemi, G. B., Mohseni, M., Ghasemi-Firouzabadi, S., Abedini, S. S., Bahman, I., Jamali, P., Azimi, S., Mojahedi, F., Dehghan, A., Shafeghati, Y., and 14 others. <strong>A clinical and molecular genetic study of 112 Iranian families with primary microcephaly.</strong> J. Med. Genet. 47: 823-828, 2010. Note: Erratum: J. Med. Genet. 51: 70 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20978018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20978018</a>] [<a href="https://doi.org/10.1136/jmg.2009.076398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20978018">Darvish et al. (2010)</a> identified 8 different homozygous mutations in the MCPH1 gene (see, e.g., <a href="#0004">607117.0004</a>-<a href="#0006">607117.0006</a>) in 8 (8.7%) of 112 Iranian families with primary microcephaly, mental retardation, and premature chromosome condensation. Six of the mutations were predicted to result in a truncated protein. One of the families and the corresponding mutation had been reported by <a href="#8" class="mim-tip-reference" title="Garshasbi, M., Motazacker, M. M., Kahrizi, K., Behjati, F., Abedini, S. S., Nieh, S. E., Firouzabadi, S. G., Becker, C., Ruschendorf, F., Nurnberg, P., Tzschach, A., Vazifehmand, R., Erdogan, F., Ullmann, R., Lenzner, S., Kuss, A. W., Ropers, H. H., Najmabadi, H. <strong>SNP array-based homozygosity mapping reveals MCPH1 deletion in family with autosomal recessive mental retardation and mild microcephaly.</strong> Hum. Genet. 118: 708-715, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16311745/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16311745</a>] [<a href="https://doi.org/10.1007/s00439-005-0104-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16311745">Garshasbi et al. (2006)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16311745+20978018" 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>Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, <a href="#4" class="mim-tip-reference" title="Dorus, S., Vallender, E. J., Evans, P. D., Anderson, J. R., Gilbert, S. L., Mahowald, M., Wyckoff, G. J., Malcom, C. M., Lahn, B. T. <strong>Accelerated evolution of nervous system genes in the origin of Homo sapiens.</strong> Cell 119: 1027-1040, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15620360/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15620360</a>] [<a href="https://doi.org/10.1016/j.cell.2004.11.040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15620360">Dorus et al. (2004)</a> examined the evolution of genes involved in diverse aspects of nervous system biology. These genes, including MCPH1, displayed significantly higher rates of protein evolution in primates than in rodents. This trend was most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution was most prominent in the lineage leading from ancestral primates to humans. <a href="#4" class="mim-tip-reference" title="Dorus, S., Vallender, E. J., Evans, P. D., Anderson, J. R., Gilbert, S. L., Mahowald, M., Wyckoff, G. J., Malcom, C. M., Lahn, B. T. <strong>Accelerated evolution of nervous system genes in the origin of Homo sapiens.</strong> Cell 119: 1027-1040, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15620360/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15620360</a>] [<a href="https://doi.org/10.1016/j.cell.2004.11.040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15620360">Dorus et al. (2004)</a> concluded that the phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15620360" 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>Similarly, <a href="#5" class="mim-tip-reference" title="Evans, P. D., Anderson, J. R., Vallender, E. J., Choi, S. S., Lahn, B. T. <strong>Reconstructing the evolutionary history of microcephalin, a gene controlling human brain size.</strong> Hum. Molec. Genet. 13: 1139-1145, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15056607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15056607</a>] [<a href="https://doi.org/10.1093/hmg/ddh126" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15056607">Evans et al. (2004)</a> showed that the evolution of microcephalin's protein sequence was highly accelerated throughout the lineage from simian ancestors to humans and chimpanzees, with the most pronounced acceleration seen in the early periods of this lineage. This accelerated evolution was coupled with signatures of positive selection. Statistical analysis suggested that about 45 advantageous amino acid changes in microcephalin might have fixed during the 25 to 30 million years of evolution from early simian progenitors to modern humans. These observations supported the notion that the molecular evolution of microcephalin may have contributed to brain expansion in the simian lineage leading to humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15056607" 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="#17" class="mim-tip-reference" title="Wang, Y., Su, B. <strong>Molecular evolution of microcephalin, a gene determining human brain size.</strong> Hum. Molec. Genet. 13: 1131-1137, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15056608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15056608</a>] [<a href="https://doi.org/10.1093/hmg/ddh127" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15056608">Wang and Su (2004)</a> sequenced the coding region of microcephalin gene in humans and 12 representative nonhuman primate species covering great apes, lesser apes, Old World monkeys, and New World monkeys. Microcephalin was highly polymorphic in human populations. Among 22 substitutions in the coding region of microcephalin gene in human populations, 15 caused amino acid changes. Neutrality tests and phylogenetic analysis indicated that the sequence variations of microcephalin in humans were likely caused by the combination of recent population expansion and Darwinian positive selection. Synonymous/nonsynonymous analyses in primates revealed positive selection on microcephalin during the origin of the last common ancestor of humans and great apes, which coincides with the drastic brain enlargement from lesser apes to great apes. A codon-based neutrality test also indicated the signal of positive selection on 5 individual amino acid sites of microcephalin, which may contribute to brain enlargement during primate evolution and human origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15056608" 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="#6" class="mim-tip-reference" title="Evans, P. D., Gilbert, S. L., Mekel-Bobrov, N., Vallender, E. J., Anderson, J. R., Vaez-Azizi, L. M., Tishkoff, S. A., Hudson, R. R., Lahn, B. T. <strong>Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.</strong> Science 309: 1717-1720, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16151009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16151009</a>] [<a href="https://doi.org/10.1126/science.1113722" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16151009">Evans et al. (2005)</a> presented evidence that haplotype 49 of microcephalin, corresponding to the C allele of the G37995C SNP, increased its frequency too rapidly to be compatible with neutral drift. This indicates that it has spread under strong positive selection. The G37995C SNP occurs in exon 8 and changes amino acid 314 from an ancestral aspartate to a histidine (D314H). Position 37995 of the genomic sequence corresponds to position 940 of the open reading frame. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16151009" 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="#2" class="mim-tip-reference" title="Currat, M., Excoffier, L., Maddison, W., Otto, S. P., Ray, N., Whitlock, M. C., Yeaman, S. <strong>Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens' and 'microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.' (Abstract)</strong> Science 313: 172 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16840683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16840683</a>] [<a href="https://doi.org/10.1126/science.1122822" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16840683">Currat et al. (2006)</a> commented on the paper by <a href="#6" class="mim-tip-reference" title="Evans, P. D., Gilbert, S. L., Mekel-Bobrov, N., Vallender, E. J., Anderson, J. R., Vaez-Azizi, L. M., Tishkoff, S. A., Hudson, R. R., Lahn, B. T. <strong>Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.</strong> Science 309: 1717-1720, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16151009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16151009</a>] [<a href="https://doi.org/10.1126/science.1113722" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16151009">Evans et al. (2005)</a>, stating that they had developed models of human history including both population growth and spatial structure that could generate the observed pattern of microcephalin haplotypes without selection. <a href="#12" class="mim-tip-reference" title="Mekel-Bobrov, N., Evans, P. D., Gilbert, S. L., Vallender, E. J., Hudson, R. R., Lahn, B. T. <strong>Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens' and 'microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.' (Abstract)</strong> Science 313: 172 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16840683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16840683</a>] [<a href="https://doi.org/10.1126/science.1122822" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16840683">Mekel-Bobrov et al. (2006)</a> responded that the demographic models adopted by <a href="#2" class="mim-tip-reference" title="Currat, M., Excoffier, L., Maddison, W., Otto, S. P., Ray, N., Whitlock, M. C., Yeaman, S. <strong>Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens' and 'microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.' (Abstract)</strong> Science 313: 172 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16840683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16840683</a>] [<a href="https://doi.org/10.1126/science.1122822" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16840683">Currat et al. (2006)</a> strongly contradicted a decade of empirical research on human demographic history and did not account for the critical features of the data on which <a href="#12" class="mim-tip-reference" title="Mekel-Bobrov, N., Evans, P. D., Gilbert, S. L., Vallender, E. J., Hudson, R. R., Lahn, B. T. <strong>Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens' and 'microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.' (Abstract)</strong> Science 313: 172 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16840683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16840683</a>] [<a href="https://doi.org/10.1126/science.1122822" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16840683">Mekel-Bobrov et al. (2006)</a> had developed their argument for selection. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16840683+16151009" 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 5 independent population-based samples comprising 2,393 individuals, <a href="#13" class="mim-tip-reference" title="Mekel-Bobrov, N., Posthuma, D., Gilbert, S. L., Lind, P., Gosso, M. F., Luciano, M., Harris, S. E., Bates, T. C., Polderman, T. J. C., Whalley, L. J., Fox, H., Starr, J. M., and 10 others. <strong>The ongoing adaptive evolution of ASPM and microcephalin is not explained by increased intelligence.</strong> Hum. Molec. Genet. 16: 600-608, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17220170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17220170</a>] [<a href="https://doi.org/10.1093/hmg/ddl487" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17220170">Mekel-Bobrov et al. (2007)</a> did not find a detectable association between the recent adaptive evolution of either the ASPM (<a href="/entry/605481">605481</a>) or microcephalin genes and normal variation in IQ. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17220170" 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="Maghirang-Rodriguez, R., Archie, J. G., Schwarz, C. E., Collins, J. S. <strong>The c.940G variant of the microcephalin (MCPH1) gene is not associated with microcephaly or mental retardation.</strong> Am. J. Med. Genet. 149A: 622-625, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19267414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19267414</a>] [<a href="https://doi.org/10.1002/ajmg.a.32721" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19267414">Maghirang-Rodriguez et al. (2009)</a> found no association between the 940G variant of MCPH1 and microcephaly or mental retardation among 1,054 affected individuals compared to 401 controls. However, in controls the frequency of the 940G allele was significantly higher among African Americans (66%) compared to Caucasians (17%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19267414" 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="#9" class="mim-tip-reference" title="Jackson, A. P., Eastwood, H., Bell, S. M., Adu, J., Toomes, C., Carr, I. M., Roberts, E., Hampshire, D. J., Crow, Y. J., Mighell, A. J., Karbani, G., Jafri, H., Rashid, Y., Mueller, R. F., Markham, A. F., Woods, C. G. <strong>Identification of microcephalin, a protein implicated in determining the size of the human brain.</strong> Am. J. Hum. Genet. 71: 136-142, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12046007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12046007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12046007[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/10.1086/341283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12046007">Jackson et al. (2002)</a> identified a C-to-G transversion at nucleotide 74 in exon 2 of the microcephalin gene, resulting in a ser25-to-ter (S25X) substitution, in 2 families with primary microcephaly (<a href="/entry/251200">251200</a>) sharing an ancestral 8p23 haplotype. All 7 affected individuals were homozygous for the mutation, and their 8 parents (obligate carriers) were heterozygous for this mutation. The S25X mutation occurred in the first BRCT domain of microcephalin and considerably truncated the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12046007" 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="Alderton, G. K., Galbiati, L., Griffith, E., Surinya, K. H., Neitzel, H., Jackson, A. P., Jeggo, P. A., O'Driscoll, M. <strong>Regulation of mitotic entry by microcephalin and its overlap with ATR signalling.</strong> Nature Cell Biol. 8: 725-733, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16783362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16783362</a>] [<a href="https://doi.org/10.1038/ncb1431" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16783362">Alderton et al. (2006)</a> found that cells expressing the S25X mutation had reduced, but residual, MCPH1 protein expression. The mutant protein would result in loss of the N-terminal BRCT domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16783362" 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>In 2 sibs, born to consanguineous parents, with microcephaly (<a href="/entry/251200">251200</a>) and premature chromosome condensation originally reported by <a href="#14" class="mim-tip-reference" title="Neitzel, H., Neumann, L. M., Schindler, D., Wirges, A., Tonnies, H., Trimborn, M., Krebsova, A., Richter, R., Sperling, K. <strong>Premature chromosome condensation in humans associated with microcephaly and mental retardation: a novel autosomal recessive condition.</strong> Am. J. Hum. Genet. 70: 1015-1022, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11857108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11857108</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11857108[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/10.1086/339518" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11857108">Neitzel et al. (2002)</a>, <a href="#16" class="mim-tip-reference" title="Trimborn, M., Bell, S. M., Felix, C., Rashid, Y., Jafri, H., Griffiths, P. D., Neumann, L. M., Krebs, A., Reis, A., Sperling, K., Neitzel, H., Jackson, A. P. <strong>Mutations in microcephalin cause aberrant regulation of chromosome condensation.</strong> Am. J. Hum. Genet. 75: 261-266, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15199523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15199523</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15199523[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/10.1086/422855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15199523">Trimborn et al. (2004)</a> sequenced the entire coding region of the MCPH1 gene; they identified a homozygous 1-bp insertion in exon 5, 427insA, resulting in a frameshift with a premature stop codon in exon 6 and, thus, a markedly truncated protein of 146 amino acids encoding only the N-terminal BRCT domain of the protein. The insertion, which occurred within a run of 6 adenines, was heterozygous in both unaffected parents and not present in 220 control alleles. <a href="#16" class="mim-tip-reference" title="Trimborn, M., Bell, S. M., Felix, C., Rashid, Y., Jafri, H., Griffiths, P. D., Neumann, L. M., Krebs, A., Reis, A., Sperling, K., Neitzel, H., Jackson, A. P. <strong>Mutations in microcephalin cause aberrant regulation of chromosome condensation.</strong> Am. J. Hum. Genet. 75: 261-266, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15199523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15199523</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15199523[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/10.1086/422855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15199523">Trimborn et al. (2004)</a> concluded that the cellular phenotype was due to functional loss of the microcephalin protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15199523+11857108" 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="Alderton, G. K., Galbiati, L., Griffith, E., Surinya, K. H., Neitzel, H., Jackson, A. P., Jeggo, P. A., O'Driscoll, M. <strong>Regulation of mitotic entry by microcephalin and its overlap with ATR signalling.</strong> Nature Cell Biol. 8: 725-733, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16783362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16783362</a>] [<a href="https://doi.org/10.1038/ncb1431" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16783362">Alderton et al. (2006)</a> found that cells expressing the 427insA mutant lacked detectable MCPH1 protein. The mutant transcript underwent nonsense-mediated decay, but residual mutant mRNA was detectable. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16783362" 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="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003620" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003620" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003620</a>
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<p>In 6 affected members of a consanguineous Iranian family with mental retardation, mild microcephaly (-3 SD), and premature chromosome condensation in at least 10 to 15% of cells (<a href="/entry/251200">251200</a>), <a href="#8" class="mim-tip-reference" title="Garshasbi, M., Motazacker, M. M., Kahrizi, K., Behjati, F., Abedini, S. S., Nieh, S. E., Firouzabadi, S. G., Becker, C., Ruschendorf, F., Nurnberg, P., Tzschach, A., Vazifehmand, R., Erdogan, F., Ullmann, R., Lenzner, S., Kuss, A. W., Ropers, H. H., Najmabadi, H. <strong>SNP array-based homozygosity mapping reveals MCPH1 deletion in family with autosomal recessive mental retardation and mild microcephaly.</strong> Hum. Genet. 118: 708-715, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16311745/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16311745</a>] [<a href="https://doi.org/10.1007/s00439-005-0104-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16311745">Garshasbi et al. (2006)</a> identified a homozygous 150- to 200-kb deletion encompassing the promoter and the first 6 exons of the MCPH1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16311745" 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> rs753597039 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs753597039;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/rs753597039?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=rs753597039" 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=rs753597039" 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=RCV000023614 OR RCV002286697" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023614, RCV002286697" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023614...</a>
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<p>In 3 affected members of a consanguineous Iranian family with microcephaly (-6 SD), moderate mental retardation, and premature chromosome condensation (<a href="/entry/251200">251200</a>), <a href="#3" class="mim-tip-reference" title="Darvish, H., Esmaeeli-Nieh, S., Monajemi, G. B., Mohseni, M., Ghasemi-Firouzabadi, S., Abedini, S. S., Bahman, I., Jamali, P., Azimi, S., Mojahedi, F., Dehghan, A., Shafeghati, Y., and 14 others. <strong>A clinical and molecular genetic study of 112 Iranian families with primary microcephaly.</strong> J. Med. Genet. 47: 823-828, 2010. Note: Erratum: J. Med. Genet. 51: 70 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20978018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20978018</a>] [<a href="https://doi.org/10.1136/jmg.2009.076398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20978018">Darvish et al. (2010)</a> identified a homozygous 1-bp insertion (566insA) in exon 6 of the MCPH1 gene, predicted to result in a frameshift. The mutation was not found in 160 German and 190 Iranian controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20978018" 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>.0005 MICROCEPHALY 1, PRIMARY, AUTOSOMAL RECESSIVE</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"><span class="text-primary">●</span> rs1488084787 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1488084787;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/rs1488084787?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=rs1488084787" 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=rs1488084787" 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=RCV000023615" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023615" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023615</a>
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<p>In 4 affected members of a consanguineous Iranian family with microcephaly (-7 to -9 SD), moderate mental retardation, and premature chromosome condensation (<a href="/entry/251200">251200</a>), <a href="#3" class="mim-tip-reference" title="Darvish, H., Esmaeeli-Nieh, S., Monajemi, G. B., Mohseni, M., Ghasemi-Firouzabadi, S., Abedini, S. S., Bahman, I., Jamali, P., Azimi, S., Mojahedi, F., Dehghan, A., Shafeghati, Y., and 14 others. <strong>A clinical and molecular genetic study of 112 Iranian families with primary microcephaly.</strong> J. Med. Genet. 47: 823-828, 2010. Note: Erratum: J. Med. Genet. 51: 70 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20978018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20978018</a>] [<a href="https://doi.org/10.1136/jmg.2009.076398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20978018">Darvish et al. (2010)</a> identified a homozygous 147C-G transversion in exon 3 of the MCPH1 gene, predicted to result in his49-to-gln (H49Q) substitution in the BRCT1 domain. The mutation was not found in 160 German and 190 Iranian controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20978018" 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> rs387906961 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906961;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/rs387906961?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=rs387906961" 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=rs387906961" 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=RCV000023616 OR RCV002287342 OR RCV004586022" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023616, RCV002287342, RCV004586022" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023616...</a>
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<p>In 3 affected members of a consanguineous Iranian family with microcephaly (-6 to -7 SD), mild to moderate mental retardation, and premature chromosome condensation (<a href="/entry/251200">251200</a>), <a href="#3" class="mim-tip-reference" title="Darvish, H., Esmaeeli-Nieh, S., Monajemi, G. B., Mohseni, M., Ghasemi-Firouzabadi, S., Abedini, S. S., Bahman, I., Jamali, P., Azimi, S., Mojahedi, F., Dehghan, A., Shafeghati, Y., and 14 others. <strong>A clinical and molecular genetic study of 112 Iranian families with primary microcephaly.</strong> J. Med. Genet. 47: 823-828, 2010. Note: Erratum: J. Med. Genet. 51: 70 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20978018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20978018</a>] [<a href="https://doi.org/10.1136/jmg.2009.076398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20978018">Darvish et al. (2010)</a> identified a homozygous 215C-T transition in exon 3 of the MCPH1 gene, predicted to result in ser72-to-leu (S72L) substitution in the BRCT1 domain. The mutation was not found in 160 German and 190 Iranian controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20978018" 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 MICROCEPHALY 1, PRIMARY, AUTOSOMAL RECESSIVE</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"><span class="text-primary">●</span> rs755862917 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs755862917;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/rs755862917?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=rs755862917" 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=rs755862917" 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=RCV000023617 OR RCV002513198" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023617, RCV002513198" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023617...</a>
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<p>In a Danish female with primary microcephaly-1 (<a href="/entry/251200">251200</a>), previously reported by <a href="#15" class="mim-tip-reference" title="Tommerup, N., Mortensen, E., Nielsen, M. H., Wegner, R.-D., Schindler, D., Mikkelsen, M. <strong>Chromosomal breakage, endomitosis, endoreduplication, and hypersensitivity toward radiomimetic and alkylating agents: a possible new autosomal recessive mutation in a girl with craniosynostosis and microcephaly.</strong> Hum. Genet. 92: 339-346, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7693575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7693575</a>] [<a href="https://doi.org/10.1007/BF01247331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7693575">Tommerup et al. (1993)</a>, <a href="#7" class="mim-tip-reference" title="Farooq, M., Baig, S., Tommerup, N., Kjaer, K. W. <strong>Craniosynostosis-microcephaly with chromosomal breakage and other abnormalities is caused by a truncating MCPH1 mutation and is allelic to premature chromosomal condensation syndrome and primary autosomal recessive microcephaly type 1.</strong> Am. J. Med. Genet. 152A: 495-497, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20101680/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20101680</a>] [<a href="https://doi.org/10.1002/ajmg.a.33234" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20101680">Farooq et al. (2010)</a> identified a homozygous 302C-G transversion in exon 4 of the MCPH1 gene, resulting in a ser101-to-ter (S101X) substitution. The truncated protein was predicted to retain the N-terminal BRCT domain but lack the 2 C-terminal BRCT domains. The patient also had craniosynostosis, ptosis, and bird-like facies with micrognathia. The cellular phenotype of chromosomal sensitivity to DNA damage was particularly severe, which the authors suggested may be related to presence of the N-terminal BRCT domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20101680+7693575" 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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[<a href="https://doi.org/10.1038/ncb1431" target="_blank">Full Text</a>]
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<strong>Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens' and 'microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.' (Abstract)</strong>
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Science 313: 172 only, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16840683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16840683</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16840683" 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/10.1126/science.1122822" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20978018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20978018</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20978018" 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.2009.076398" target="_blank">Full Text</a>]
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Dorus, S., Vallender, E. J., Evans, P. D., Anderson, J. R., Gilbert, S. L., Mahowald, M., Wyckoff, G. J., Malcom, C. M., Lahn, B. T.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15620360/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15620360</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15620360" 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.cell.2004.11.040" target="_blank">Full Text</a>]
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Evans, P. D., Anderson, J. R., Vallender, E. J., Choi, S. S., Lahn, B. T.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15056607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15056607</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15056607" 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/ddh126" target="_blank">Full Text</a>]
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Evans, P. D., Gilbert, S. L., Mekel-Bobrov, N., Vallender, E. J., Anderson, J. R., Vaez-Azizi, L. M., Tishkoff, S. A., Hudson, R. R., Lahn, B. T.
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<strong>Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16151009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16151009</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16151009" 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/10.1126/science.1113722" target="_blank">Full Text</a>]
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Farooq, M., Baig, S., Tommerup, N., Kjaer, K. W.
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<strong>Craniosynostosis-microcephaly with chromosomal breakage and other abnormalities is caused by a truncating MCPH1 mutation and is allelic to premature chromosomal condensation syndrome and primary autosomal recessive microcephaly type 1.</strong>
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Am. J. Med. Genet. 152A: 495-497, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20101680/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20101680</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20101680" 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/10.1002/ajmg.a.33234" target="_blank">Full Text</a>]
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<a id="Garshasbi2006" class="mim-anchor"></a>
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Garshasbi, M., Motazacker, M. M., Kahrizi, K., Behjati, F., Abedini, S. S., Nieh, S. E., Firouzabadi, S. G., Becker, C., Ruschendorf, F., Nurnberg, P., Tzschach, A., Vazifehmand, R., Erdogan, F., Ullmann, R., Lenzner, S., Kuss, A. W., Ropers, H. H., Najmabadi, H.
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<strong>SNP array-based homozygosity mapping reveals MCPH1 deletion in family with autosomal recessive mental retardation and mild microcephaly.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16311745/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16311745</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16311745" 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/s00439-005-0104-y" target="_blank">Full Text</a>]
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Jackson, A. P., Eastwood, H., Bell, S. M., Adu, J., Toomes, C., Carr, I. M., Roberts, E., Hampshire, D. J., Crow, Y. J., Mighell, A. J., Karbani, G., Jafri, H., Rashid, Y., Mueller, R. F., Markham, A. F., Woods, C. G.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12046007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12046007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12046007[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=12046007" 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/10.1086/341283" target="_blank">Full Text</a>]
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Lin, S.-Y., Rai, R., Li, K., Xu, Z.-X., Elledge, S. J.
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<strong>BRIT1/MCPH1 is a DNA damage responsive protein that regulates the Brca1-Chk1 pathway, implicating checkpoint dysfunction in microcephaly.</strong>
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Proc. Nat. Acad. Sci. 102: 15105-15109, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16217032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16217032</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16217032[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=16217032" 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/10.1073/pnas.0507722102" target="_blank">Full Text</a>]
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Maghirang-Rodriguez, R., Archie, J. G., Schwarz, C. E., Collins, J. S.
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<strong>The c.940G variant of the microcephalin (MCPH1) gene is not associated with microcephaly or mental retardation.</strong>
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Am. J. Med. Genet. 149A: 622-625, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19267414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19267414</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19267414" 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/10.1002/ajmg.a.32721" target="_blank">Full Text</a>]
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Mekel-Bobrov, N., Evans, P. D., Gilbert, S. L., Vallender, E. J., Hudson, R. R., Lahn, B. T.
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<strong>Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens' and 'microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.' (Abstract)</strong>
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Science 313: 172 only, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16840683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16840683</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16840683" 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/10.1126/science.1122822" target="_blank">Full Text</a>]
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<a id="Mekel-Bobrov2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Mekel-Bobrov, N., Posthuma, D., Gilbert, S. L., Lind, P., Gosso, M. F., Luciano, M., Harris, S. E., Bates, T. C., Polderman, T. J. C., Whalley, L. J., Fox, H., Starr, J. M., and 10 others.
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<strong>The ongoing adaptive evolution of ASPM and microcephalin is not explained by increased intelligence.</strong>
|
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Hum. Molec. Genet. 16: 600-608, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17220170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17220170</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17220170" 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/ddl487" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Neitzel2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Neitzel, H., Neumann, L. M., Schindler, D., Wirges, A., Tonnies, H., Trimborn, M., Krebsova, A., Richter, R., Sperling, K.
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<strong>Premature chromosome condensation in humans associated with microcephaly and mental retardation: a novel autosomal recessive condition.</strong>
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Am. J. Hum. Genet. 70: 1015-1022, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11857108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11857108</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11857108[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=11857108" 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/10.1086/339518" 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="15" class="mim-anchor"></a>
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<a id="Tommerup1993" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tommerup, N., Mortensen, E., Nielsen, M. H., Wegner, R.-D., Schindler, D., Mikkelsen, M.
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<strong>Chromosomal breakage, endomitosis, endoreduplication, and hypersensitivity toward radiomimetic and alkylating agents: a possible new autosomal recessive mutation in a girl with craniosynostosis and microcephaly.</strong>
|
|
Hum. Genet. 92: 339-346, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7693575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7693575</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7693575" 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/BF01247331" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Trimborn2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Trimborn, M., Bell, S. M., Felix, C., Rashid, Y., Jafri, H., Griffiths, P. D., Neumann, L. M., Krebs, A., Reis, A., Sperling, K., Neitzel, H., Jackson, A. P.
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<strong>Mutations in microcephalin cause aberrant regulation of chromosome condensation.</strong>
|
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Am. J. Hum. Genet. 75: 261-266, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15199523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15199523</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15199523[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=15199523" 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/10.1086/422855" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Wang2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wang, Y., Su, B.
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<strong>Molecular evolution of microcephalin, a gene determining human brain size.</strong>
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Hum. Molec. Genet. 13: 1131-1137, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15056608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15056608</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15056608" 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/ddh127" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Xu2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Xu, X., Lee, J., Stern, D. F.
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<strong>Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1.</strong>
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J. Biol. Chem. 279: 34091-34094, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15220350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15220350</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15220350" 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/10.1074/jbc.C400139200" target="_blank">Full Text</a>]
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</p>
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</ol>
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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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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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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>
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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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Cassandra L. Kniffin - updated : 6/30/2011
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 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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Cassandra L. Kniffin - updated : 2/21/2011<br>Cassandra L. Kniffin - updated : 7/12/2010<br>Cassandra L. Kniffin - updated : 4/16/2010<br>Patricia A. Hartz - updated : 11/7/2006<br>George E. Tiller - updated : 9/7/2006<br>George E. Tiller - updated : 9/7/2006<br>Patricia A. Hartz - updated : 8/18/2006<br>Ada Hamosh - updated : 8/7/2006<br>Cassandra L. Kniffin - updated : 3/27/2006<br>Patricia A. Hartz - updated : 1/27/2006<br>Ada Hamosh - updated : 9/27/2005<br>Stylianos E. Antonarakis - updated : 1/10/2005<br>Victor A. McKusick - updated : 8/12/2004
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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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 : 7/26/2002
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</span>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </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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carol : 07/20/2020
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 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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carol : 03/05/2014<br>wwang : 7/14/2011<br>ckniffin : 6/30/2011<br>wwang : 6/8/2011<br>wwang : 3/1/2011<br>ckniffin : 2/21/2011<br>wwang : 7/14/2010<br>ckniffin : 7/12/2010<br>wwang : 4/29/2010<br>ckniffin : 4/16/2010<br>mgross : 11/13/2006<br>terry : 11/7/2006<br>alopez : 9/7/2006<br>alopez : 9/7/2006<br>mgross : 8/21/2006<br>terry : 8/18/2006<br>alopez : 8/9/2006<br>terry : 8/7/2006<br>wwang : 4/6/2006<br>ckniffin : 3/27/2006<br>mgross : 2/1/2006<br>terry : 1/27/2006<br>alopez : 9/29/2005<br>terry : 9/27/2005<br>mgross : 1/10/2005<br>tkritzer : 8/20/2004<br>tkritzer : 8/17/2004<br>terry : 8/12/2004<br>carol : 6/8/2004<br>mgross : 8/7/2002<br>mgross : 8/6/2002<br>mgross : 8/6/2002<br>mgross : 7/26/2002
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</span>
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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 class="container visible-print-block">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 607117
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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MICROCEPHALIN 1; MCPH1
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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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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</p>
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<div>
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<h4>
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<span class="mim-font">
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MCPH1 GENE<br />
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MICROCEPHALIN<br />
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BRCT-REPEAT INHIBITOR OF TERT EXPRESSION 1; BRIT1
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</span>
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</h4>
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: MCPH1</em></strong>
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</span>
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</p>
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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: 8p23.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 8:6,406,627-6,648,508 </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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<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="1">
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<span class="mim-font">
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8p23.1
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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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Microcephaly 1, primary, autosomal recessive
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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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251200
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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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Autosomal recessive
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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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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The MCPH1 gene encodes a regulator of chromosome condensation (Trimborn et al., 2004). </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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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>To identify the causative gene in a form of primary microcephaly linked to chromosome 8p23 (MCPH1; 251200), Jackson et al. (2002) sought a founder effect in 2 linked families and then sequenced positional candidates. Of 2 genes identified in the MCPH1 interval, angiopoietin-2 (ANGPT2; 601922) showed no changes. However, the other gene, which was previously uncharacterized, showed a nonsense mutation (607117.0001) in both families sharing the ancestral 8p23 haplotype. Jackson et al. (2002) termed the predicted 835-amino acid protein encoded by this gene microcephalin. Microcephalin contains 3 BRCA1 (113705) C-terminal (BRCT) domains. It shares only 57% identity with its mouse ortholog, with the most conserved regions being the BRCT domains, where there is 80% identity. </p><p>Using RT-PCR of fetal tissues, Jackson et al. (2002) confirmed that microcephalin is expressed in fetal brain. A similar level of expression was present in fetal liver and kidney, and transcripts were detectable at low levels in a range of other fetal tissues, as well as in a number of adult tissues. In situ hybridization experiments on fetal mouse sections showed that microcephalin is expressed during neurogenesis. In fetal brain, high levels of gene expression localized to the developing forebrain and, in particular, to the walls of the lateral ventricles. Progenitor cells in this region divide to produce neurons that migrate to form the cerebral cortex. </p><p>Using Western blot analysis, Xu et al. (2004) detected a 100-kD MCPH1 protein in human cell lines. </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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<h4>
|
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<span class="mim-font">
|
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<strong>Gene Function</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Lin et al. (2005) examined the role of BRIT1 in DNA damage response and found that it was required for intra-S and G2/M checkpoints after irradiation damage in a human osteosarcoma cell line. These BRIT1 activities appeared to result from regulation or activation of at least 3 other checkpoint regulators, CHK1 (CHEK1; 603078), BRCA1, and NBS1 (602667). </p><p>Using immunofluorescence, Xu et al. (2004) showed MCPH1 colocalized in ionizing irradiation (IR)-induced foci with NFBD1 (MDC1; 607593) and other DNA damage checkpoint proteins in human embryonic kidney cells following IR exposure. Inhibition of MCPH1 expression by small interfering RNA led to defective IR-induced intra-S-phase and G2/M checkpoints and was associated with decreased BRCA1 and CHK1 mRNA and protein. </p><p>Alderton et al. (2006) found defective G2/M checkpoint arrest, nuclear fragmentation after DNA damage, and supernumerary mitotic centrosomes in human lymphoblastoid cell lines with different truncating mutations in MCPH1. Mutant cells failed to inhibit CDC45 (603465) loading onto chromatin after replication arrest. They also showed low levels of tyr15-phosphorylated CDK1 (CDC2; 116940) in S and G2 phase, which correlated with elevated frequency of G2-like cells displaying premature chromosome condensation. Alderton et al. (2006) concluded that MCPH1 has a role in maintaining inhibitory CDK1 phosphorylation, which prevents premature entry into mitosis. </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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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By genomic sequence analysis, Jackson et al. (2002) determined that the MCPH1 gene contains 14 exons. </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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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By positional cloning, Jackson et al. (2002) mapped the MCPH1 gene to the primary microcephaly-1 critical region on chromosome 8p23. Jackson et al. (2002) mapped the mouse Mcph1 gene to chromosome 8A2, a region that also contains the Angpt2 gene and thus shows homology of synteny to human chromosome 8p23. </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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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Jackson et al. (2002) identified a homozygous mutation in the microcephalin gene (S25X; 607117.0001) in 2 families with primary microcephaly-1 (MCPH1; 251200) sharing an ancestral 8p23 haplotype. All 7 affected individuals were homozygous for the mutation, and their 8 parents (obligate carriers) were heterozygous for this mutation. The S25X mutation occurred in the first BRCT domain and considerably truncated the microcephalin protein. </p><p>In 2 sibs, born of consanguineous parents, with microcephaly and premature chromosome condensation syndrome originally reported by Neitzel et al. (2002), Trimborn et al. (2004) identified a homozygous 1-bp insertion (427insA; 607117.0002) in exon 5 of the MCPH1 gene. The cellular phenotype showed premature chromosome condensation in the early G2 phase of the cell cycle, which may be a useful diagnostic marker for individuals with mutation in the MCPH1 gene. Trimborn et al. (2004) demonstrated that siRNA-mediated depletion of MCPH1 is sufficient to reproduce this cellular phenotype, and also showed that MCPH1-deficient cells exhibit delayed decondensation postmitosis. These findings implicated microcephalin as a regulator of chromosome condensation and linked the apparently disparate fields of neurogenesis and chromosome biology. </p><p>Darvish et al. (2010) identified 8 different homozygous mutations in the MCPH1 gene (see, e.g., 607117.0004-607117.0006) in 8 (8.7%) of 112 Iranian families with primary microcephaly, mental retardation, and premature chromosome condensation. Six of the mutations were predicted to result in a truncated protein. One of the families and the corresponding mutation had been reported by Garshasbi et al. (2006). </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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<h4>
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<span class="mim-font">
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<strong>Evolution</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, Dorus et al. (2004) examined the evolution of genes involved in diverse aspects of nervous system biology. These genes, including MCPH1, displayed significantly higher rates of protein evolution in primates than in rodents. This trend was most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution was most prominent in the lineage leading from ancestral primates to humans. Dorus et al. (2004) concluded that the phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development. </p><p>Similarly, Evans et al. (2004) showed that the evolution of microcephalin's protein sequence was highly accelerated throughout the lineage from simian ancestors to humans and chimpanzees, with the most pronounced acceleration seen in the early periods of this lineage. This accelerated evolution was coupled with signatures of positive selection. Statistical analysis suggested that about 45 advantageous amino acid changes in microcephalin might have fixed during the 25 to 30 million years of evolution from early simian progenitors to modern humans. These observations supported the notion that the molecular evolution of microcephalin may have contributed to brain expansion in the simian lineage leading to humans. </p><p>Wang and Su (2004) sequenced the coding region of microcephalin gene in humans and 12 representative nonhuman primate species covering great apes, lesser apes, Old World monkeys, and New World monkeys. Microcephalin was highly polymorphic in human populations. Among 22 substitutions in the coding region of microcephalin gene in human populations, 15 caused amino acid changes. Neutrality tests and phylogenetic analysis indicated that the sequence variations of microcephalin in humans were likely caused by the combination of recent population expansion and Darwinian positive selection. Synonymous/nonsynonymous analyses in primates revealed positive selection on microcephalin during the origin of the last common ancestor of humans and great apes, which coincides with the drastic brain enlargement from lesser apes to great apes. A codon-based neutrality test also indicated the signal of positive selection on 5 individual amino acid sites of microcephalin, which may contribute to brain enlargement during primate evolution and human origin. </p><p>Evans et al. (2005) presented evidence that haplotype 49 of microcephalin, corresponding to the C allele of the G37995C SNP, increased its frequency too rapidly to be compatible with neutral drift. This indicates that it has spread under strong positive selection. The G37995C SNP occurs in exon 8 and changes amino acid 314 from an ancestral aspartate to a histidine (D314H). Position 37995 of the genomic sequence corresponds to position 940 of the open reading frame. </p><p>Currat et al. (2006) commented on the paper by Evans et al. (2005), stating that they had developed models of human history including both population growth and spatial structure that could generate the observed pattern of microcephalin haplotypes without selection. Mekel-Bobrov et al. (2006) responded that the demographic models adopted by Currat et al. (2006) strongly contradicted a decade of empirical research on human demographic history and did not account for the critical features of the data on which Mekel-Bobrov et al. (2006) had developed their argument for selection. </p><p>In a study of 5 independent population-based samples comprising 2,393 individuals, Mekel-Bobrov et al. (2007) did not find a detectable association between the recent adaptive evolution of either the ASPM (605481) or microcephalin genes and normal variation in IQ. </p><p>Maghirang-Rodriguez et al. (2009) found no association between the 940G variant of MCPH1 and microcephaly or mental retardation among 1,054 affected individuals compared to 401 controls. However, in controls the frequency of the 940G allele was significantly higher among African Americans (66%) compared to Caucasians (17%). </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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<h4>
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|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
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</span>
|
|
<strong>7 Selected Examples):</strong>
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</span>
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</h4>
|
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<div>
|
|
<p />
|
|
</div>
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<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 MICROCEPHALY 1, PRIMARY, AUTOSOMAL RECESSIVE</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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|
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MCPH1, SER25TER
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<br />
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SNP: rs121434305,
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gnomAD: rs121434305,
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|
|
ClinVar: RCV000003618, RCV003555906
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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>Jackson et al. (2002) identified a C-to-G transversion at nucleotide 74 in exon 2 of the microcephalin gene, resulting in a ser25-to-ter (S25X) substitution, in 2 families with primary microcephaly (251200) sharing an ancestral 8p23 haplotype. All 7 affected individuals were homozygous for the mutation, and their 8 parents (obligate carriers) were heterozygous for this mutation. The S25X mutation occurred in the first BRCT domain of microcephalin and considerably truncated the protein. </p><p>Alderton et al. (2006) found that cells expressing the S25X mutation had reduced, but residual, MCPH1 protein expression. The mutant protein would result in loss of the N-terminal BRCT domain. </p>
|
|
</span>
|
|
</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>.0002 MICROCEPHALY 1, PRIMARY, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MCPH1, 1-BP INS, 427A
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|
|
<br />
|
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|
|
SNP: rs199422125,
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|
|
|
|
|
|
ClinVar: RCV000003619, RCV000454240
|
|
|
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|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs, born to consanguineous parents, with microcephaly (251200) and premature chromosome condensation originally reported by Neitzel et al. (2002), Trimborn et al. (2004) sequenced the entire coding region of the MCPH1 gene; they identified a homozygous 1-bp insertion in exon 5, 427insA, resulting in a frameshift with a premature stop codon in exon 6 and, thus, a markedly truncated protein of 146 amino acids encoding only the N-terminal BRCT domain of the protein. The insertion, which occurred within a run of 6 adenines, was heterozygous in both unaffected parents and not present in 220 control alleles. Trimborn et al. (2004) concluded that the cellular phenotype was due to functional loss of the microcephalin protein. </p><p>Alderton et al. (2006) found that cells expressing the 427insA mutant lacked detectable MCPH1 protein. The mutant transcript underwent nonsense-mediated decay, but residual mutant mRNA was detectable. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 MICROCEPHALY 1, PRIMARY, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MCPH1, 150-KB DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000003620
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 6 affected members of a consanguineous Iranian family with mental retardation, mild microcephaly (-3 SD), and premature chromosome condensation in at least 10 to 15% of cells (251200), Garshasbi et al. (2006) identified a homozygous 150- to 200-kb deletion encompassing the promoter and the first 6 exons of the MCPH1 gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 MICROCEPHALY 1, PRIMARY, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MCPH1, 1-BP INS, 566A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs753597039,
|
|
|
|
|
|
gnomAD: rs753597039,
|
|
|
|
|
|
ClinVar: RCV000023614, RCV002286697
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 affected members of a consanguineous Iranian family with microcephaly (-6 SD), moderate mental retardation, and premature chromosome condensation (251200), Darvish et al. (2010) identified a homozygous 1-bp insertion (566insA) in exon 6 of the MCPH1 gene, predicted to result in a frameshift. The mutation was not found in 160 German and 190 Iranian controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 MICROCEPHALY 1, PRIMARY, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MCPH1, HIS49GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1488084787,
|
|
|
|
|
|
gnomAD: rs1488084787,
|
|
|
|
|
|
ClinVar: RCV000023615
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 affected members of a consanguineous Iranian family with microcephaly (-7 to -9 SD), moderate mental retardation, and premature chromosome condensation (251200), Darvish et al. (2010) identified a homozygous 147C-G transversion in exon 3 of the MCPH1 gene, predicted to result in his49-to-gln (H49Q) substitution in the BRCT1 domain. The mutation was not found in 160 German and 190 Iranian controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 MICROCEPHALY 1, PRIMARY, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MCPH1, SER72LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906961,
|
|
|
|
|
|
gnomAD: rs387906961,
|
|
|
|
|
|
ClinVar: RCV000023616, RCV002287342, RCV004586022
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 affected members of a consanguineous Iranian family with microcephaly (-6 to -7 SD), mild to moderate mental retardation, and premature chromosome condensation (251200), Darvish et al. (2010) identified a homozygous 215C-T transition in exon 3 of the MCPH1 gene, predicted to result in ser72-to-leu (S72L) substitution in the BRCT1 domain. The mutation was not found in 160 German and 190 Iranian controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 MICROCEPHALY 1, PRIMARY, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MCPH1, SER101TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs755862917,
|
|
|
|
|
|
gnomAD: rs755862917,
|
|
|
|
|
|
ClinVar: RCV000023617, RCV002513198
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Danish female with primary microcephaly-1 (251200), previously reported by Tommerup et al. (1993), Farooq et al. (2010) identified a homozygous 302C-G transversion in exon 4 of the MCPH1 gene, resulting in a ser101-to-ter (S101X) substitution. The truncated protein was predicted to retain the N-terminal BRCT domain but lack the 2 C-terminal BRCT domains. The patient also had craniosynostosis, ptosis, and bird-like facies with micrognathia. The cellular phenotype of chromosomal sensitivity to DNA damage was particularly severe, which the authors suggested may be related to presence of the N-terminal BRCT domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
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|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Alderton, G. K., Galbiati, L., Griffith, E., Surinya, K. H., Neitzel, H., Jackson, A. P., Jeggo, P. A., O'Driscoll, M.
|
|
<strong>Regulation of mitotic entry by microcephalin and its overlap with ATR signalling.</strong>
|
|
Nature Cell Biol. 8: 725-733, 2006.
|
|
|
|
|
|
[PubMed: 16783362]
|
|
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|
|
[Full Text: https://doi.org/10.1038/ncb1431]
|
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</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Currat, M., Excoffier, L., Maddison, W., Otto, S. P., Ray, N., Whitlock, M. C., Yeaman, S.
|
|
<strong>Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens' and 'microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.' (Abstract)</strong>
|
|
Science 313: 172 only, 2006.
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|
[PubMed: 16840683]
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|
[Full Text: https://doi.org/10.1126/science.1122822]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Darvish, H., Esmaeeli-Nieh, S., Monajemi, G. B., Mohseni, M., Ghasemi-Firouzabadi, S., Abedini, S. S., Bahman, I., Jamali, P., Azimi, S., Mojahedi, F., Dehghan, A., Shafeghati, Y., and 14 others.
|
|
<strong>A clinical and molecular genetic study of 112 Iranian families with primary microcephaly.</strong>
|
|
J. Med. Genet. 47: 823-828, 2010. Note: Erratum: J. Med. Genet. 51: 70 only, 2014.
|
|
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|
|
[PubMed: 20978018]
|
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|
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[Full Text: https://doi.org/10.1136/jmg.2009.076398]
|
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
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Evans, P. D., Gilbert, S. L., Mekel-Bobrov, N., Vallender, E. J., Anderson, J. R., Vaez-Azizi, L. M., Tishkoff, S. A., Hudson, R. R., Lahn, B. T.
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Jackson, A. P., Eastwood, H., Bell, S. M., Adu, J., Toomes, C., Carr, I. M., Roberts, E., Hampshire, D. J., Crow, Y. J., Mighell, A. J., Karbani, G., Jafri, H., Rashid, Y., Mueller, R. F., Markham, A. F., Woods, C. G.
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<strong>BRIT1/MCPH1 is a DNA damage responsive protein that regulates the Brca1-Chk1 pathway, implicating checkpoint dysfunction in microcephaly.</strong>
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Maghirang-Rodriguez, R., Archie, J. G., Schwarz, C. E., Collins, J. S.
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<strong>The c.940G variant of the microcephalin (MCPH1) gene is not associated with microcephaly or mental retardation.</strong>
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[PubMed: 19267414]
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Mekel-Bobrov, N., Evans, P. D., Gilbert, S. L., Vallender, E. J., Hudson, R. R., Lahn, B. T.
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<strong>Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens' and 'microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.' (Abstract)</strong>
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Mekel-Bobrov, N., Posthuma, D., Gilbert, S. L., Lind, P., Gosso, M. F., Luciano, M., Harris, S. E., Bates, T. C., Polderman, T. J. C., Whalley, L. J., Fox, H., Starr, J. M., and 10 others.
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<strong>The ongoing adaptive evolution of ASPM and microcephalin is not explained by increased intelligence.</strong>
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Neitzel, H., Neumann, L. M., Schindler, D., Wirges, A., Tonnies, H., Trimborn, M., Krebsova, A., Richter, R., Sperling, K.
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Tommerup, N., Mortensen, E., Nielsen, M. H., Wegner, R.-D., Schindler, D., Mikkelsen, M.
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<strong>Chromosomal breakage, endomitosis, endoreduplication, and hypersensitivity toward radiomimetic and alkylating agents: a possible new autosomal recessive mutation in a girl with craniosynostosis and microcephaly.</strong>
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Trimborn, M., Bell, S. M., Felix, C., Rashid, Y., Jafri, H., Griffiths, P. D., Neumann, L. M., Krebs, A., Reis, A., Sperling, K., Neitzel, H., Jackson, A. P.
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Xu, X., Lee, J., Stern, D. F.
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<strong>Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1.</strong>
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[PubMed: 15220350]
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Cassandra L. Kniffin - updated : 6/30/2011<br>Cassandra L. Kniffin - updated : 2/21/2011<br>Cassandra L. Kniffin - updated : 7/12/2010<br>Cassandra L. Kniffin - updated : 4/16/2010<br>Patricia A. Hartz - updated : 11/7/2006<br>George E. Tiller - updated : 9/7/2006<br>George E. Tiller - updated : 9/7/2006<br>Patricia A. Hartz - updated : 8/18/2006<br>Ada Hamosh - updated : 8/7/2006<br>Cassandra L. Kniffin - updated : 3/27/2006<br>Patricia A. Hartz - updated : 1/27/2006<br>Ada Hamosh - updated : 9/27/2005<br>Stylianos E. Antonarakis - updated : 1/10/2005<br>Victor A. McKusick - updated : 8/12/2004
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