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Entry
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- *309550 - FRAGILE X MESSENGER RIBONUCLEOPROTEIN 1; FMR1
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*309550</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>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#nomenclature">Nomenclature</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#history">History</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/309550">Table View</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></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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<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=ENSG00000102081;t=ENST00000370475" 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=2332" 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=309550" 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=ENSG00000102081;t=ENST00000370475" 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_001185075,NM_001185076,NM_001185081,NM_001185082,NM_002024,NR_033699,NR_033700" 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_002024" 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=309550" 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=02398&isoform_id=02398_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/FMR1" 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/182673,296588,388726,388728,388734,388736,388738,388740,388742,388744,388748,388750,388752,388754,457235,457236,457237,457238,457239,457240,544328,553287,553288,553289,553290,553291,4261928,4503765,7705107,24658648,56270285,62087956,109631996,119581697,119581698,119581699,119581700,119581701,119581702,119581703,119581704,119581705,119581706,119581707,194376586,194380324,297374777,297374779,297374789,297374791,512393278,512393280,512393282,582054406,608785279,608785281,608785283,815830571,815830573,815830575,1483526864" 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/Q06787" 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=2332" 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=ENSG00000102081;t=ENST00000370475" 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=FMR1" 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=FMR1" 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+2332" 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/FMR1" 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:2332" 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/2332" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chrX&hgg_gene=ENST00000370475.9&hgg_start=147911919&hgg_end=147951125&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:3775" 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:3775" 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="#mimMedlinePlusGeneticsFold" id="mimMedlinePlusGeneticsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Consumer-friendly information about the effects of genetic variation on human health."><span id="mimMedlinePlusGeneticsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>MedlinePlus Genetics</div>
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<div id="mimMedlinePlusGeneticsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://medlineplus.gov/genetics/condition/fragile-x-syndrome" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">Fragile X syndrome </a></div><div style="margin-left: 0.5em;"><a href="https://medlineplus.gov/genetics/gene/fmr1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">FMR1 gene </a></div>
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</div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=309550[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 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=309550[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/FMR1/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/ENSG00000102081" 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=FMR1" 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=FMR1" 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=FMR1" 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="http://www.LOVD.nl/FMR1" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=FMR1&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/PA28191" 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:3775" 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/FBgn0028734.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:95564" 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/FMR1#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:95564" 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/2332/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA002455/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=2332" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-020731-6" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:309550" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=FMR1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 1332509007, 448045004, 613003<br />
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<strong>ICD10CM:</strong> Q99.2<br />
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<strong>ICD9CM:</strong> 759.83<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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309550
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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FRAGILE X MESSENGER RIBONUCLEOPROTEIN 1; FMR1
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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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<a id="alternativeTitles" class="mim-anchor"></a>
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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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</span>
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</p>
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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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FMRP TRANSLATIONAL REGULATOR 1<br />
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FRAGILE X MENTAL RETARDATION PROTEIN; FMRP
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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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<a id="includedTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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FRAGILE SITE, FOLIC ACID TYPE, RARE, fraXq27.3, INCLUDED; FRAXA, INCLUDED
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</span>
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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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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=FMR1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FMR1</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/X/769?start=-3&limit=10&highlight=769">Xq27.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:147911919-147951125&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">X:147,911,919-147,951,125</a> </span>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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Phenotype
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View Clinical Synopses
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Phenotype <br /> MIM number
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Phenotype <br /> mapping key
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Xq27.3
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Fragile X syndrome
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<a href="/entry/300624"> 300624 </a>
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<abbr class="mim-tip-hint" title="X-linked dominant">XLD</abbr>
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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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Fragile X tremor/ataxia syndrome
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<span class="mim-font">
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<a href="/entry/300623"> 300623 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="X-linked dominant">XLD</abbr>
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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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Premature ovarian failure 1
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<a href="/entry/311360"> 311360 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="X-linked">XL</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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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/309550" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/309550" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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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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<a id="text" class="mim-anchor"></a>
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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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</span>
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</h4>
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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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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>The selective RNA-binding protein FMRP forms a messenger ribonucleoprotein complex that associates with polyribosomes, suggesting that it is involved in translation (<a href="#63" class="mim-tip-reference" title="Jin, P., Zarnescu, D. C., Ceman, S., Nakamoto, M., Mowrey, J., Jongens, T. A., Nelson, D. L., Moses, K., Warren, S. T. <strong>Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway.</strong> Nature Neurosci. 7: 113-117, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14703574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14703574</a>] [<a href="https://doi.org/10.1038/nn1174" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14703574">Jin et al., 2004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14703574" 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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<br />
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<div>
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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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<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 id="mimCloningFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p>Warren et al. (<a href="#149" class="mim-tip-reference" title="Warren, S. T., Zhang, F., Licameli, G. R., Peters, J. F. <strong>The fragile X site in somatic cell hybrids: an approach for molecular cloning of fragile sites.</strong> Science 237: 420-423, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3603029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3603029</a>] [<a href="https://doi.org/10.1126/science.3603029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3603029">1987</a>, <a href="#150" class="mim-tip-reference" " title="Warren, S. T., Zhang, F. P., Sutcliffe, J. S., Peters, J. F. <strong>Strategy for molecular cloning of the fragile X site DNA.</strong> Am. J. Med. Genet. 30: 613-623, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3177473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3177473</a>] [<a href="https://doi.org/10.1002/ajmg.1320300162" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3177473">1988</a>, <a href="#148" class="mim-tip-reference" title="Warren, S. T., Knight, S. J. L., Peters, J. F., Stayton, C. L., Consalez, G. G., Zhang, F. P. <strong>Isolation of the human chromosomal band Xq28 within somatic cell hybrids by fragile X site breakage.</strong> Proc. Nat. Acad. Sci. 87: 3856-3860, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2339126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2339126</a>] [<a href="https://doi.org/10.1073/pnas.87.10.3856" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2339126">1990</a>) presented strategies for the molecular cloning of the fragile X syndrome (FXS; <a href="/entry/300624">300624</a>) gene using mapping information from affected families. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2339126+3177473+3603029" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#142" class="mim-tip-reference" title="Verkerk, A. J. M. H., Pieretti, M., Sutcliffe, J. S., Fu, Y.-H., Kuhl, D. P. A., Pizzuti, A., Reiner, O., Richards, S., Victoria, M. F., Zhang, F., Eussen, B. E., van Ommen, G.-J. B., Blonden, L. A. J., Riggins, G. J., Chastain, J. L., Kunst, C. B., Galjaard, H., Caskey, C. T., Nelson, D. L., Oostra, B. A., Warren, S. T. <strong>Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome.</strong> Cell 65: 905-914, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1710175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1710175</a>] [<a href="https://doi.org/10.1016/0092-8674(91)90397-h" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1710175">Verkerk et al. (1991)</a> identified the FMR1 gene within a 4-cosmid contig of YAC DNA spanning the fragile X syndrome breakpoint cluster region on Xq27-q28. The authors isolated cDNA clones corresponding to the gene from a human fetal brain cDNA library. The predicted sequence of the FMR1 protein contains a nuclear translocation signal. The gene-encoding region contains a CpG island previously shown to be hypermethylated in fragile X patients (<a href="#12" class="mim-tip-reference" title="Bell, M. V., Hirst, M. C., Nakahori, Y., MacKinnon, R. N., Roche, A., Flint, T. J., Jacobs, P. A., Tommerup, N., Tranebjaerg, L., Froster-Iskenius, U., Kerr, B., Turner, G., Lindenbaum, R. H., Winter, R., Pembrey, M., Thibodeau, S., Davies, K. E. <strong>Physical mapping across the fragile X: hypermethylation and clinical expression of the fragile X syndrome.</strong> Cell 64: 861-866, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1997211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1997211</a>] [<a href="https://doi.org/10.1016/0092-8674(91)90514-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1997211">Bell et al., 1991</a>; <a href="#55" class="mim-tip-reference" title="Heitz, D., Rousseau, F., Devys, D., Saccone, S., Abderrahim, H., Le Paslier, D., Cohen, D., Vincent, A., Toniolo, D., Della Valle, G., Johnson, S., Schlessinger, D., Oberle, I., Mandel, J. L. <strong>Isolation of sequences that span the fragile X and identification of a fragile X-related CpG island.</strong> Science 251: 1236-1239, 1991. Note: Erratum: Science 252: 494 only, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2006411/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2006411</a>] [<a href="https://doi.org/10.1126/science.2006411" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2006411">Heitz et al., 1991</a>). A 7.4-kb EcoRI fragment encompassing the region was identified in fragile X genomic DNA; the same fragment was 5.1 kb in normal X chromosomes, indicating that the region undergoes a variable increase in size in the fragile X chromosome. A CGG trinucleotide repeat, which is reiterated 30 times in the normal mRNA, was identified 250 bp distal to the well-known CpG island. Northern blot analysis detected a 4.8-kb mRNA in human brain. The findings suggested that the FMR1 gene is likely involved in fragile X syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1710175+1997211+2006411" 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="#125" class="mim-tip-reference" title="Siomi, H., Siomi, M. C., Nussbaum, R. L., Dreyfuss, G. <strong>The protein product of the fragile X gene, FMR1, has characteristics of an RNA-binding protein.</strong> Cell 74: 291-298, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7688265/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7688265</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90420-u" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7688265">Siomi et al. (1993)</a> reported that the deduced 594-amino acid FMR1 protein has 2 tandem KH domains in its N-terminal half and an RGG box near its C terminus. The KH domains and RGG box are associated with RNA binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7688265" 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 polyclonal antibodies to study sera from normal individuals, <a href="#140" class="mim-tip-reference" title="Verheij, C., Bakker, C. E., de Graaff, E., Keulemans, J., Willemsen, R., Verkerk, A. J. M. H., Galjaard, H., Reuser, A. J. J., Hoogeveen, A. T., Oostra, B. A. <strong>Characterization and localization of the FMR-1 gene product associated with fragile X syndrome.</strong> Nature 363: 722-724, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8515814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8515814</a>] [<a href="https://doi.org/10.1038/363722a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8515814">Verheij et al. (1993)</a> identified 4 different FMR1 protein products, possibly resulting from alternative splicing. All these proteins were missing in cell lines from fragile X patients not expressing FMR1 mRNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8515814" 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="#7" class="mim-tip-reference" title="Ashley, C. T., Sutcliffe, J. S., Kunst, C. B., Leiner, H. A., Eichler, E. E., Nelson, D. L., Warren, S. T. <strong>Human and murine FMR-1: alternative splicing and translational initiation downstream of the CGG-repeat.</strong> Nature Genet. 4: 244-251, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8358432/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8358432</a>] [<a href="https://doi.org/10.1038/ng0793-244" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8358432">Ashley et al. (1993)</a> isolated and characterized cDNA clones encoding the murine homolog, Fmr1, which exhibits marked sequence identity with the human gene, including the conservation of the CGG repeat. A conserved ATG downstream of the CGG repeat in both human and mouse and an in-frame stop codon in other human 5-prime cDNA sequences demarcate the FMR1 coding region and confine the CGG repeat to the 5-prime untranslated region. <a href="#7" class="mim-tip-reference" title="Ashley, C. T., Sutcliffe, J. S., Kunst, C. B., Leiner, H. A., Eichler, E. E., Nelson, D. L., Warren, S. T. <strong>Human and murine FMR-1: alternative splicing and translational initiation downstream of the CGG-repeat.</strong> Nature Genet. 4: 244-251, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8358432/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8358432</a>] [<a href="https://doi.org/10.1038/ng0793-244" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8358432">Ashley et al. (1993)</a> presented evidence for alternative splicing of the FMR1 gene in mouse and human brain and showed that one of these splicing events alters the FMR1 reading frame, predicting isoforms with novel carboxy termini. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8358432" 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="Alpatov, R., Lesch, B. J., Nakamoto-Kinoshita, M., Blanco, A., Chen, S., Stutzer, A., Armache, K. J., Simon, M. D., Xu, C., Ali, M., Murn, J., Prisic, S., Kutateladze, T. G., Vakoc, C. R., Min, J., Kingston, R. E., Fischle, W., Warren, S. T., Page, D. C., Shi, Y. <strong>A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response.</strong> Cell 157: 869-881, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24813610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24813610</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24813610[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2014.03.040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24813610">Alpatov et al. (2014)</a> identified an Agenet domain at the N terminus of FMRP. The Agenet domain consists of 2 adjacent Tudor domains referred to as 'N-terminal domain of FMRP 1' (NDF1) and NDF2. The Agenet domain of FMRP belongs to the Royal family of chromatin-binding proteins. Immunofluorescence analysis of chromosome spreads of adult mouse spermatocytes detected Fmrp puncta on condensed pachytene-stage chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24813610" 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="#36" class="mim-tip-reference" title="Eichler, E. E., Richards, S., Gibbs, R. A., Nelson, D. L. <strong>Fine structure of the human FMR1 gene.</strong> Hum. Molec. Genet. 2: 1147-1153, 1993. Note: Erratum: Hum. Molec. Genet. 3: 684-685, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8401496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8401496</a>] [<a href="https://doi.org/10.1093/hmg/2.8.1147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8401496">Eichler et al. (1993)</a> determined that the FMR1 gene contains 17 exons spanning 38 kb. Splice donors and acceptors located in the 5-prime portion of the gene demonstrated greater adherence to consensus than did those in the 3-prime end, providing a possible explanation for alternative splicing in FMR1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8401496" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#129" class="mim-tip-reference" title="Smith, K. T., Coffee, B., Reines, D. <strong>Occupancy and synergistic activation of the FMR1 promoter by Nrf-1 and Sp1 in vivo.</strong> Hum. Molec. Genet. 13: 1611-1621, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15175277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15175277</a>] [<a href="https://doi.org/10.1093/hmg/ddh172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15175277">Smith et al. (2004)</a> examined the promoter region of the FMR1 gene and identified binding sites for several transcription factors, including AP2 (TFAP2A; <a href="/entry/107580">107580</a>), NRF1 (<a href="/entry/600879">600879</a>), MYC (<a href="/entry/190080">190080</a>), and SP1 (<a href="/entry/189906">189906</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15175277" 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="#101" class="mim-tip-reference" title="Naumann, A., Hochstein, N., Weber, S., Fanning, E., Doerfler, W. <strong>A distinct DNA-methylation boundary in the 5-prime-upstream sequence of the FMR1 promoter binds nuclear proteins and is lost in fragile X syndrome.</strong> Am. J. Hum. Genet. 85: 606-616, 2009. Note: Erratum: Am. J. Hum. Genet. 86: 98-100, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19853235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19853235</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19853235[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2009.09.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19853235">Naumann et al. (2009)</a> stated that the promoter region of the FMR1 gene lacks a typical TATAA box. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19853235" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>DNA-Methylation Boundary in 5-prime Upstream Region</em></strong></p><p>
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<a href="#101" class="mim-tip-reference" title="Naumann, A., Hochstein, N., Weber, S., Fanning, E., Doerfler, W. <strong>A distinct DNA-methylation boundary in the 5-prime-upstream sequence of the FMR1 promoter binds nuclear proteins and is lost in fragile X syndrome.</strong> Am. J. Hum. Genet. 85: 606-616, 2009. Note: Erratum: Am. J. Hum. Genet. 86: 98-100, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19853235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19853235</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19853235[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2009.09.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19853235">Naumann et al. (2009)</a> identified 104 CpG dinucleotides in a 5.5-kb segment of the 5-prime upstream region of FMR1. These CpGs could be separated into a long, far upstream segment of methylated CpG pairs and a shorter, downstream segment of unmethylated CpG pairs covering the promoter region of FMR1 and extending to the CGG repeat region. The methylation boundary has a transition zone with a methylation mosaic on its downstream side. A similar methylation boundary is conserved in the mouse Fmr1 gene. <a href="#101" class="mim-tip-reference" title="Naumann, A., Hochstein, N., Weber, S., Fanning, E., Doerfler, W. <strong>A distinct DNA-methylation boundary in the 5-prime-upstream sequence of the FMR1 promoter binds nuclear proteins and is lost in fragile X syndrome.</strong> Am. J. Hum. Genet. 85: 606-616, 2009. Note: Erratum: Am. J. Hum. Genet. 86: 98-100, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19853235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19853235</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19853235[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2009.09.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19853235">Naumann et al. (2009)</a> showed that the isolated transition sequence in the methylation boundary bound nuclear proteins from a human colorectal cell line. Competition studies showed that formation of these distinct protein-DNA complexes occurred in the presence or absence of DNA methylation. <a href="#101" class="mim-tip-reference" title="Naumann, A., Hochstein, N., Weber, S., Fanning, E., Doerfler, W. <strong>A distinct DNA-methylation boundary in the 5-prime-upstream sequence of the FMR1 promoter binds nuclear proteins and is lost in fragile X syndrome.</strong> Am. J. Hum. Genet. 85: 606-616, 2009. Note: Erratum: Am. J. Hum. Genet. 86: 98-100, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19853235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19853235</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19853235[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2009.09.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19853235">Naumann et al. (2009)</a> proposed that the methylation boundary carries a specific chromatin structure that delineates a hypermethylated area in the genome from the unmethylated FMR1 promoter, protecting it from the spreading of DNA methylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19853235" 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="#112" class="mim-tip-reference" title="Poustka, A., Dietrich, A., Langenstein, G., Toniolo, D., Warren, S. T., Lehrach, H. <strong>Physical map of human Xq27-qter: localizing the region of the fragile X mutation.</strong> Proc. Nat. Acad. Sci. 88: 8302-8306, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1924290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1924290</a>] [<a href="https://doi.org/10.1073/pnas.88.19.8302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1924290">Poustka et al. (1991)</a> described a physical map of the end of chromosome Xq encompassing the region from Xq27.2 to the telomere, inclusive of band Xq28. The map covered a total of 12 Mb of DNA and extended from the telomere to a location 3 Mb proximal to the most likely position of the fragile X mutation. The map determined order and position of loci throughout the Xq28 region and localized cell line breakpoints marking the fragile X region to an interval of 300-700 kb between 8 and 8.7 Mb proximal to the Xq telomere. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1924290" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Faust, C. J., Verkerk, A. J. M. H., Wilson, P. J., Morris, C. P., Hopwood, J. J., Oostra, B. A., Herman, G. E. <strong>Genetic mapping on the mouse X chromosome of human cDNA clones for the fragile X and Hunter syndromes.</strong> Genomics 12: 814-817, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1572654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1572654</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90314-i" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1572654">Faust et al. (1992)</a> and <a href="#79" class="mim-tip-reference" title="Laval, S. H., Blair, H. J., Hirst, M. C., Davies, K. E., Boyd, Y. <strong>Mapping of FMR1, the gene implicated in fragile X-linked mental retardation, on the mouse X chromosome.</strong> Genomics 12: 818-821, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1572655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1572655</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90315-j" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1572655">Laval et al. (1992)</a> determined the location of the corresponding gene on the mouse X chromosome by use of human cDNA clones in an interspecific backcross. Both groups found preservation of the order of loci, although no fragile site had been detected microscopically in that region of the mouse X chromosome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1572654+1572655" 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 use of transient expression in COS-1 cells, <a href="#140" class="mim-tip-reference" title="Verheij, C., Bakker, C. E., de Graaff, E., Keulemans, J., Willemsen, R., Verkerk, A. J. M. H., Galjaard, H., Reuser, A. J. J., Hoogeveen, A. T., Oostra, B. A. <strong>Characterization and localization of the FMR-1 gene product associated with fragile X syndrome.</strong> Nature 363: 722-724, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8515814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8515814</a>] [<a href="https://doi.org/10.1038/363722a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8515814">Verheij et al. (1993)</a> demonstrated intracellular localization of the FMR1 gene products. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8515814" 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 monoclonal antibodies specific for the FMR1 protein, <a href="#31" class="mim-tip-reference" title="Devys, D., Lutz, Y., Rouyer, N., Bellocq, J.-P., Mandel, J.-L. <strong>The FMR-1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation.</strong> Nature Genet. 4: 335-340, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8401578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8401578</a>] [<a href="https://doi.org/10.1038/ng0893-335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8401578">Devys et al. (1993)</a> detected 4 or 5 protein bands in cells of normal males and of males carrying a premutation (an elongation of 70 to 200 bp), which were absent in affected males with a full mutation (FM). Immunohistochemistry showed a cytoplasmic localization of the FMR1 protein. The highest levels were observed in neurons, while glial cells contained very low levels. In epithelial tissues, levels of FMR1 were higher in dividing layers. In adult testes, FMR1 was detected only in spermatogonia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8401578" 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="Abitbol, M., Menini, C., Delezoide, A.-L., Rhyner, T., Vekemans, M., Mallet, J. <strong>Nucleus basalis magnocellularis and hippocampus are the major sites of FMR-1 expression in the human fetal brain.</strong> Nature Genet. 4: 147-153, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8348153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8348153</a>] [<a href="https://doi.org/10.1038/ng0693-147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8348153">Abitbol et al. (1993)</a> used in situ hybridization to demonstrate that FMR1 mRNAs are expressed in human fetal brain from an early stage in proliferating and migrating cells of the nervous system and retina as well as cartilaginous structures, including branchial cartilage, and liver. In the brain of 25-week-old human fetuses, FMR1 mRNA was produced in highest levels in cholinergic neurons of the nucleus basalis magnocellularis and in pyramidal neurons of the hippocampus. The early transcription and distribution of the gene suggested that alterations of FMR1 gene expression contributes to the pathogenesis of the fragile X syndrome, especially the mental retardation. <a href="#9" class="mim-tip-reference" title="Bachner, D., Steinbach, P., Wohrle, D., Just, W., Vogel, W., Hameister, H., Manca, A., Poustka, A. <strong>Enhanced Fmr-1 expression in testis. (Letter)</strong> Nature Genet. 4: 115-116, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8348147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8348147</a>] [<a href="https://doi.org/10.1038/ng0693-115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8348147">Bachner et al. (1993)</a> presented evidence suggesting that the FMR1 gene serves a function in the mature testis, as reflected by high expression in spermatogonia and not in Sertoli cells. They suggested further that FMR1 expression in spermatogonia is necessary for germ cell proliferation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8348153+8348147" 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="Ashley, C. T., Jr., Wilkinson, K. D., Reines, D., Warren, S. T. <strong>FMR1 protein: conserved RNP family domains and selective RNA binding.</strong> Science 262: 563-566, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7692601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7692601</a>] [<a href="https://doi.org/10.1126/science.7692601" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7692601">Ashley et al. (1993)</a> identified ribonucleoprotein particle domains within the FMR protein and showed that RNA bound in stoichiometric ratios, suggesting that there are 2 RNA binding sites per FMR protein molecule. The protein was able to bind to its own message with high affinity and interacted with approximately 4% of human fetal brain messages. <a href="#6" class="mim-tip-reference" title="Ashley, C. T., Jr., Wilkinson, K. D., Reines, D., Warren, S. T. <strong>FMR1 protein: conserved RNP family domains and selective RNA binding.</strong> Science 262: 563-566, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7692601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7692601</a>] [<a href="https://doi.org/10.1126/science.7692601" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7692601">Ashley et al. (1993)</a> postulated that the absence of the normal interaction of the FMR protein with a subset of RNA molecules might result in the pleiotropic phenotype associated with the fragile X syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7692601" 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="#125" class="mim-tip-reference" title="Siomi, H., Siomi, M. C., Nussbaum, R. L., Dreyfuss, G. <strong>The protein product of the fragile X gene, FMR1, has characteristics of an RNA-binding protein.</strong> Cell 74: 291-298, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7688265/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7688265</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90420-u" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7688265">Siomi et al. (1993)</a> demonstrated that the FMR1 protein contains 2 types of sequence motifs characteristic of RNA-binding proteins: an RGG box and 2 heterogeneous nuclear ribonucleoprotein (hnRNP) K homology (KH) domains. They also demonstrated that FMR1 binds RNA in vitro. Using antibodies to FMR1, they detected its expression in cells of unaffected humans but little or no FMR1 in patients with fragile X syndrome. It is noteworthy that a pathogenic point mutation (I304N; <a href="#0001">309550.0001</a>) described by <a href="#29" class="mim-tip-reference" title="De Boulle, K., Verkerk, A. J. M. H., Reyniers, E., Vits, L., Hendrickx, J., Van Roy, B., Van Den Bos, F., de Graaff, E., Oostra, B. A., Willems, P. J. <strong>A point mutation in the FMR-1 gene associated with fragile X mental retardation.</strong> Nature Genet. 3: 31-35, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8490650/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8490650</a>] [<a href="https://doi.org/10.1038/ng0193-31" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8490650">de Boulle et al. (1993)</a> is in one of the most highly conserved residues of one of these RNA-binding domains. The KH domain, a highly conserved domain originally described in the pre-mRNA-binding hnRNP K protein, contains approximately 50 amino acids found in a diverse group of RNA-binding proteins. Using mutagenesis of KH domains in hnRNP K and FMR1, <a href="#124" class="mim-tip-reference" title="Siomi, H., Choi, M., Siomi, M. C., Nussbaum, R. L., Dreyfuss, G. <strong>Essential role for KH domains in RNA binding: impaired RNA binding by a mutation in the KH domain of FMR1 that causes fragile X syndrome.</strong> Cell 77: 33-39, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8156595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8156595</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90232-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8156595">Siomi et al. (1994)</a> found that conserved residues of all 3 KH domains of hnRNP K were required for its wildtype RNA binding. The results demonstrated an essential role for KH domains in RNA binding and strengthened the connection between the fragile X syndrome and loss of RNA-binding activity of FMR1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7688265+8490650+8156595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#67" class="mim-tip-reference" title="Khandjian, E. W., Corbin, F., Woerly, S., Rousseau, F. <strong>The fragile X mental retardation protein is associated with ribosomes.</strong> Nature Genet. 12: 91-93, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528261</a>] [<a href="https://doi.org/10.1038/ng0196-91" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528261">Khandjian et al. (1996)</a> observed that the FMR protein cosediments with polyribosomes after centrifugation in sucrose density gradients. Specifically, it was associated with the ribosomal 60S subunit and possessed the characteristics of a nonintegral ribosomal protein. Immunofluorescent studies showed a tight colocalization of FMRP with cytoplasmic ribosomes in NIH 3T3 and HeLa cells and in primary cultures of neurons. The authors concluded that fragile X mental retardation may result from defects in the translational machinery due to absence of FMRP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8528261" 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>FMR1 protein and the fragile X-related proteins 1 (FXR1; <a href="/entry/600819">600819</a>) and 2 (FXR2; <a href="/entry/605339">605339</a>) form a family with functional similarities such as RNA binding, polyribosomal association, and nucleocytoplasmic shuttling. Using several FMR1 deletion mutants in coimmunoprecipitation experiments, <a href="#126" class="mim-tip-reference" title="Siomi, M. C., Zhang, Y., Siomi, H., Dreyfuss, G. <strong>Specific sequences in the fragile X syndrome protein FMR1 and the FXR proteins mediate their binding to 60S ribosomal subunits and the interactions among them.</strong> Molec. Cell. Biol. 16: 3825-3832, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8668200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8668200</a>] [<a href="https://doi.org/10.1128/MCB.16.7.3825" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8668200">Siomi et al. (1996)</a> identified amino acids 359 to 472, which are encoded by exons 13 and 14, as the 60S ribosomal subunit-binding region. They found that amino acids 171 to 211 are sufficient for FMR1 interaction with FXR2 and that FMR1 is not required for the association of FXR1 or FXR2 with the 60S ribosomal subunit. FXR1 and FXR2 associated with 60S ribosomal subunits in cells lacking FMR1 and in cells derived from a fragile X syndrome patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8668200" 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="#134" class="mim-tip-reference" title="Tamanini, F., Bontekoe, C., Bakker, C. E., van Unen, L., Anar, B., Willemsen, R., Yoshida, M., Galjaard, H., Oostra, B. A., Hoogeveen, A. T. <strong>Different targets for the fragile X-related proteins revealed by their distinct nuclear localizations.</strong> Hum. Molec. Genet. 8: 863-869, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10196376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10196376</a>] [<a href="https://doi.org/10.1093/hmg/8.5.863" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10196376">Tamanini et al. (1999)</a> found that FMR1 and FXR1 proteins shuttle between cytoplasm and nucleoplasm, while FXR2 protein shuttles between cytoplasm and nucleolus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10196376" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By immunofluorescence studies, <a href="#127" class="mim-tip-reference" title="Sittler, A., Devys, D., Weber, C., Mandel, J.-L. <strong>Alternative splicing of exon 14 determines nuclear or cytoplasmic localisation of fmr1 protein isoforms.</strong> Hum. Molec. Genet. 5: 95-102, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8789445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8789445</a>] [<a href="https://doi.org/10.1093/hmg/5.1.95" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8789445">Sittler et al. (1996)</a> found that splice variants of FMR1 that exclude exon 14 sequences (and have alternate C-terminal regions) are nuclear. Analysis of various deletion mutants suggested the presence of a cytoplasmic retention domain encoded in exon 14 and of a nuclear association domain encoded within the first 8 exons that appeared, however, to lack a typical nuclear localization signal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8789445" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#38" class="mim-tip-reference" title="Feng, Y., Absher, D., Eberhart, D. E., Brown, V., Malter, H. E., Warren, S. T. <strong>FMRP associates with polyribosomes as an mRNP, and the I304N mutation of severe fragile X syndrome abolishes this association.</strong> Molec. Cell 1: 109-118, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9659908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9659908</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80012-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9659908">Feng et al. (1997)</a> demonstrated that normal FMRP associates with elongating polyribosomes via large mRNP particles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9659908" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#81" class="mim-tip-reference" title="Lewis, H. A., Musunuru, K., Jensen, K. B., Edo, C., Chen, H., Darnell, R. B., Burley, S. K. <strong>Sequence-specific RNA binding by a Nova KH domain: implications for paraneoplastic disease and the fragile X syndrome.</strong> Cell 100: 323-332, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10676814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10676814</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80668-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10676814">Lewis et al. (2000)</a> determined the structure of the KH3 domain of NOVA2 (<a href="/entry/601991">601991</a>) interacting with single-stranded RNA at 2.4-angstrom resolution. The structure of the KH3 domain bound to a stem loop RNA resembled a molecular vise, with 5-prime-UCAC-3-prime pinioned between an invariant gly-X-X-gly motif and the variable loop. Tetranucleotide recognition was supported by an aliphatic alpha-helix/beta-sheet RNA-binding platform, which mimicked 5-prime-UG-3-prime by making Watson-Crick-like hydrogen bonds with 5-prime-CA-3-prime. Sequence conservation suggested that fragile X mental retardation results from perturbation of RNA binding by the KH2 domain of the FMR1 protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10676814" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Darnell, J. C., Jensen, K. B., Jin, P., Brown, V., Warren, S. T., Darnell, R. B. <strong>Fragile X mental retardation protein targets G quartet mRNAs important for neuronal function.</strong> Cell 107: 489-499, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11719189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11719189</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00566-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11719189">Darnell et al. (2001)</a> used RNA selection to demonstrate that the FMRP RGG box binds intramolecular G quartets. These data allowed them to identify mRNAs encoding proteins involved in synaptic or developmental neurobiology that harbor FMRP-binding elements. The majority of these mRNAs had an altered polysome association in fragile X patient cells. These data demonstrated that G quartets serve as physiologically relevant targets for FMRP and identified mRNAs whose dysregulation may underlie human mental retardation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11719189" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#76" class="mim-tip-reference" title="Laggerbauer, B., Ostareck, D., Keidel, E.-M., Ostareck-Lederer, A., Fischer, U. <strong>Evidence that fragile X mental retardation protein is a negative regulator of translation.</strong> Hum. Molec. Genet. 10: 329-338, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11157796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11157796</a>] [<a href="https://doi.org/10.1093/hmg/10.4.329" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11157796">Laggerbauer et al. (2001)</a> showed that FMR1 strongly inhibited translation of various mRNAs at nanomolar concentrations in both rabbit reticulocyte lysate and microinjected Xenopus laevis oocytes. The effect was specific for FMR1, since other proteins with similar RNA-binding domains, including the autosomal homologs of FMR1, FXR1, and FXR2, failed to suppress translation in the same concentration range. Initial studies addressing the underlying mechanism of inhibition suggested that FMR1 may inhibit the assembly of 80S ribosomes on the target mRNAs. The I304N mutation rendered FMR1 incapable of interfering with translation in both test systems, and severely impaired homooligomerization of FMR1. The failure of FMR1 I304N to suppress translation was not due to its reduced affinity for mRNA or its interacting proteins FXR1 and FXR2. The authors hypothesized that inhibition of translation may be a function of FMR1 in vivo, and that failure of mutant FMR1 protein to oligomerize may contribute to the pathophysiologic events leading to fragile X syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11157796" 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 microarray analysis, <a href="#15" class="mim-tip-reference" title="Brown, V., Jin, P., Ceman, S., Darnell, J. C., O'Donnell, W. T., Tenenbaum, S. A., Jin, X., Feng, Y., Wilkinson, K. D., Keene, J. D., Darnell, R. B., Warren, S. T. <strong>Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome.</strong> Cell 107: 477-487, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11719188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11719188</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00568-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11719188">Brown et al. (2001)</a> identified 432 associated mRNAs from mouse brain that coimmunoprecipitated mRNA with the FMRP ribonucleoprotein complex. Quantitative RT-PCR confirmed some to be more than 60-fold enriched in the immunoprecipitant. In parallel studies, mRNAs from polyribosomes of fragile X cells were used to probe microarrays. Despite equivalent cytoplasmic abundance, 251 mRNAs had an abnormal polyribosome profile in the absence of FMRP. Although this represented less than 2% of the total messages, 50% of the coimmunoprecipitated mRNAs with expressed human orthologs were found in this group. Nearly 70% of those transcripts found in both studies contained a G quartet structure, demonstrated as an in vitro FMRP target. <a href="#15" class="mim-tip-reference" title="Brown, V., Jin, P., Ceman, S., Darnell, J. C., O'Donnell, W. T., Tenenbaum, S. A., Jin, X., Feng, Y., Wilkinson, K. D., Keene, J. D., Darnell, R. B., Warren, S. T. <strong>Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome.</strong> Cell 107: 477-487, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11719188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11719188</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00568-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11719188">Brown et al. (2001)</a> concluded that translational dysregulation of mRNAs normally associated with FMRP may be the proximal cause of fragile X syndrome, and they identified candidate genes relevant to this phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11719188" 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="#106" class="mim-tip-reference" title="Oostra, B. A., Chiurazzi, P. <strong>The fragile X gene and its function.</strong> Clin. Genet. 60: 399-408, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11846731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11846731</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2001.600601.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11846731">Oostra and Chiurazzi (2001)</a> reviewed the FMR1 gene and FMR1 protein function, including information on animal models for fragile X syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11846731" 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 CpG methylation-deficient Drosophila cells, <a href="#129" class="mim-tip-reference" title="Smith, K. T., Coffee, B., Reines, D. <strong>Occupancy and synergistic activation of the FMR1 promoter by Nrf-1 and Sp1 in vivo.</strong> Hum. Molec. Genet. 13: 1611-1621, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15175277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15175277</a>] [<a href="https://doi.org/10.1093/hmg/ddh172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15175277">Smith et al. (2004)</a> demonstrated in vivo that Nrf1 (<a href="/entry/600879">600879</a>) and Sp1 (<a href="/entry/189906">189906</a>) are strong, synergistic activators of an unmethylated human FMR1-driven reporter, while USF1/2 (<a href="/entry/191523">191523</a>, <a href="/entry/600390">600390</a>) and Max (<a href="/entry/154950">154950</a>) repressed this activation. In addition, analyses of transcription factor activity upon DNA methylation of the reporter showed that Sp1 activity was largely intact when the promoter was densely methylated, but Nrf1 transactivation was very sensitive to dense methylation. Notably, Nrf1 transactivation was relatively insensitive to methylation of cytosines only at its binding site. FMR1 reporter activity was also reduced in HeLa cells after expression of a short interfering RNA directed against endogenous Nrf1. Sp1 and Nrf1 occupied the human FMR1 promoter in vivo, and these interactions were disrupted in fragile X patient cells. In addition, Max resided at the FMR1 promoter, and USF1/2, but not c-Myc (<a href="/entry/190080">190080</a>), were present at endogenous FMR1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15175277" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a mouse fibroblast model system, <a href="#17" class="mim-tip-reference" title="Castets, M., Schaeffer, C., Bechara, E., Schenck, A., Khandjian, E. W., Luche, S., Moine, H., Rabilloud, T., Mandel, J.-L., Bardoni, B. <strong>FMRP interferes with the Rac1 pathway and controls actin cytoskeleton dynamics in murine fibroblasts.</strong> Hum. Molec. Genet. 14: 835-844, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15703194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15703194</a>] [<a href="https://doi.org/10.1093/hmg/ddi077" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15703194">Castets et al. (2005)</a> demonstrated that FMRP and the Rac1 (<a href="/entry/602048">602048</a>) pathway are connected. Rac1 activation induced relocalization of FMRP interactors CYFIP1 (<a href="/entry/606322">606322</a>), FXR1, NUFIP1 (<a href="/entry/604354">604354</a>), and NUFIP2 (<a href="/entry/609356">609356</a>) to actin ring areas. Moreover, Rac1-induced actin remodeling was altered in fibroblasts lacking FMRP or carrying a point mutation in the KH1 or in the KH2 RNA-binding domain. Absence of wildtype FMRP resulted in lowered levels of phospho-cofilin (CFL1; <a href="/entry/601442">601442</a>), which is a major mediator of Rac1 signaling, and increased levels of the phospho-cofilin phosphatase PPP2CA (<a href="/entry/176915">176915</a>). FMRP bound with high affinity to the 5-prime-UTR of PPP2CA-beta mRNA and is a likely negative regulator of its translation. <a href="#17" class="mim-tip-reference" title="Castets, M., Schaeffer, C., Bechara, E., Schenck, A., Khandjian, E. W., Luche, S., Moine, H., Rabilloud, T., Mandel, J.-L., Bardoni, B. <strong>FMRP interferes with the Rac1 pathway and controls actin cytoskeleton dynamics in murine fibroblasts.</strong> Hum. Molec. Genet. 14: 835-844, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15703194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15703194</a>] [<a href="https://doi.org/10.1093/hmg/ddi077" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15703194">Castets et al. (2005)</a> suggested a role for FMRP in modulation of actin dynamics, which is a key process in morphogenesis of dendritic spines. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15703194" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To identify the RNA target for the KH2 domain of FMR1, <a href="#26" class="mim-tip-reference" title="Darnell, J. C., Fraser, C. E., Mostovetsky, O., Stefani, G., Jones, T. A., Eddy, S. R., Darnell, R. B. <strong>Kissing complex RNAs mediate interaction between the fragile-X mental retardation protein KH2 domain and brain polyribosomes.</strong> Genes Dev. 19: 903-918, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15805463/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15805463</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15805463[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/10.1101/gad.1276805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15805463">Darnell et al. (2005)</a> performed RNA selection with both full-length FMR1 and isolated KH2 domains. They determined that, unlike other characterized KH domains, the FMR1 KH2 domain bound to an RNA complex termed a loop-loop pseudoknot, or 'kissing complex.' The association of FMR1 with mouse brain polyribosomes was abrogated by competition with kissing complex RNAs, but not by G quartet RNAs. <a href="#26" class="mim-tip-reference" title="Darnell, J. C., Fraser, C. E., Mostovetsky, O., Stefani, G., Jones, T. A., Eddy, S. R., Darnell, R. B. <strong>Kissing complex RNAs mediate interaction between the fragile-X mental retardation protein KH2 domain and brain polyribosomes.</strong> Genes Dev. 19: 903-918, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15805463/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15805463</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15805463[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/10.1101/gad.1276805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15805463">Darnell et al. (2005)</a> concluded that kissing complex motifs are targets for FMR1 translational regulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15805463" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#83" class="mim-tip-reference" title="Lim, J. H., Booker, A. B., Luo, T., Williams, T., Furuta, Y., Lagutin, O., Oliver, G., Sargent, T. D., Fallon, J. R. <strong>AP-2-alpha selectively regulates fragile X mental retardation-1 gene transcription during embryonic development.</strong> Hum. Molec. Genet. 14: 2027-2034, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15930016/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15930016</a>] [<a href="https://doi.org/10.1093/hmg/ddi207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15930016">Lim et al. (2005)</a> tested the role of the transcription factor AP2-alpha (TFAP2A; <a href="/entry/107580">107580</a>) in regulating Fmr1 expression. Chromatin immunoprecipitation showed that AP2-alpha associated with the Fmr1 promoter in vivo. Fmr1 transcript levels were reduced approximately 4-fold in homozygous null AP2-alpha mutant mice at embryonic day 18.5 when compared with normal littermates. AP2-alpha exhibited a strong gene dosage effect, with heterozygous mice showing an approximately 2-fold reduction in Fmr1 levels. Examination of conditional AP2-alpha mutant mice indicated that the transcription factor played a major role in regulating Fmr1 expression in embryos, but not in adults. Overexpression of a dominant-negative AP2-alpha in Xenopus embryos led to reduced Fmr1 levels. Exogenous wildtype AP2-alpha rescued Fmr1 expression in embryos where endogenous AP2-alpha had been suppressed. <a href="#83" class="mim-tip-reference" title="Lim, J. H., Booker, A. B., Luo, T., Williams, T., Furuta, Y., Lagutin, O., Oliver, G., Sargent, T. D., Fallon, J. R. <strong>AP-2-alpha selectively regulates fragile X mental retardation-1 gene transcription during embryonic development.</strong> Hum. Molec. Genet. 14: 2027-2034, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15930016/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15930016</a>] [<a href="https://doi.org/10.1093/hmg/ddi207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15930016">Lim et al. (2005)</a> concluded that AP2-alpha associates with the Fmr1 promoter in vivo and selectively regulates Fmr1 transcription during embryonic development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15930016" 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>NXF1 (<a href="/entry/602647">602647</a>) and NXF2 (<a href="/entry/300315">300315</a>) belong to a family of evolutionarily conserved nuclear export factors. Using immunoprecipitation analysis and quantitative real-time RT-PCR, <a href="#160" class="mim-tip-reference" title="Zhang, M., Wang, Q., Huang, Y. <strong>Fragile X mental retardation protein FMRP and the RNA export factor NXF2 associate with and destabilize Nxf1 mRNA in neuronal cells.</strong> Proc. Nat. Acad. Sci. 104: 10057-10062, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17548835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17548835</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17548835[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.0700169104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17548835">Zhang et al. (2007)</a> showed that Fmrp and Nxf2 were present in Nxf1 mRNA-containing ribonucleoprotein particles in cultured mouse neuronal cells. Expression of Nxf2 led to destabilization of Nxf1 mRNA, and this effect was abolished when Fmrp expression was reduced by small interfering RNA. <a href="#160" class="mim-tip-reference" title="Zhang, M., Wang, Q., Huang, Y. <strong>Fragile X mental retardation protein FMRP and the RNA export factor NXF2 associate with and destabilize Nxf1 mRNA in neuronal cells.</strong> Proc. Nat. Acad. Sci. 104: 10057-10062, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17548835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17548835</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17548835[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.0700169104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17548835">Zhang et al. (2007)</a> concluded that FMRP and NXF2 collaborate to destabilize NXF1 mRNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17548835" 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 yeast 2-hybrid analysis of a human fetal brain cDNA library, <a href="#28" class="mim-tip-reference" title="Davidovic, L., Jaglin, X. H., Lepagnol-Bestel, A.-M., Tremblay, S., Simonneau, M., Bardoni, B., Khandjian, E. W. <strong>The fragile X mental retardation protein is a molecular adaptor between the neurospecific KIF3C kinesin and dendritic RNA granules.</strong> Hum. Molec. Genet. 16: 3047-3058, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17881655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17881655</a>] [<a href="https://doi.org/10.1093/hmg/ddm263" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17881655">Davidovic et al. (2007)</a> showed that the neurospecific kinesin KIF3C (<a href="/entry/602845">602845</a>) interacted directly with FMRP. Time-lapse videomicroscopy of cultured rat hippocampal neurons showed that a dominant-negative Kif3c mutant impeded the distal transport of Fmrp-containing RNA granules. <a href="#28" class="mim-tip-reference" title="Davidovic, L., Jaglin, X. H., Lepagnol-Bestel, A.-M., Tremblay, S., Simonneau, M., Bardoni, B., Khandjian, E. W. <strong>The fragile X mental retardation protein is a molecular adaptor between the neurospecific KIF3C kinesin and dendritic RNA granules.</strong> Hum. Molec. Genet. 16: 3047-3058, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17881655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17881655</a>] [<a href="https://doi.org/10.1093/hmg/ddm263" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17881655">Davidovic et al. (2007)</a> concluded that FMRP acts as a molecular adaptor between mRNA granules and the molecular machinery that transports mRNAs along neuronal microtubules. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17881655" 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="#32" class="mim-tip-reference" title="Dictenberg, J. B., Swanger, S. A., Antar, L. N., Singer, R. H., Bassell, G. J. <strong>A direct role for FMRP in activity-dependent dendritic mRNA transport links filopodial-spine morphogenesis to fragile X syndrome.</strong> Dev. Cell 14: 926-939, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18539120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18539120</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18539120[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.devcel.2008.04.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18539120">Dictenberg et al. (2008)</a> showed that mouse Fmr1 had a role in rapid, activity-regulated transport of mRNAs important for synaptogenesis and neuronal plasticity. In hippocampal neurons derived from wildtype mice, Fmr1 acted as an adaptor for kinesin light chain (KLC1; <a href="/entry/600025">600025</a>) to promote stimulus-induced mRNA transport. However, Fmr1-knockout (KO) brains showed widespread uncoupling of Fmr1 target mRNAs from kinesin. Acute suppression of Fmr1 transport in wildtype neurons resulted in diminished mRNA transport and a significant increase in the length and number of dendritic filopodia-spine protrusions that was similar to that observed in human fragile X syndrome and its mouse model. <a href="#32" class="mim-tip-reference" title="Dictenberg, J. B., Swanger, S. A., Antar, L. N., Singer, R. H., Bassell, G. J. <strong>A direct role for FMRP in activity-dependent dendritic mRNA transport links filopodial-spine morphogenesis to fragile X syndrome.</strong> Dev. Cell 14: 926-939, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18539120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18539120</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18539120[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.devcel.2008.04.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18539120">Dictenberg et al. (2008)</a> proposed that altered stimulus-induced synaptic localization and transport kinetics of FMR1 target mRNAs may be involved in the translational and synaptic defects in fragile X syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18539120" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#110" class="mim-tip-reference" title="Piazzon, N., Rage, F., Schlotter, F., Moine, H., Branlant, C., Massenet, S. <strong>In vitro and in cellulo evidences for association of the survival of motor neuron complex with the fragile X mental retardation protein.</strong> J. Biol. Chem. 283: 5598-5610, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18093976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18093976</a>] [<a href="https://doi.org/10.1074/jbc.M707304200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18093976">Piazzon et al. (2008)</a> found that FMRP and SMN (see SMN1; <a href="/entry/600354">600354</a>), a protein complex essential for assembly of spliceosomal U small nuclear RNPs, partially colocalized in cell bodies and neural processes of transfected primary cultured rat hypothalamic neurons. Immunoprecipitation experiments revealed an association between FMRP and the SMN complex in human neuroblastoma and murine motor neuron cell lines. Site-directed mutagenesis and in vitro assays showed that the interaction involved the C-terminal region of FMRP and the conserved YG box and the region encoded by exon 7 of SMN1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18093976" 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="#109" class="mim-tip-reference" title="Pfeiffer, B. E., Zang, T., Wilkerson, J. R., Taniguchi, M., Maksimova, M. A., Smith, L. N., Cowan, C. W., Huber, K. M. <strong>Fragile X mental retardation protein is required for synapse elimination by the activity-dependent transcription factor MEF2.</strong> Neuron 66: 191-197, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20434996/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20434996</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20434996[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2010.03.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20434996">Pfeiffer et al. (2010)</a> found that synapse elimination by the activity-dependent transcription factor MEF2 (<a href="/entry/600660">600660</a>) requires functional FMRP downstream. In wildtype murine neurons, postsynaptic activation of MEF2 led to a structural and functional elimination of synapses, whereas MEF2 activation in neurons derived from Fmr1-knockout mice had no effect on synapse structure or function. Postsynaptic expression of FMRP restored MEF2-dependent synapse elimination. Coimmunoprecipitation studies did not indicate an interaction between the 2 proteins, and <a href="#109" class="mim-tip-reference" title="Pfeiffer, B. E., Zang, T., Wilkerson, J. R., Taniguchi, M., Maksimova, M. A., Smith, L. N., Cowan, C. W., Huber, K. M. <strong>Fragile X mental retardation protein is required for synapse elimination by the activity-dependent transcription factor MEF2.</strong> Neuron 66: 191-197, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20434996/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20434996</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20434996[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2010.03.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20434996">Pfeiffer et al. (2010)</a> suggested that FMRP may regulate the processing, transport, or translation of MEF2 transcripts or that transcripts of other genes are involved. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20434996" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To identify the importance of methylation of RGG box arginines for FMRP function, <a href="#13" class="mim-tip-reference" title="Blackwell, E., Zhang, X., Ceman, S. <strong>Arginines of the RGG box regulate FMRP association with polyribosomes and mRNA.</strong> Hum. Molec. Genet. 19: 1314-1323, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20064924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20064924</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20064924[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20064924">Blackwell et al. (2010)</a> examined their role in polyribosome and mRNA association. Arginines 533 and 538 were required for normal FMRP polyribosome association, whereas all 4 arginines played a role in RNA binding, depending on the identity of the RNA. The model G-quadruplex RNA sc1 required arginines 533 and 538 for normal association with FMRP, whereas AATYK (AATK; <a href="/entry/605276">605276</a>) mRNA did not. In vitro methylation of FMRP-bearing arginine substitutions inhibited sc1 binding but not AATYK binding. In addition, PRMT1 (<a href="/entry/602950">602950</a>) coimmunoprecipitated with FMRP isolated from cells, and siRNAs directed against PRMT1 led to reduced FMRP methylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20064924" 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="#8" class="mim-tip-reference" title="Auerbach, B. D., Osterweil, E. K., Bear, M. F. <strong>Mutations causing syndromic autism define an axis of synaptic pathophysiology.</strong> Nature 480: 63-68, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22113615/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22113615</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22113615[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10658" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22113615">Auerbach et al. (2011)</a> used electrophysiologic and biochemical assays of neuronal protein synthesis in the hippocampus of Tsc2 (<a href="/entry/191092">191092</a>) heterozygote and Fmr1-null male mice to show that synaptic dysfunction caused by these mutations falls at opposite ends of a physiologic spectrum. Synaptic, biochemical, and cognitive defects in these mutants were corrected by treatments that modulated metabotropic Grm5 (<a href="/entry/604102">604102</a>) in opposite directions, and deficits in the mutants disappeared in mice bred to carry both mutations. <a href="#8" class="mim-tip-reference" title="Auerbach, B. D., Osterweil, E. K., Bear, M. F. <strong>Mutations causing syndromic autism define an axis of synaptic pathophysiology.</strong> Nature 480: 63-68, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22113615/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22113615</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22113615[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10658" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22113615">Auerbach et al. (2011)</a> concluded that normal synaptic plasticity and cognition occur within an optimal range of metabotropic glutamate receptor-mediated protein synthesis, and deviations in either direction can lead to shared behavioral impairments. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22113615" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Baudouin, S. J., Gaudias, J., Gerharz, S., Hatstatt, L., Zhou, K., Punnakkal, P., Tanaka, K. F., Spooren, W., Hen, R., De Zeeuw, C. I., Vogt, K., Scheiffele, P. <strong>Shared synaptic pathophysiology in syndromic and nonsyndromic rodent models of autism.</strong> Science 338: 128-132, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22983708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22983708</a>] [<a href="https://doi.org/10.1126/science.1224159" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22983708">Baudouin et al. (2012)</a> discovered an unexpected convergence of synaptic pathophysiology in a nonsyndromic form of autism (due to mutation in the neuroligin-3 gene; <a href="/entry/300336">300336</a>) with those in fragile X syndrome (due to silencing of the FMR1 gene). Neuroligin-3 knockout mice exhibited disrupted heterosynaptic competition and perturbed metabotropic glutamate receptor-dependent synaptic plasticity, a hallmark of fragile X. These phenotypes could be rescued by reexpression of neuroligin-3 in juvenile mice, highlighting the possibility of reverting neuronal circuit alterations in autism after the completion of development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22983708" 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="#4" class="mim-tip-reference" title="Ascano, M., Jr., Mukherjee, N., Bandaru, P., Miller, J. B., Nusbaum, J. D., Corcoran, D. L., Langlois, C., Munschauer, M., Dewell, S., Hafner, M., Williams, Z., Ohler, U., Tuschl, T. <strong>FMRP targets distinct mRNA sequence elements to regulate protein expression.</strong> Nature 492: 382-386, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23235829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23235829</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23235829[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature11737" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23235829">Ascano et al. (2012)</a> reported the discovery of distinct RNA recognition elements that correspond to the 2 independent RNA-binding domains of FMRP, in addition to the binding sites within the mRNA targets for the wildtype and I304N mutant FMRP isoforms and the FMRP paralogs FXR1P and FXR2P, also known as FXR1 (<a href="/entry/600819">600819</a>) and FXR2 (<a href="/entry/605339">605339</a>), respectively. RNA recognition element frequency, ratio, and distribution determine the target mRNA association with FMRP. Among highly enriched targets, <a href="#4" class="mim-tip-reference" title="Ascano, M., Jr., Mukherjee, N., Bandaru, P., Miller, J. B., Nusbaum, J. D., Corcoran, D. L., Langlois, C., Munschauer, M., Dewell, S., Hafner, M., Williams, Z., Ohler, U., Tuschl, T. <strong>FMRP targets distinct mRNA sequence elements to regulate protein expression.</strong> Nature 492: 382-386, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23235829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23235829</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23235829[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature11737" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23235829">Ascano et al. (2012)</a> identified many genes involved in autism spectrum disorder (see <a href="/entry/209850">209850</a>) and showed that FMRP affects their protein levels in human cell culture, mouse ovaries, and human brain. Notably, <a href="#4" class="mim-tip-reference" title="Ascano, M., Jr., Mukherjee, N., Bandaru, P., Miller, J. B., Nusbaum, J. D., Corcoran, D. L., Langlois, C., Munschauer, M., Dewell, S., Hafner, M., Williams, Z., Ohler, U., Tuschl, T. <strong>FMRP targets distinct mRNA sequence elements to regulate protein expression.</strong> Nature 492: 382-386, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23235829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23235829</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23235829[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature11737" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23235829">Ascano et al. (2012)</a> discovered that these targets are also dysregulated in Fmr1-null mouse ovaries showing signs of premature follicular overdevelopment. <a href="#4" class="mim-tip-reference" title="Ascano, M., Jr., Mukherjee, N., Bandaru, P., Miller, J. B., Nusbaum, J. D., Corcoran, D. L., Langlois, C., Munschauer, M., Dewell, S., Hafner, M., Williams, Z., Ohler, U., Tuschl, T. <strong>FMRP targets distinct mRNA sequence elements to regulate protein expression.</strong> Nature 492: 382-386, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23235829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23235829</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23235829[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature11737" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23235829">Ascano et al. (2012)</a> concluded that FMRP targets share signaling pathways across different cellular contexts and that their results provided a ranked list of genes as basis for the pursuit of therapeutic targets for fragile X syndrome and autism spectrum disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23235829" 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 wildtype and knockout mutant mouse embryonic fibroblasts (MEFs) and wildtype and FMRP-knockdown HeLa cells, <a href="#3" class="mim-tip-reference" title="Alpatov, R., Lesch, B. J., Nakamoto-Kinoshita, M., Blanco, A., Chen, S., Stutzer, A., Armache, K. J., Simon, M. D., Xu, C., Ali, M., Murn, J., Prisic, S., Kutateladze, T. G., Vakoc, C. R., Min, J., Kingston, R. E., Fischle, W., Warren, S. T., Page, D. C., Shi, Y. <strong>A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response.</strong> Cell 157: 869-881, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24813610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24813610</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24813610[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2014.03.040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24813610">Alpatov et al. (2014)</a> found that nuclear FMRP functions as a chromatin-binding protein that responds to DNA single-strand breaks. The N-terminal Agenet domain was required for this function and bound preferentially to methylated histone H3. FMRP was recruited to chromatin in response to replication stress, and loss of FMRP compromised subsequent phosphorylation of H2AX (H2AFX; <a href="/entry/601772">601772</a>). However, Fmrp chromatin-binding defective mutant mice were not compromised in translation-dependent trafficking of Glur1 (GRIA1; <a href="/entry/138248">138248</a>), indicating that nuclear and cytoplasmic functions of FMRP are independent. Fmrp was loaded onto chromosomes during meiosis in male mice and regulated placement of phosphorylated H2ax. A proportion of Fmrp mutant spermatocytes showed defective chromosome synapsis and defective resolution of single-strand intermediates during meiotic prophase. <a href="#3" class="mim-tip-reference" title="Alpatov, R., Lesch, B. J., Nakamoto-Kinoshita, M., Blanco, A., Chen, S., Stutzer, A., Armache, K. J., Simon, M. D., Xu, C., Ali, M., Murn, J., Prisic, S., Kutateladze, T. G., Vakoc, C. R., Min, J., Kingston, R. E., Fischle, W., Warren, S. T., Page, D. C., Shi, Y. <strong>A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response.</strong> Cell 157: 869-881, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24813610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24813610</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24813610[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2014.03.040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24813610">Alpatov et al. (2014)</a> hypothesized that FMRP performs a docking function to regulate accessibility of DNA damage response protein to chromatin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24813610" 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="#44" class="mim-tip-reference" title="Greenblatt, E. J., Spradling, A. C. <strong>Fragile X mental retardation 1 gene enhances the translation of large autism-related proteins.</strong> Science 361: 709-712, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30115809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30115809</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30115809[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aas9963" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30115809">Greenblatt and Spradling (2018)</a> analyzed quiescent Drosophila oocytes, which, like neural synapses, depend heavily on translating stored mRNA. Ribosome profiling revealed that Fmr1 enhances rather than represses the translation of mRNAs that overlap previously identified Fmr1 targets, and acts preferentially on large proteins. Human homologs of at least 20 targets were associated with dominant intellectual disability, and 30 others with recessive neurodevelopmental dysfunction. Unlike stored wildtype oocytes, stored oocytes lacking Fmr1 usually generate embryos with severe neural defects, which suggests that translation of multiple large proteins by stored mRNAs is defective in fragile X syndrome and possibly other autism spectrum disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30115809" 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 NMR spectroscopy of minimal condensates formed from the C-terminal disordered regions of 2 interacting translational regulators, FMRP and CAPRIN1 (<a href="/entry/601178">601178</a>), <a href="#68" class="mim-tip-reference" title="Kim, T. H., Tsang, B., Vernon, R. M., Sonenberg, N., Kay, L. E., Forman-Kay, J. D. <strong>Phospho-dependent phase separation of FMRP and CAPRIN1 recapitulates regulation of translation and deadenylation.</strong> Science 365: 825-829, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31439799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31439799</a>] [<a href="https://doi.org/10.1126/science.aax4240" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31439799">Kim et al. (2019)</a> observed interactions involving arginine-rich and aromatic-rich regions. <a href="#68" class="mim-tip-reference" title="Kim, T. H., Tsang, B., Vernon, R. M., Sonenberg, N., Kay, L. E., Forman-Kay, J. D. <strong>Phospho-dependent phase separation of FMRP and CAPRIN1 recapitulates regulation of translation and deadenylation.</strong> Science 365: 825-829, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31439799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31439799</a>] [<a href="https://doi.org/10.1126/science.aax4240" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31439799">Kim et al. (2019)</a> found that different FMRP serine/threonine and CAPRIN1 tyrosine phosphorylation patterns controlled phase separation propensity with RNA, including subcompartmentalization, and tuned deadenylation and translation rates in vitro. <a href="#68" class="mim-tip-reference" title="Kim, T. H., Tsang, B., Vernon, R. M., Sonenberg, N., Kay, L. E., Forman-Kay, J. D. <strong>Phospho-dependent phase separation of FMRP and CAPRIN1 recapitulates regulation of translation and deadenylation.</strong> Science 365: 825-829, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31439799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31439799</a>] [<a href="https://doi.org/10.1126/science.aax4240" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31439799">Kim et al. (2019)</a> concluded that the resulting evidence for residue-specific interactions underlying co-phase separation, phosphorylation-modulated condensate architecture, and enzymatic activity within condensates had implications for how the integration of signaling pathways controls RNA processing and translation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31439799" 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><strong><em>Fragile X Syndrome</em></strong></p><p>
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<a href="#73" class="mim-tip-reference" title="Kremer, E. J., Pritchard, M., Lynch, M., Yu, S., Holman, K., Baker, E., Warren, S. T., Schlessinger, D., Sutherland, G. R., Richards, R. I. <strong>Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n.</strong> Science 252: 1711-1714, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1675488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1675488</a>] [<a href="https://doi.org/10.1126/science.1675488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1675488">Kremer et al. (1991)</a> demonstrated that an unstable expanded trinucleotide (CCG)n repeat sequence (<a href="#0004">309550.0004</a>) in the 5-prime untranslated region of the FMR1 gene is the basis of fragile X syndrome (FXS; <a href="/entry/300624">300624</a>). The authors showed that normal X chromosomes have about 40 +/- 25 copies of (CCG)n and that within these limits the sequence is a stable DNA polymorphism. The fragile X genotype was characterized by an increased amount of unstable DNA that maps to the repeat. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1675488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Devys, D., Biancalana, V., Rousseau, F., Boue, J., Mandel, J. L., Oberle, I. <strong>Analysis of full fragile X mutations in fetal tissues and monozygotic twins indicate that abnormal methylation and somatic heterogeneity are established early in development.</strong> Am. J. Med. Genet. 43: 208-216, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1605193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1605193</a>] [<a href="https://doi.org/10.1002/ajmg.1320430134" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1605193">Devys et al. (1992)</a> noted that there are 2 main types of mutations involved in fragile X syndrome. Premutations, which do not cause mental retardation, are characterized by an elongation of 70 to 500 bp with little or no somatic heterogeneity and without abnormal methylation. Full mutations are associated with high risk of mental retardation and consist of a 600 bp or more amplification, often with extensive somatic heterogeneity and abnormal DNA methylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1605193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By using microdissected markers close to the fragile site, <a href="#12" class="mim-tip-reference" title="Bell, M. V., Hirst, M. C., Nakahori, Y., MacKinnon, R. N., Roche, A., Flint, T. J., Jacobs, P. A., Tommerup, N., Tranebjaerg, L., Froster-Iskenius, U., Kerr, B., Turner, G., Lindenbaum, R. H., Winter, R., Pembrey, M., Thibodeau, S., Davies, K. E. <strong>Physical mapping across the fragile X: hypermethylation and clinical expression of the fragile X syndrome.</strong> Cell 64: 861-866, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1997211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1997211</a>] [<a href="https://doi.org/10.1016/0092-8674(91)90514-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1997211">Bell et al. (1991)</a> demonstrated that the fragile X syndrome is not associated with large structural rearrangements in Xq27.3 but is associated with methylation of DNA sequences distal to the fragile site. Significant differences were observed in the pulsed field gel electrophoresis pattern observed after BssHII digestion of DNA from fragile X-positive, mentally retarded individuals compared with normal male controls. A 600-kb band was either absent or of reduced intensity in affected males. The pattern was normal in normal, fragile X-negative transmitting males, whereas their mentally retarded, fragile X-positive grandsons lacked the fragment. These observations suggested that the absence of the band is the result of methylation of the BssHII site. The findings were considered consistent with Laird's hypothesis of imprinting at this locus and with a 2-step process for the expression of the disease (<a href="#77" class="mim-tip-reference" title="Laird, C. D., Jaffe, E., Karpen, G., Lamb, M., Nelson, R. <strong>Fragile sites in human chromosomes as regions of late-replicating DNA.</strong> Trends Genet. 3: 274-281, 1987."None>Laird et al., 1987</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1997211" 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="#105" class="mim-tip-reference" title="Oberle, I., Rousseau, F., Heitz, D., Kretz, C., Devys, D., Hanauer, A., Boue, J., Bertheas, M. F., Mandel, J. L. <strong>Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome.</strong> Science 252: 1097-1102, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2031184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2031184</a>] [<a href="https://doi.org/10.1126/science.252.5009.1097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2031184">Oberle et al. (1991)</a> found that probes adjacent to a single CpG island that was mapped at or very near the fragile site detected very localized DNA rearrangements that constitute the fragile X mutations. These rearrangements occurred in a 550-bp GC-rich fragment. Phenotypically normal, transmitting males had a 150- to 400-bp insertion that was inherited by their daughters either unchanged or with little change in size. Fragile X-positive persons in the next generation had much larger fragments that differed among sibs and showed a generally heterogeneous pattern indicating somatic mutation. The mutated allele appeared unmethylated in normal transmitting males, methylated only on the inactive X chromosome in their daughters, and totally methylated in most fragile X males. However, some males had a mosaic pattern. Expression of the fragile X syndrome thus appears to result from a 2-step mutation as well as highly localized methylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2031184" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#121" class="mim-tip-reference" title="Rousseau, F., Heitz, D., Mandel, J.-L. <strong>The unstable and methylatable mutations causing the fragile X syndrome.</strong> Hum. Mutat. 1: 91-96, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301206</a>] [<a href="https://doi.org/10.1002/humu.1380010202" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1301206">Rousseau et al. (1992)</a> reviewed the 'unstable and methylatable mutations causing the fragile X syndrome.' They pointed out that the CGG repeat is in phase with the following protein coding sequence and, if translated, would code for a stretch of 6 to 54 arginines. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1301206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By studying chorionic villi from 10 fetuses with a full mutation, <a href="#30" class="mim-tip-reference" title="Devys, D., Biancalana, V., Rousseau, F., Boue, J., Mandel, J. L., Oberle, I. <strong>Analysis of full fragile X mutations in fetal tissues and monozygotic twins indicate that abnormal methylation and somatic heterogeneity are established early in development.</strong> Am. J. Med. Genet. 43: 208-216, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1605193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1605193</a>] [<a href="https://doi.org/10.1002/ajmg.1320430134" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1605193">Devys et al. (1992)</a> found that somatic heterogeneity of the full mutation is established during the very early stages of embryogenesis. Abnormal methylation was present in 8 of 9 villi analyzed. The pattern of mosaicism was strictly identical in 2 pairs of monozygotic twins, indicating that the somatic heterogeneity and abnormal methylation are established early in development. FMR1 mRNA was absent in those with the full mutation, with the exception of mosaics. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1605193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#130" class="mim-tip-reference" title="Smits, A. P. T., Dreesen, J. C. F. M., Post, J. G., Smeets, D. F. C. M., de Die-Smulders, C., Spaans-van der Bijl, T., Govaerts, L. C. P., Warren, S. T., Oostra, B. A., van Oost, B. A. <strong>The fragile X syndrome: no evidence for any recent mutations.</strong> J. Med. Genet. 30: 94-96, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8445628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8445628</a>] [<a href="https://doi.org/10.1136/jmg.30.2.94" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8445628">Smits et al. (1993)</a> stated that they had been unable to demonstrate de novo FMR1 mutations in 84 probands referred to them to date. Interestingly, they also demonstrated the same FMR1 expansion mutation in 5 fragile X probands with common ancestors married in 1747. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8445628" 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 survey of 222 unrelated mentally retarded individuals attending Spanish special schools, <a href="#94" class="mim-tip-reference" title="Mila, M., Sanchez, A., Badenas, C., Brun, C., Jimenez, D., Villa, M. P., Castellvi-Bel, S., Estivill, X. <strong>Screening for FMR1 and FMR2 mutations in 222 individuals from Spanish special schools: identification of a case of FRAXE-associated mental retardation.</strong> Hum. Genet. 100: 503-507, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9341861/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9341861</a>] [<a href="https://doi.org/10.1007/s004390050542" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9341861">Mila et al. (1997)</a> found 11 boys with full mutations in the FMR1 gene and 1 boy with a CCG repeat expansion in the FMR2 gene (see <a href="/entry/309548">309548</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9341861" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Colak, D., Zaninovic, N., Cohen, M. S., Rosenwaks, Z., Yang, W.-Y., Gerhardt, J., Disney, M. D., Jaffrey, S. R. <strong>Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome.</strong> Science 343: 1002-1005, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24578575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24578575</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24578575[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1245831" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24578575">Colak et al. (2014)</a> demonstrated that FMR1 silencing is mediated by the FMR1 mRNA. The FMR1 mRNA contains the transcribed CGG-repeat tract as part of the 5-prime untranslated region, which hybridizes to the complementary CGG-repeat portion of the FMR1 gene to form an RNA/DNA duplex. Disrupting the interaction of the mRNA with the CGG-repeat portion of the FMR1 gene prevents promoter silencing. <a href="#24" class="mim-tip-reference" title="Colak, D., Zaninovic, N., Cohen, M. S., Rosenwaks, Z., Yang, W.-Y., Gerhardt, J., Disney, M. D., Jaffrey, S. R. <strong>Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome.</strong> Science 343: 1002-1005, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24578575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24578575</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24578575[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1245831" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24578575">Colak et al. (2014)</a> concluded that their data linked trinucleotide repeat expansion to a form of RNA-directed gene silencing mediated by direct interactions of the trinucleotide repeat RNA and DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24578575" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Deletions in the FMR1 Gene</em></strong></p><p>
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In a fragile X-negative mentally retarded male who presented with the clinical phenotype of the fragile X syndrome, <a href="#155" class="mim-tip-reference" title="Wohrle, D., Kotzot, D., Hirst, M. C., Manca, A., Korn, B., Schmidt, A., Barbi, G., Rott, H.-D., Poustka, A., Davies, K. E., Steinbach, P. <strong>A microdeletion of less than 250 kb, including the proximal part of the FMR-1 gene and the fragile-X site, in a male with the clinical phenotype of fragile-X syndrome.</strong> Am. J. Hum. Genet. 51: 299-306, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1642231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1642231</a>]" pmid="1642231">Wohrle et al. (1992)</a> found a microdeletion of less than 250 kb, including the methylated island and at least 5 exons of the FMR1 gene. The data supported the hypothesis that loss of function of the FMR1 gene is responsible for the clinical phenotype of the fragile X syndrome and opened the possibility that pathogenetic mechanisms other than amplification of the CGG repeat can have the same phenotypic consequences. <a href="#155" class="mim-tip-reference" title="Wohrle, D., Kotzot, D., Hirst, M. C., Manca, A., Korn, B., Schmidt, A., Barbi, G., Rott, H.-D., Poustka, A., Davies, K. E., Steinbach, P. <strong>A microdeletion of less than 250 kb, including the proximal part of the FMR-1 gene and the fragile-X site, in a male with the clinical phenotype of fragile-X syndrome.</strong> Am. J. Hum. Genet. 51: 299-306, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1642231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1642231</a>]" pmid="1642231">Wohrle et al. (1992)</a> indicated that they had started a systematic screening of sporadic cases of the fragile X syndrome in which the individuals are cytogenetically negative. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1642231" 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="#42" class="mim-tip-reference" title="Gedeon, A. K., Baker, E., Robinson, H., Partington, M. W., Gross, B., Manca, A., Korn, B., Poustka, A., Yu, S., Sutherland, G. R., Mulley, J. C. <strong>Fragile X syndrome without CCG amplification has an FMR1 deletion.</strong> Nature Genet. 1: 341-344, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302032</a>] [<a href="https://doi.org/10.1038/ng0892-341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1302032">Gedeon et al. (1992)</a> described a patient with typical clinical features of the fragile X syndrome but without cytogenetic expression of the fragile X and without an amplified CCG trinucleotide repeat fragment. The patient had a previously uncharacterized submicroscopic deletion encompassing the CCG repeat, the entire FMR1 gene, and about 2.5 megabases of flanking sequences. Random X inactivation was found in the patient's mother, who was shown to be a carrier of the deletion. <a href="#136" class="mim-tip-reference" title="Tarleton, J., Richie, R., Schwartz, C., Rao, K., Aylsworth, A. S., Lachiewicz, A. <strong>An extensive de novo deletion removing FMR1 in a patient with mental retardation and the fragile X syndrome phenotype.</strong> Hum. Molec. Genet. 2: 1973-1974, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8281165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8281165</a>] [<a href="https://doi.org/10.1093/hmg/2.11.1973" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8281165">Tarleton et al. (1993)</a> described a de novo deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8281165+1302032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#92" class="mim-tip-reference" title="Meijer, H., de Graaff, E., Merckx, D. M. L., Jongbloed, R. J. E., de Die-Smulders, C. E. M., Engelen, J. J. M., Fryns, J.-P., Curfs, P. M. G., Oostra, B. A. <strong>A deletion of 1.6 kb proximal to the CGG repeat of the FMR1 gene causes the clinical phenotype of the fragile X syndrome.</strong> Hum. Molec. Genet. 3: 615-620, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8069307/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8069307</a>] [<a href="https://doi.org/10.1093/hmg/3.4.615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8069307">Meijer et al. (1994)</a> reported a family in which 11 individuals had a 1.6-kb deletion proximal to the CGG repeat of the FMR1 gene as the cause of the fragile X syndrome. Although fragile X chromosomes were not cytologically detectable, all 4 affected males and 2 of the carrier females showed the characteristic clinical phenotype. Using RT-PCR, <a href="#92" class="mim-tip-reference" title="Meijer, H., de Graaff, E., Merckx, D. M. L., Jongbloed, R. J. E., de Die-Smulders, C. E. M., Engelen, J. J. M., Fryns, J.-P., Curfs, P. M. G., Oostra, B. A. <strong>A deletion of 1.6 kb proximal to the CGG repeat of the FMR1 gene causes the clinical phenotype of the fragile X syndrome.</strong> Hum. Molec. Genet. 3: 615-620, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8069307/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8069307</a>] [<a href="https://doi.org/10.1093/hmg/3.4.615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8069307">Meijer et al. (1994)</a> demonstrated that FMR1 was not expressed in the affected males, strongly suggesting that the FMR1 promoter sequences 5-prime to the CGG repeat were missing. The deletion patients had approximately 45 CGG repeats in the FMR1 gene; however, these were not interspersed by AGG triplets that are usually present in both normal and expanded repeats. <a href="#92" class="mim-tip-reference" title="Meijer, H., de Graaff, E., Merckx, D. M. L., Jongbloed, R. J. E., de Die-Smulders, C. E. M., Engelen, J. J. M., Fryns, J.-P., Curfs, P. M. G., Oostra, B. A. <strong>A deletion of 1.6 kb proximal to the CGG repeat of the FMR1 gene causes the clinical phenotype of the fragile X syndrome.</strong> Hum. Molec. Genet. 3: 615-620, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8069307/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8069307</a>] [<a href="https://doi.org/10.1093/hmg/3.4.615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8069307">Meijer et al. (1994)</a> hypothesized that an expansion of the repeat occurred prior to the occurrence of the deletion, and that the deletion removed the 5-prime part of the CGG repeat containing the AGG triplets. Transmission of the deletion through the family could be traced back to the deceased grandfather of the affected males, which supported the hypothesis that the FMR1 gene product is not required for spermatogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8069307" 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="#57" class="mim-tip-reference" title="Hirst, M., Grewal, P., Flannery, A., Slatter, R., Maher, E., Barton, D., Fryns, J.-P., Davies, K. <strong>Two new cases of FMR1 deletion associated with mental impairment.</strong> Am. J. Hum. Genet. 56: 67-74, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7825604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7825604</a>]" pmid="7825604">Hirst et al. (1995)</a> reported 2 unrelated males with fragile X syndrome due to deletion of the FMR1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7825604" 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="#116" class="mim-tip-reference" title="Quan, F., Zonana, J., Gunter, K., Peterson, K. L., Magenis, R. E., Popovich, B. W. <strong>An atypical case of fragile X syndrome caused by a deletion that includes the FMR1 gene.</strong> Am. J. Hum. Genet. 56: 1042-1051, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7726157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7726157</a>]" pmid="7726157">Quan et al. (1995)</a> described a phenotypically atypical case of fragile X syndrome caused by a deletion that included the entire FMR1 gene and at least 9.0 Mb of flanking DNA. The proband was a 6-year-old mentally retarded male with obesity and anal atresia. The diagnosis of fragile X syndrome was established by the failure of the proband's DNA to hybridize to a restriction fragment specific for the 5-prime end of the FMR1 gene. The analysis of flanking markers in the interval Xq26.3-q28 indicated a deletion extending from between 160- to 500-kb distal, and 9.0-Mb proximal, to the FMR1 gene. High-resolution chromosome banding confirmed a deletion with breakpoints in Xq26.3 and Xq27.3. This deletion was maternally transmitted and arose as a new mutation on the grandpaternal X chromosome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7726157" 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="#115" class="mim-tip-reference" title="Quan, F., Grompe, M., Jakobs, P., Popovich, B. W. <strong>Spontaneous deletion in the FMR1 gene in a patient with fragile X syndrome and cherubism.</strong> Hum. Molec. Genet. 4: 1681-1684, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8541863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8541863</a>] [<a href="https://doi.org/10.1093/hmg/4.9.1681" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8541863">Quan et al. (1995)</a> described a patient with mosaicism for expansion and deletion of the FMR1 CGG repeat. The deletion was in approximately 85% of the patient's cells. In addition to mental retardation, the affected male had cherubism (see <a href="/entry/118400">118400</a>), although this was presumably unrelated. Previous work suggested that the expansion of the maternally derived allele occurs mitotically during early embryonic development. The failure to observe the expanded FMR1 alleles in the germline suggested that the expansion event occurred between days 5 and 20 of development, after the separation of the germline but before the divergence of tissue types. The findings of <a href="#115" class="mim-tip-reference" title="Quan, F., Grompe, M., Jakobs, P., Popovich, B. W. <strong>Spontaneous deletion in the FMR1 gene in a patient with fragile X syndrome and cherubism.</strong> Hum. Molec. Genet. 4: 1681-1684, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8541863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8541863</a>] [<a href="https://doi.org/10.1093/hmg/4.9.1681" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8541863">Quan et al. (1995)</a> of mosaicism for expansion and deletion were consistent with this model of fragile X expansion. The detection of premutation-sized alleles in the proband was consistent with the transmission of a maternal premutation-sized FMR1 allele and postzygotic expansion. An unmethylated CpG island upstream of the FMR1 deletion indicated that the expansion and deletion of the CGG repeat occurred before FMR1 methylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8541863" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Premature Ovarian Failure and Premutation Alleles</em></strong></p><p>
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Fragile X premutations in female carriers appear to be a risk factor for premature ovarian failure (POF1; <a href="/entry/311360">311360</a>), defined as menopause at age less than 40 years. <a href="#99" class="mim-tip-reference" title="Murray, A., Webb, J., Grimley, S., Conway, G., Jacobs, P. <strong>Studies of FRAXA and FRAXE in women with premature ovarian failure.</strong> J. Med. Genet. 35: 637-640, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9719368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9719368</a>] [<a href="https://doi.org/10.1136/jmg.35.8.637" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9719368">Murray et al. (1998)</a> screened 147 women with idiopathic premature ovarian failure and found a significant association with premutations in the FMR1 gene (<a href="#0004">309550.0004</a>), with 6 women having premutations, including 4 familial and 2 sporadic cases, but no women with full mutations in the FMR1 gene. There were no pre- or full mutations of the FMR2 gene (<a href="/entry/309548">309548</a>), but there was an excess of small alleles with fewer than 11 repeats at this locus. <a href="#99" class="mim-tip-reference" title="Murray, A., Webb, J., Grimley, S., Conway, G., Jacobs, P. <strong>Studies of FRAXA and FRAXE in women with premature ovarian failure.</strong> J. Med. Genet. 35: 637-640, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9719368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9719368</a>] [<a href="https://doi.org/10.1136/jmg.35.8.637" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9719368">Murray et al. (1998)</a> concluded that premutations of FMR1 can affect ovarian development or function, or both. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9719368" 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 an international collaborative study of 760 women from fragile X families, <a href="#2" class="mim-tip-reference" title="Allingham-Hawkins, D. J., Babul-Hirji, R., Chitayat, D., Holden, J. J. A., Yang, K. T., Lee, C., Hudson, R., Gorwill, H., Nolin, S. L., Glicksman, A., Jenkins, E. C., Brown, W. T., and 27 others. <strong>Fragile X premutation is a significant risk factor for premature ovarian failure: the international collaborative POF in fragile X study--preliminary data.</strong> Am. J. Med. Genet. 83: 322-325, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10208170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10208170</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10208170[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="10208170">Allingham-Hawkins et al. (1999)</a> found that 395 carried a premutation, 128 carried a full mutation, and 237 were noncarriers. In 63 (16%) of the premutation carriers, menopause occurred before the age of 40, compared with none of the full-mutation carriers and 1 (0.4%) of the controls, indicating a significant association between premature menopause and premutation carrier status. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10208170" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Fragile X Tremor/Ataxia Syndrome (FXTAS) and Premutation Alleles</em></strong></p><p>
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<a href="#49" class="mim-tip-reference" title="Hagerman, R. J., Leehey, M., Heinrichs, W., Tassone, F., Wilson, R., Hills, J., Grigsby, J., Gage, B., Hagerman, P. J. <strong>Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X.</strong> Neurology 57: 127-130, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11445641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11445641</a>] [<a href="https://doi.org/10.1212/wnl.57.1.127" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11445641">Hagerman et al. (2001)</a> reported 5 men with a fragile X premutation, ranging from 78 to 98 repeats, who presented in the sixth decade with progressive intention tremor, parkinsonism, cognitive decline, generalized atrophy on MRI, and impotence (FXTAS; <a href="/entry/300623">300623</a>). Levels of FMR1 mRNA were 2 to 4 times higher than normal, which the authors suggested resulted in a pathogenic gain-of-function effect. <a href="#80" class="mim-tip-reference" title="Leehey, M. A., Munhoz, R. P., Lang, A. E., Brunberg, J. A., Grigsby, J., Greco, C., Jacquemont, S., Tassone, F., Lozano, A. M., Hagerman, P. J., Hagerman, R. J. <strong>The fragile X premutation presenting as essential tremor.</strong> Arch. Neurol. 60: 117-121, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12533098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12533098</a>] [<a href="https://doi.org/10.1001/archneur.60.1.117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12533098">Leehey et al. (2003)</a> reported 2 unrelated men who presented with essential tremor at ages 58 and 49 years and were later found to carry a fragile X premutation (90 and 160 repeats, respectively). Besides the disabling intention tremor, both patients had tandem gait difficulties, generalized brain atrophy, and elevated FMR1 mRNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11445641+12533098" 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="#41" class="mim-tip-reference" title="Garcia-Arocena, D., Yang, J. E., Brouwer, J. R., Tassone, F., Iwahashi, C., Berry-Kravis, E. M., Goetz, C. G., Sumis, A. M., Zhou, L., Nguyen, D. V., Campos, L., Howell, E., Ludwig, A., Greco, C., Willemsen, R., Hagerman, R. J., Hagerman, P. J. <strong>Fibroblast phenotype in male carriers of FMR1 premutation alleles.</strong> Hum. Molec. Genet. 19: 299-312, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19864489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19864489</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19864489[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp497" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19864489">Garcia-Arocena et al. (2010)</a> reported a cellular endophenotype involving increased stress response involving increase expression of HSP27 (HSPB1; <a href="/entry/602195">602195</a>), HSP70 (HSPA1A; <a href="/entry/140550">140550</a>) and CRYAB (<a href="/entry/123590">123590</a>) and altered lamin A/C (LMNA; <a href="/entry/150330">150330</a>) expression/organization in cultured skin fibroblasts from 11 male carriers of premutation alleles of the FMR1 gene, including 6 patients with FXTAS and 5 premutation carriers with no clinical evidence of FXTAS, compared with 6 controls. A similar abnormal cellular phenotype was found in central nervous system tissue from 10 patients with FXTAS. There was an analogous abnormal cellular distribution of lamin A/C isoforms in knock-in mice bearing the expanded CGG repeat in the murine Fmr1 gene. These alterations were evident even in mouse embryonic fibroblasts, raising the possibility that, in humans, the expanded-repeat mRNA may trigger pathogenic mechanisms early in development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19864489" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Additional Studies on Premutation/Intermediate Alleles</em></strong></p><p>
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Using fluorescence-based RT-PCR, <a href="#137" class="mim-tip-reference" title="Tassone, F., Hagerman, R. J., Taylor, A. K., Gane, L. W., Godfrey, T. E., Hagerman, P. J. <strong>Elevated levels of FMR1 mRNA in carrier males: a new mechanism of involvement in the fragile-X syndrome.</strong> Am. J. Hum. Genet. 66: 6-15, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10631132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10631132</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10631132[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/10.1086/302720" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10631132">Tassone et al. (2000)</a> found that FMR1 mRNA levels were increased in peripheral blood lymphocytes from 16 male carriers of premutation alleles (55 to 192 repeats) compared to normal controls. The increase was approximately 5-fold in 7 carriers with over 100 repeats. No increase in FMRP mRNA stability was observed in a lymphoblastoid cell line with 160 repeats derived from a carrier male, indicating that the increased mRNA levels resulted from an increased rate of transcription. Cells from carriers of premutation alleles showed decreased immunostaining for the FMRP protein, suggesting a defect in translation. <a href="#137" class="mim-tip-reference" title="Tassone, F., Hagerman, R. J., Taylor, A. K., Gane, L. W., Godfrey, T. E., Hagerman, P. J. <strong>Elevated levels of FMR1 mRNA in carrier males: a new mechanism of involvement in the fragile-X syndrome.</strong> Am. J. Hum. Genet. 66: 6-15, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10631132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10631132</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10631132[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/10.1086/302720" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10631132">Tassone et al. (2000)</a> postulated that diminished translation efficiency of FMRP mRNA in premutation carriers resulted in compensatory increased transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10631132" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a highly sensitive quantification assay, <a href="#65" class="mim-tip-reference" title="Kenneson, A., Zhang, F., Hagedorn, C.. H., Warren, S. T. <strong>Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate-length and premutation carriers.</strong> Hum. Molec. Genet. 10: 1449-1454, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11448936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11448936</a>] [<a href="https://doi.org/10.1093/hmg/10.14.1449" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11448936">Kenneson et al. (2001)</a> demonstrated significantly diminished levels of the FMRP protein in transformed cells derived from carriers of premutation alleles (105 to 130 repeats) and intermediate alleles (48 and 55 repeats). The protein levels were negatively correlated with repeat number. Despite reduced FMRP, these carrier alleles overexpressed FMR1 mRNA, resulting in a positive correlation between repeat number and FMR1 mRNA. <a href="#65" class="mim-tip-reference" title="Kenneson, A., Zhang, F., Hagedorn, C.. H., Warren, S. T. <strong>Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate-length and premutation carriers.</strong> Hum. Molec. Genet. 10: 1449-1454, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11448936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11448936</a>] [<a href="https://doi.org/10.1093/hmg/10.14.1449" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11448936">Kenneson et al. (2001)</a> concluded that biochemical abnormalities are already present in premutation FMR1 alleles, which may explain the phenotypic features reported in some of these carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11448936" 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="#20" class="mim-tip-reference" title="Chen, L.-S., Tassone, F., Sahota, P., Hagerman, P. J. <strong>The (CGG)n repeat element within the 5-prime untranslated region on the FMR1 message provides both positive and negative cis effects on in vivo translation of a downstream reporter.</strong> Hum. Molec. Genet. 12: 3067-3074, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14519687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14519687</a>] [<a href="https://doi.org/10.1093/hmg/ddg331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14519687">Chen et al. (2003)</a> examined the influence of the CGG repeat on translation by transfecting human neural and kidney-derived cell lines with the FMR1 5-prime UTR of various CGG premutation repeat lengths (0 to 99) and a downstream reporter. For both cell types, the CGG element exerted distinct effects on reporter expression, depending on the length of the repeat. For lengths of 30 repeats or more, luciferase expression decreased with increasing repeat length, despite a slight increase in mRNA level for the larger repeats. However, for smaller alleles (0 to 30), reporter expression actually increased by nearly 2-fold with increasing repeat length in the absence of any change in mRNA level. <a href="#20" class="mim-tip-reference" title="Chen, L.-S., Tassone, F., Sahota, P., Hagerman, P. J. <strong>The (CGG)n repeat element within the 5-prime untranslated region on the FMR1 message provides both positive and negative cis effects on in vivo translation of a downstream reporter.</strong> Hum. Molec. Genet. 12: 3067-3074, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14519687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14519687</a>] [<a href="https://doi.org/10.1093/hmg/ddg331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14519687">Chen et al. (2003)</a> concluded that the CGG repeat element can exert both positive (less than 30 repeats) and negative (greater than 30 repeats) effects on translation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14519687" 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="Beilina, A., Tassone, F., Schwartz, P. H., Sahota, P., Hagerman, P. J. <strong>Redistribution of transcription start sites within the FMR1 promoter region with expansion of the downstream CGG-repeat element.</strong> Hum. Molec. Genet. 13: 543-549, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14722156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14722156</a>] [<a href="https://doi.org/10.1093/hmg/ddh053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14722156">Beilina et al. (2004)</a> used 5-prime-RLM-RACE to examine the influence of CGG repeat number on the utilization of transcription start sites in normal (less than 55) and premutation (greater than 54 and less than 200) cell lines of both nonneural (lymphoblastoid) and neural (primary astrocyte) origin. FMR1 transcription in both cell lines was initiated from several start sites within an approximately 50-nucleotide region that lies approximately 130 nucleotides upstream of the CGG repeat element. For normal alleles, most transcripts initiated from the downstream-most start site. As the size of the CGG repeat expanded into the premutation range, initiation shifted to the upstream sites, suggesting that the CGG element may act as a downstream enhancer/modulator of transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14722156" 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>From a screening study of 1,253 males attending Tasmanian schools, <a href="#86" class="mim-tip-reference" title="Loesch, D. Z., Bui, Q. M., Huggins, R. M., Mitchell, R. J., Hagerman, R. J., Tassone, F. <strong>Transcript levels of the intermediate size or grey zone fragile X mental retardation 1 alleles are raised, and correlate with the number of CGG repeats.</strong> J. Med. Genet. 44: 200-204, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16905681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16905681</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16905681[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2006.043950" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16905681">Loesch et al. (2007)</a> identified 33 carriers of intermediate or 'gray zone' alleles, defined by the authors as 41 to 60 CGG repeats. Twenty carriers were special educational needs students attending regular schools, 10 were regular students, and 3 were brothers of special needs students previously identified as gray zone carriers. <a href="#86" class="mim-tip-reference" title="Loesch, D. Z., Bui, Q. M., Huggins, R. M., Mitchell, R. J., Hagerman, R. J., Tassone, F. <strong>Transcript levels of the intermediate size or grey zone fragile X mental retardation 1 alleles are raised, and correlate with the number of CGG repeats.</strong> J. Med. Genet. 44: 200-204, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16905681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16905681</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16905681[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2006.043950" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16905681">Loesch et al. (2007)</a> found significantly increased transcriptional activity in intermediate carriers relative to carriers of common alleles of 5 to 40 repeats (p less than 0.001). Piecewise linear regression revealed that the threshold for onset of the increase in mRNA levels is at approximately 39 repeats, and that the reduction in the rate of this increase is at approximately 54 repeats. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16905681" 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="#61" class="mim-tip-reference" title="Jenkins, E. C., Tassone, F., Ye, L., Gu, H., Xi, M., Velinov, M., Brown, W. T., Hagerman, R. J., Hagerman, P. J. <strong>Reduced telomere length in older men with premutation alleles of the fragile X mental retardation 1 gene.</strong> Am. J. Med. Genet. 146A: 1543-1546, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18478592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18478592</a>] [<a href="https://doi.org/10.1002/ajmg.a.32342" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18478592">Jenkins et al. (2008)</a> quantified the telomere length in T lymphocytes from older male carriers of premutation FMR1 alleles, with or without FXTAS, and FXTAS with dementia. Shorter telomeres (relative to age-matched controls) were observed in 5 of 5 individuals with FXTAS and dementia, in 2 of 2 individuals with FXTAS without dementia, and in 3 of 3 individuals with the fragile X premutation only (p values ranged from less than 0.001 to less than 0.05; student's t-test), indicating that telomere shortening is associated with the FMR1 premutation expansion. A comparison of control, premutation, FXTAS, and FXTAS with dementia samples showed nearly equal degrees of shortening relative to controls among the 3 premutation sample groups. <a href="#61" class="mim-tip-reference" title="Jenkins, E. C., Tassone, F., Ye, L., Gu, H., Xi, M., Velinov, M., Brown, W. T., Hagerman, R. J., Hagerman, P. J. <strong>Reduced telomere length in older men with premutation alleles of the fragile X mental retardation 1 gene.</strong> Am. J. Med. Genet. 146A: 1543-1546, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18478592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18478592</a>] [<a href="https://doi.org/10.1002/ajmg.a.32342" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18478592">Jenkins et al. (2008)</a> suggested that telomere shortening may serve as a biomarker for cellular dysregulation that may precede the development of the symptoms of FXTAS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18478592" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Studies on Mechanisms of Repeat Instability</em></strong></p><p>
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The 'Sherman paradox' was applied to the following phenomenon observed in fragile X syndrome: 20% of males who carry a fragile X chromosome are phenotypically normal; their daughters, to whom they transmit the fragile X chromosome, are likewise normal, but their grandsons are often affected. The brothers of the clinically normal, transmitting males have a low risk, while grandsons and great-grandsons have much higher risks. <a href="#39" class="mim-tip-reference" title="Fu, Y.-H., Kuhl, D. P. A., Pizzuti, A., Pieretti, M., Sutcliffe, J. S., Richards, S., Verkerk, A. J. M. H., Holden, J. J. A., Fenwick, R. G., Jr., Warren, S. T., Oostra, B. A., Nelson, D. L., Caskey, C. T. <strong>Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox.</strong> Cell 67: 1047-1058, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1760838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1760838</a>] [<a href="https://doi.org/10.1016/0092-8674(91)90283-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1760838">Fu et al. (1991)</a> demonstrated that the Sherman paradox is related to the particular structure of the (CGG)n repeat found in the coding sequence of the FMR1 gene. The range of allele sizes varied from 6 to 54 repeats in normal individuals. Premutations showing no phenotypic effect in fragile X families ranged in size from 52 to more than 200 repeats. All alleles with greater than 52 repeats, including those identified in a normal family, were meiotically unstable, with a mutation frequency of 1, while 75 meioses of alleles of 46 repeats and below showed no mutation. Demonstration of mosaicism suggested that premutation alleles are also mitotically unstable. <a href="#39" class="mim-tip-reference" title="Fu, Y.-H., Kuhl, D. P. A., Pizzuti, A., Pieretti, M., Sutcliffe, J. S., Richards, S., Verkerk, A. J. M. H., Holden, J. J. A., Fenwick, R. G., Jr., Warren, S. T., Oostra, B. A., Nelson, D. L., Caskey, C. T. <strong>Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox.</strong> Cell 67: 1047-1058, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1760838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1760838</a>] [<a href="https://doi.org/10.1016/0092-8674(91)90283-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1760838">Fu et al. (1991)</a> showed that the risk of expansion during oogenesis to the full mutation increased with the number of repeats, thus explaining the Sherman paradox, which might be viewed as an example of the phenomenon of anticipation. Remarkably, the premutation expands to a full mutation only when it is transmitted by a female; consequently, daughters of normal transmitting males have only the premutation and never the full mutation, and never show mental retardation or cytogenetic expression of the fragile X syndrome. Furthermore, daughters of affected males do not express the fragile X syndrome at either the clinical or the cytogenetic level. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1760838" 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 the sperm in 4 male fragile X patients, <a href="#118" class="mim-tip-reference" title="Reyniers, E., Vits, L., De Boulle, K., Van Roy, B., Van Velzen, D., de Graaff, E., Verkerk, A. J. M. H., Jorens, H. Z. J., Darby, J. K., Oostra, B., Willems, P. J. <strong>The full mutation in the FMR-1 gene of male fragile X patients is absent in their sperm.</strong> Nature Genet. 4: 143-148, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8348152/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8348152</a>] [<a href="https://doi.org/10.1038/ng0693-143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8348152">Reyniers et al. (1993)</a> found that only the premutation was present, although the full mutation was present in peripheral lymphocytes. They concluded that expansion of the premutation to the full mutation in this disorder does not occur in meiosis but in a postzygotic stage. The same conclusion was supported by the finding of <a href="#74" class="mim-tip-reference" title="Kruyer, H., Mila, M., Glover, G., Carbonell, P., Ballesta, F., Estivill, X. <strong>Fragile X syndrome and the (CGG)n mutation: two families with discordant MZ twins.</strong> Am. J. Hum. Genet. 54: 437-442, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8116613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8116613</a>]" pmid="8116613">Kruyer et al. (1994)</a> in 2 affected monozygotic brothers who differed in the number of CGG repeats, indicating mitotic instability. The work of <a href="#154" class="mim-tip-reference" title="Wohrle, D., Hennig, I., Vogel, W., Steinbach, P. <strong>Mitotic stability of fragile X mutations in differentiated cells indicates early post-conceptional trinucleotide repeat expansion.</strong> Nature Genet. 4: 140-142, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8348151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8348151</a>] [<a href="https://doi.org/10.1038/ng0693-140" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8348151">Wohrle et al. (1993)</a> also suggested that the expansion of an FMR1 premutation to a full mutation occurs mitotically during a postzygotic stage. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8348152+8116613+8348151" 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="#162" class="mim-tip-reference" title="Zhong, N., Dobkin, C., Brown, W. T. <strong>A complex mutable polymorphism located within the fragile X gene.</strong> Nature Genet. 5: 248-253, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8275089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8275089</a>] [<a href="https://doi.org/10.1038/ng1193-248" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8275089">Zhong et al. (1993)</a> described a second mutable sequence within the FMR1 gene. <a href="#119" class="mim-tip-reference" title="Richards, R. I., Holman, K., Kozman, H., Kremer, E., Lynch, M., Pritchard, M., Yu, S., Mulley, J., Sutherland, G. R. <strong>Fragile X syndrome: genetic localisation by linkage mapping of two microsatellite repeats FRAXAC1 and FRAXAC2 which immediately flank the fragile site.</strong> J. Med. Genet. 28: 818-823, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1757956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1757956</a>] [<a href="https://doi.org/10.1136/jmg.28.12.818" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1757956">Richards et al. (1991)</a> had described 2 polymorphic markers, designated AC1 and AC2, located within FMR1 and flanking the unstable (CGG)n repeat by approximately 10 kb. <a href="#162" class="mim-tip-reference" title="Zhong, N., Dobkin, C., Brown, W. T. <strong>A complex mutable polymorphism located within the fragile X gene.</strong> Nature Genet. 5: 248-253, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8275089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8275089</a>] [<a href="https://doi.org/10.1038/ng1193-248" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8275089">Zhong et al. (1993)</a> confirmed linkage disequilibrium of the (CGG)n repeat with AC1 but found linkage equilibrium with AC2, which they also found was highly mutable. A mutation rate of 3.3% was observed but only among fragile X maternally-derived meioses. The finding of a second mutable locus within FMR1 suggested that the target for tandem repeat instability may not be confined to the (CGG)n repeat alone but may also involve microsatellites. <a href="#162" class="mim-tip-reference" title="Zhong, N., Dobkin, C., Brown, W. T. <strong>A complex mutable polymorphism located within the fragile X gene.</strong> Nature Genet. 5: 248-253, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8275089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8275089</a>] [<a href="https://doi.org/10.1038/ng1193-248" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8275089">Zhong et al. (1993)</a> cited evidence that the AC sequence is located within intron 2 of the FMR1 gene and is adjacent to an Alu element. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1757956+8275089" 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 daughter of a female carrier of the fragile X mutation, <a href="#139" class="mim-tip-reference" title="van den Ouweland, A. M. W., Deelen, W. H., Kunst, C. B., Uzielli, M.-L. G., Nelson, D. L., Warren, S. T., Oostra, B. A., Halley, D. J. J. <strong>Loss of mutation at the FMR1 locus through multiple exchanges between maternal X chromosomes.</strong> Hum. Molec. Genet. 3: 1823-1827, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849707</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1823" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849707">van den Ouweland et al. (1994)</a> found a haplotype using flanking markers that predicted she had inherited the fragile X premutation chromosome. However, the CGG repeat sequence and the intragenic polymorphic marker FMRb showed the normal maternal alleles, while 2 other intragenic markers, FMRa and FRAXAC2, and other more distant markers, showed the risk haplotype. These observations were interpreted as indicating gene conversion and might represent back mutation at the FMR1 locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849707" 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="#104" class="mim-tip-reference" title="Nolin, S. L., Lewis, F. A., III, Ye, L. L., Houck, G. E., Jr., Glicksman, A. E., Limprasert, P., Li, S. Y., Zhong, N., Ashley, A. E., Feingold, E., Sherman, S. L., Brown, W. T. <strong>Familial transmission of the FMR1 GCC repeat.</strong> Am. J. Hum. Genet. 59: 1252-1261, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8940270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8940270</a>]" pmid="8940270">Nolin et al. (1996)</a> examined transmission of the FMR1 (CGG)n repeat in 191 families with fragile X and in the general population. They reported that when fathers have (CGG)n expansions in the premutation range (greater than 80 repeats) the daughters frequently inherited smaller repeat expansions. A similar repeat number was inherited more often than expected by chance among a sibship segregating fragile X. They concluded that this familial clustering, observed in the offspring of both males and females with a premutation, implies that there may be an additional factor, independent of parental repeat size, that influences (CGG)n repeat instability. <a href="#104" class="mim-tip-reference" title="Nolin, S. L., Lewis, F. A., III, Ye, L. L., Houck, G. E., Jr., Glicksman, A. E., Limprasert, P., Li, S. Y., Zhong, N., Ashley, A. E., Feingold, E., Sherman, S. L., Brown, W. T. <strong>Familial transmission of the FMR1 GCC repeat.</strong> Am. J. Hum. Genet. 59: 1252-1261, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8940270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8940270</a>]" pmid="8940270">Nolin et al. (1996)</a> found that gray-zone alleles (40 to 60 repeats) in families with no previous history of fragile X syndrome varied in their stability but that there was no repeat expansion to the full fragile X mutation in 1 generation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8940270" 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>It had been suggested that expansion of the CGG repeat in the FMR1 gene is a postzygotic event with the germline protected. From an analysis of intact ovaries of full-mutation fetuses, <a href="#88" class="mim-tip-reference" title="Malter, H. E., Iber, J. C., Willemsen, R., de Graaff, E., Tarleton, J. C., Leisti, J., Warren, S. T., Oostra, B. A. <strong>Characterization of the full fragile X syndrome mutation in fetal gametes.</strong> Nature Genet. 15: 165-169, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9020841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9020841</a>] [<a href="https://doi.org/10.1038/ng0297-165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9020841">Malter et al. (1997)</a> showed that only full-expansion alleles could be detected in oocyte, but in the unmethylated state. Similarly, the testis of a 13-week full-mutation fetus showed no evidence of premutations, while a 17-week full mutation fetus exhibited some germ cells with attributes of premutations. These data discounted the hypothesis that the germline is protected from full expansion and suggested that full-mutation contraction occurs in the immature testis. Thus, full expansion may already exist in the maternal oocyte, or postzygotic expansion, if it occurs, arises quite early in development prior to germline segregation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9020841" 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="#75" class="mim-tip-reference" title="Kunst, C. B., Leeflang, E. P., Iber, J. C., Arnheim, N., Warren, S. T. <strong>The effect of FMR1 CGG repeat interruptions on mutation frequency as measured by sperm typing.</strong> J. Med. Genet. 34: 627-631, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9279752/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9279752</a>] [<a href="https://doi.org/10.1136/jmg.34.8.627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9279752">Kunst et al. (1997)</a> studied the influence of AGG interruptions on CGG repeat stability. In the sorted sperm of 2 donors, each with 39 total repeats but distinct AGG interruption patterns, there was approximately 15% variation in repeat length in each case. However, the male with 29 perfect repeats showed 3% expansion changes while the male with 19 perfect repeats had none. <a href="#75" class="mim-tip-reference" title="Kunst, C. B., Leeflang, E. P., Iber, J. C., Arnheim, N., Warren, S. T. <strong>The effect of FMR1 CGG repeat interruptions on mutation frequency as measured by sperm typing.</strong> J. Med. Genet. 34: 627-631, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9279752/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9279752</a>] [<a href="https://doi.org/10.1136/jmg.34.8.627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9279752">Kunst et al. (1997)</a> also noted that all variant sperm showed expansion or contraction of the 3-prime end of the repeat array. <a href="#75" class="mim-tip-reference" title="Kunst, C. B., Leeflang, E. P., Iber, J. C., Arnheim, N., Warren, S. T. <strong>The effect of FMR1 CGG repeat interruptions on mutation frequency as measured by sperm typing.</strong> J. Med. Genet. 34: 627-631, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9279752/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9279752</a>] [<a href="https://doi.org/10.1136/jmg.34.8.627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9279752">Kunst et al. (1997)</a> concluded that these data are consistent with the hypothesis that perfect repeat tracts influence repeat stability and that changes of the FMR1 repeat exhibit polarity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9279752" 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>Patients with hereditary nonpolyposis colon cancer (HNPCC; <a href="/entry/120435">120435</a>) resulting from mutation in a mismatch repair gene such as MLH1 (<a href="/entry/120436">120436</a>) show instability of repeat sequences. <a href="#40" class="mim-tip-reference" title="Fulchignoni-Lataud, M. C., Olchwang, S., Serre, J. L. <strong>The fragile X CGG repeat shows a marked level of instability in hereditary non-polyposis colorectal cancer patients.</strong> Europ. J. Hum. Genet. 5: 89-93, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9195158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9195158</a>]" pmid="9195158">Fulchignoni-Lataud et al. (1997)</a> found that peripheral blood leukocytes from HNPCC patients showed roughly twice as great allele variation of the FMR1 CGG repeat as did controls, especially when patients carried mutations in MLH1. The findings suggested that instability within nonneoplastic cells of a subset of HNPCC patients might be a mechanism for transition from normal to the premutation range of the FMR1 CGG repeat. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9195158" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Crawford, D. C., Wilson, B., Sherman, S. L. <strong>Factors involved in the initial mutation of the fragile X CGG repeat as determined by sperm small pool PCR.</strong> Hum. Molec. Genet. 9: 2909-2918, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11092767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11092767</a>] [<a href="https://doi.org/10.1093/hmg/9.19.2909" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11092767">Crawford et al. (2000)</a> performed small pool (SP)-PCR on sperm and blood DNA from 7 unaffected males whose repeat sizes ranged from 20 to 33. Regression analyses suggested that components of the repeat structure, such as the number of interruptions and purity of the 3-prime end of the repeat, are important determinants of germline repeat instability. In contrast, elements other than repeat structure, such as haplotype background, seemed to have an impact on somatic repeat instability. The factors identified for either cell type, however, explained only a small portion of the variance, suggesting to the authors that other factors may be involved in this process. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11092767" 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="#62" class="mim-tip-reference" title="Jin, P., Warren, S. T. <strong>Understanding the molecular basis of fragile X syndrome.</strong> Hum. Molec. Genet. 9: 901-908, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10767313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10767313</a>] [<a href="https://doi.org/10.1093/hmg/9.6.901" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10767313">Jin and Warren (2000)</a> reviewed the molecular mechanism of CGG repeat expansion and physiologic functions of the FMR1 protein. <a href="#107" class="mim-tip-reference" title="Oostra, B. A., Willemsen, R. <strong>A fragile balance: FMR1 expression levels.</strong> Hum. Molec. Genet. 12: R249-R257, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12952862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12952862</a>] [<a href="https://doi.org/10.1093/hmg/ddg298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12952862">Oostra and Willemsen (2003)</a> reviewed expression of FMR1 in the context of trinucleotide repeat expansion and human disease states. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10767313+12952862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#77" class="mim-tip-reference" title="Laird, C. D., Jaffe, E., Karpen, G., Lamb, M., Nelson, R. <strong>Fragile sites in human chromosomes as regions of late-replicating DNA.</strong> Trends Genet. 3: 274-281, 1987."None>Laird et al. (1987)</a> proposed that regions of late replicating DNA are present at fragile sites in human chromosomes. <a href="#51" class="mim-tip-reference" title="Hansen, R. S., Canfield, T. K., Lamb, M. M., Gartler, S. M., Laird, C. D. <strong>Association of fragile X syndrome with delayed replication of the FMR1 gene.</strong> Cell 73: 1403-1409, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8324827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8324827</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90365-w" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8324827">Hansen et al. (1993)</a> found that cells derived from normal individuals replicated late in S phase, whereas cells from fragile X patients replicated later, with the major peak of replication occurring in G2/M phase. Delayed replication timing was observed on both sides of the expanded repeat, suggesting that the stalling of a replication fork at the expanded region was not the direct cause of replication delay. <a href="#131" class="mim-tip-reference" title="Subramanian, P. S., Nelson, D. L., Chinault, A. C. <strong>Large domains of apparent delayed replication timing associated with triplet repeat expansion at FRAXA and FRAXE.</strong> Am. J. Hum. Genet. 59: 407-416, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8755928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8755928</a>]" pmid="8755928">Subramanian et al. (1996)</a> found that cells from individuals with a full FMR1 repeat expansion displayed a region of delayed replication timing; the apparent timing of the earlier-replicating allele in female cells in this region was intermediate between normal and affected alleles in male cells, a finding in accordance with expectations of a mixed population of cells resulting from random X inactivation. In this assay, relative times of replication of specific loci were inferred from the ratios of singlet and doublet fluorescence in situ hybridization signals in interphase nuclei. Trinucleotide repeat expansion thus may be acting in the Xq27.3-q28 region to alter long-range chromatin structure that could influence transcription of gene sequences within the affected domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8324827+8755928" 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="#157" class="mim-tip-reference" title="Yeshaya, J., Shalgi, R., Shohat, M., Avivi, L. <strong>Replication timing of the various FMR1 alleles detected by FISH: inferences regarding their transcriptional status.</strong> Hum. Genet. 102: 6-14, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9490300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9490300</a>] [<a href="https://doi.org/10.1007/s004390050647" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9490300">Yeshaya et al. (1998)</a> studied replication timing of the fragile X locus relative to the nontranscribed late replicating alpha-satellite region of chromosome X in lymphocytes and amniocytes from normal males, males with fragile X, and males who were premutation carriers. Three distinct populations were identified among the various samples. The first population had a high frequency of cells showing a doublet FMR1; this pattern, indicating early replication of FMR1, characterized cell populations of normal males. The second population had a high frequency of cells showing a singlet FMR1; this pattern, indicating very late replication of FMR1, characterized the population of fragile X patients. The third population had about one-half of the cells showing a singlet FMR1 and the other half with a doublet FMR1, indicating somatic variation in the replication timing of FMR1. This was the pattern seen in the population of premutation carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9490300" 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>Instability of the fragile X CGG repeat involves both maternally-derived expansions and deletions in the gametes of full-mutation males. Using an SV40 primate replication system, <a href="#102" class="mim-tip-reference" title="Nichol Edamura, K. N., Leonard, M. R., Pearson, C. E. <strong>Role of replication and CpG methylation in fragile X syndrome CGG deletions in primate cells.</strong> Am. J. Hum. Genet. 76: 302-311, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15625623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15625623</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15625623[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/10.1086/427928" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15625623">Nichol Edamura et al. (2005)</a> investigated the effect of CGG tract length, DNA replication direction, location of replication initiation, and CpG methylation upon CGG stability. Replication-dependent deletions with 53 CGG repeats were observed when replication was initiated proximal to the repeat, with CGG as the lagging-strand template. When they initiated replication further from the repeat, while maintaining CGG as the lagging-strand template or using CCG as the lagging-strand template, significant instability was not observed. CpG methylation of the unstable template stabilized the repeat, decreasing both the frequency and the magnitude of deletion events. Furthermore, CpG methylation slowed the efficiency of replication for all templates. Interestingly, replication forks displayed no evidence of a block at the CGG repeat tract, regardless of replication direction or CpG methylation status. Templates with 20 CGG repeats were stable under all circumstances. These results showed that CGG deletions occur during replication and are sensitive to replication-fork dynamics, tract length, and CpG methylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15625623" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#138" class="mim-tip-reference" title="Terracciano, A., Pomponi, M. G., Marino, G. M. E., Chiurazzi, P., Rinaldi, M. M., Dobosz, M., Neri, G. <strong>Expansion to a full mutation of a FMR1 intermediate allele over two generations.</strong> Europ. J. Hum. Genet. 12: 333-336, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14735162/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14735162</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201154" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14735162">Terracciano et al. (2004)</a> reported a family in which unstable transmission of an intermediate 44 CGG fragile X allele from the maternal grandfather occurred, with expansion first to a premutated allele of 61 CGGs in a daughter and then to a fully mutated allele in her child, representing a rare progression from intermediate to full mutation in just 2 generations. <a href="#163" class="mim-tip-reference" title="Zuniga, A., Juan, J., Mila, M., Guerrero, A. <strong>Expansion of an intermediate allele of the FMR1 gene in only two generations. (Letter)</strong> Clin. Genet. 68: 471-473, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16207218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16207218</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2005.00514.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16207218">Zuniga et al. (2005)</a> reported another family in which an intermediate fragile X allele expanded to a fully mutated allele in 2 generations. The maternal grandmother carried an intermediate fragile X allele with 45 CGG repeats, which expanded to premutated alleles of 80 and 90 repeats in her 2 daughters, respectively, and then to fully mutated alleles in each daughter's son. Sequencing showed absence of AGG interruptions that are believed to ensure repeat stability from 1 generation to another. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14735162+16207218" 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="#103" class="mim-tip-reference" title="Nolin, S. L., Ding, X., Houck, G. E., Brown, W. T., Dobkin, C. <strong>Fragile X full mutation alleles composed of few alleles: implications for CGG repeat expansion.</strong> Am. J. Med. Genet. 146A: 60-65, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18074381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18074381</a>] [<a href="https://doi.org/10.1002/ajmg.a.32087" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18074381">Nolin et al. (2008)</a> found that leukocyte samples from individuals with full expansion FMR1 alleles showed only 1 to 4 major alleles per individual when analyzed in the absence of ethidium bromide. In contrast, full mutations in chorionic villi exhibited greater heterogeneity. Analysis of 9 mother-offspring pairs showed expansion of the allele in the offspring. The findings suggested that extensive heterogeneity of full mutation fragments often reported as 'smears' by Southern analysis is an artifact, and that somatic instability in the FMR1 CGG repeat is limited to early embryogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18074381" 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>Using the G6PD Mediterranean variant as a marker, <a href="#120" class="mim-tip-reference" title="Rocchi, M., Archidiacono, N., Rinaldi, A., Filippi, G., Bartolucci, G., Fancello, G. S., Siniscalco, M. <strong>Mental retardation in heterozygotes for the fragile-X mutation: evidence in favor of an X inactivation-dependent effect.</strong> Am. J. Hum. Genet. 46: 738-743, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2316520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2316520</a>]" pmid="2316520">Rocchi et al. (1990)</a> investigated the number of somatic cells (fibroblasts or red cells) with an active fragile X chromosome. They found a significant inverse correlation between IQ level in heterozygotes and the percentage of fibroblasts with the fragile X as the active chromosome. In contrast, no significant correlation was found between IQ and the red cell data, suggesting somatic selection against hematopoietic stem cells with an active fragile X. In studies of peripheral lymphocytes, <a href="#151" class="mim-tip-reference" title="Webb, T., Jacobs, P. A. <strong>Fragile Xq27.3 in female heterozygotes for the Martin-Bell syndrome.</strong> J. Med. Genet. 27: 627-631, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2246771/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2246771</a>] [<a href="https://doi.org/10.1136/jmg.27.10.627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2246771">Webb and Jacobs (1990)</a> found that the number of active fra(X) chromosomes was consistently higher in retarded heterozygous females than in mentally normal heterozygous females. A review of the findings in the literature showed the same result. <a href="#66" class="mim-tip-reference" title="Khalifa, M. M., Reiss, A. L., Migeon, B. R. <strong>Methylation status of genes flanking the fragile site in males with the fragile-X syndrome: a test of the imprinting hypothesis.</strong> Am. J. Hum. Genet. 46: 744-753, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2316521/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2316521</a>]" pmid="2316521">Khalifa et al. (1990)</a> found no evidence that DNA methylation in the vicinity of the fragile X site influences the phenotype of the syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2316521+2316520+2246771" 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="#122" class="mim-tip-reference" title="Rousseau, F., Heitz, D., Tarleton, J., MacPherson, J., Malmgren, H., Dahl, N., Barnicoat, A., Mathew, C., Mornet, E., Tejada, I., Maddalena, A., Spiegel, R., Schinzel, A., Marcos, J. A. G., Schorderet, D. F., Schaap, T., Maccioni, L., Russo, S., Jacobs, P. A., Schwartz, C., Mandel, J. L. <strong>A multicenter study on genotype-phenotype correlations in the fragile X syndrome, using direct diagnosis with probe StB12.3: the first 2,253 cases.</strong> Am. J. Hum. Genet. 55: 225-237, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8037202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8037202</a>]" pmid="8037202">Rousseau et al. (1994)</a> reported the results of a 14-center collaborative study of genotype-phenotype correlations in the fragile X syndrome involving 318 affected families comprising 539 individuals with a fragile X premutation and 693 with a typical full fragile X mutation. Mental status of those with a premutation did not differ from those with a normal genotype. Both abnormal methylation of the FMR1 site and size of the expansion were highly correlated with cytogenetics, facial dysmorphism, macroorchidism, and mental retardation. There was a significantly higher prevalence of 'mosaic' cases among males with a full mutation (12%) than among females with a full mutation (6%); the mosaic males had a larger expansion than did the mosaic females. 'Mosaics' are individuals carrying the full mutation who also have some premutations in some of their cells. Among 164 independent couples, 3 unrelated husbands carried a premutation, suggesting that the prevalence of fragile X premutations in the general population is approximately 0.9% of the X chromosomes. The data validated the use of direct DNA testing for fragile X diagnosis and carrier identification. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8037202" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#69" class="mim-tip-reference" title="Kirchgessner, C. U., Warren, S. T., Willard, H. F. <strong>X inactivation of the FMR1 fragile X mental retardation gene.</strong> J. Med. Genet. 32: 925-929, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8825916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8825916</a>] [<a href="https://doi.org/10.1136/jmg.32.12.925" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8825916">Kirchgessner et al. (1995)</a> determined that the FMR1 gene is subject to X inactivation by studying inactive X chromosomes in somatic cell hybrids that contained an active or inactive human X chromosome and in a female patient with a large deletion surrounding the FMR1 gene. The findings were consistent with the results of previous studies of DNA methylation of FMR1 and supported the involvement of X inactivation in the variable phenotype of females with full mutations of the FMR1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8825916" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#132" class="mim-tip-reference" title="Sun, Y. J., Baumer, A. <strong>Nonrandom X inactivation and selection of fragile X full mutation in fetal fibroblasts.</strong> Am. J. Med. Genet. 86: 162-164, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10449653/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10449653</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19990910)86:2<162::aid-ajmg14>3.0.co;2-d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10449653">Sun and Baumer (1999)</a> studied a fibroblast culture from a 20-week female fetus who was diagnosed as a full mutation heterozygote. Higher passage cells showed a complete absence of cells in which the normal X chromosome would be inactivated. Studies of a control fibroblast culture derived from a female fetus with normal FMR1 alleles showed no selection. The study indicated nonrandom X inactivation and suggested a selection process that is dependent on the activation status of the X chromosome carrying an FMR1 full mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10449653" 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="#113" class="mim-tip-reference" title="Primerano, B., Tassone, F., Hagerman, R. J., Hagerman, P., Amaldi, F., Bagni, C. <strong>Reduced FMR1 mRNA translation efficiency in fragile X patients with premutations.</strong> RNA 8: 1482-1488, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12515381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12515381</a>]" pmid="12515381">Primerano et al. (2002)</a> noted that lymphoblastoid cells from patients with the full fragile X mutation (greater than 200 CGG repeats) have essentially absent levels of FMR1 mRNA and FMR1 protein, consistent with hypermethylation of the FMR1 gene and complete transcriptional silencing of the gene. In cells from 3 patients with premutation alleles (97, 170, and 195 CGG repeats), <a href="#113" class="mim-tip-reference" title="Primerano, B., Tassone, F., Hagerman, R. J., Hagerman, P., Amaldi, F., Bagni, C. <strong>Reduced FMR1 mRNA translation efficiency in fragile X patients with premutations.</strong> RNA 8: 1482-1488, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12515381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12515381</a>]" pmid="12515381">Primerano et al. (2002)</a> found significantly increased levels of FMR1 mRNA compared with normal controls, and the level of mRNA increased with longer CGG repeats in the premutation range. However, overexpression of the mRNA from the premutation expanded alleles was not associated with increased levels of FMRP protein, suggesting a defect in translation. An analysis of polysomes and mRNA showed that the association of mRNA with polysomes progressively decreased with increasing allele expansion. Thus, in cases with premutation, impaired FMR1 translation leads to lower FMRP levels and clinical involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12515381" 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 boy with speech and developmental delay and low normal IQ measures, <a href="#135" class="mim-tip-reference" title="Tarleton, J., Kenneson, A., Taylor, A. K., Crandall, K., Fletcher, R., Casey, R., Hart, P. S., Hatton, D., Fisch, G., Warren, S. T. <strong>A single base alteration in the CGG repeat region of FMR1: possible effects on gene expression and phenotype.</strong> J. Med. Genet. 39: 196-200, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11897823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11897823</a>] [<a href="https://doi.org/10.1136/jmg.39.3.196" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11897823">Tarleton et al. (2002)</a> identified a G-to-C point mutation within the CGG repeat region of FMR1. The patient had a 31-repeat segment, within the normal range, but was originally thought to have a deletion in the FMR1 gene. Peripheral blood analysis showed a 24% reduction in the FMR protein. <a href="#135" class="mim-tip-reference" title="Tarleton, J., Kenneson, A., Taylor, A. K., Crandall, K., Fletcher, R., Casey, R., Hart, P. S., Hatton, D., Fisch, G., Warren, S. T. <strong>A single base alteration in the CGG repeat region of FMR1: possible effects on gene expression and phenotype.</strong> J. Med. Genet. 39: 196-200, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11897823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11897823</a>] [<a href="https://doi.org/10.1136/jmg.39.3.196" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11897823">Tarleton et al. (2002)</a> suggested that the mild phenotype resulted from the mild change in FMRP expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11897823" 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="#48" class="mim-tip-reference" title="Hagerman, P. J., Hagerman, R. J. <strong>The fragile-X premutation: a maturing perspective.</strong> Am. J. Hum. Genet. 74: 805-816, 2004. Note: Erratum: Am. J. Hum. Genet. 75: 352 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15052536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15052536</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15052536[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/10.1086/386296" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15052536">Hagerman and Hagerman (2004)</a> pointed out that carriers of premutation alleles (55 to 200 CGG repeats) of the FMR1 gene can present with 1 or more of 3 distinct clinical disorders: mild cognitive and/or behavioral deficits on the fragile X spectrum; premature ovarian failure; and fragile X tremor/ataxia syndrome (FXTAS). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15052536" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 621 children, <a href="#85" class="mim-tip-reference" title="Loat, C. S., Craig, G., Plomin, R., Craig, I. W. <strong>Investigating the relationship between FMR1 allele length and cognitive ability in children: a subtle effect of the normal allele range on the normal ability range?</strong> Ann. Hum. Genet. 70: 555-565, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16907702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16907702</a>] [<a href="https://doi.org/10.1111/j.1469-1809.2006.00269.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16907702">Loat et al. (2006)</a> observed an inverse association between between FMR1 allele length and cognitive ability in boys. There was a significant negative correlation between nonverbal ability at age 4 years (p = 0.048) and academic achievement in math (p = 0.003) and English (p = 0.011) at 7 years. There was also a negative correlation between repeat size and IQ in a cohort of 122 students with high IQ. However, only 35 (3.5%) of 1,016 X chromosomes harbored more than 40 CGG repeats, and there was no difference in the incidence of alleles with greater than 40 repeats between the groups of children with high, control, and low cognitive ability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16907702" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#98" class="mim-tip-reference" title="Murray, A., Schoemaker, M. J., Bennett, C. E., Ennis, S., Macpherson, J. N., Jones, M., Morris, D. H., Orr, N., Ashworth, A., Jacobs, P. A., Swerdlow, A. J. <strong>Population-based estimates of the prevalence of FMR1 expansion mutations in women with early menopause and primary ovarian insufficiency.</strong> Genet. Med. 16: 19-24, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23703681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23703681</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23703681[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/gim.2013.64" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23703681">Murray et al. (2014)</a> studied FMR1 CGG repeat number in more than 2,000 women from the Breakthrough Generations Study who underwent menopause before the age of 46. The authors determined the prevalence of premutation FMR1 alleles (55-200 CGG repeats) and intermediate (45-54 CGG repeats) alleles in 254 women with primary ovarian failure (<a href="/entry/311360">311360</a>), defined as menopause prior to the age of 40, and 1,881 with early menopause, defined as menopause between the ages of 40 and 45. The prevalence of the premutation was 2.0% in primary ovarian failure and 0.7% in early menopause compared with 0.4% in controls, corresponding to odds ratios of 5.4 (95% CI = 1.7-17.4; p = 0.004) for primary ovarian failure and 2.0 (95% CI = 0.8-5.1; p = 0.12) for early menopause. Intermediate alleles were not significant risk factors for either early menopause or primary ovarian failure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23703681" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Methylation</em></strong></p><p>
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In 2 clinically normal brothers, <a href="#128" class="mim-tip-reference" title="Smeets, H. J. M., Smits, A. P. T., Verheij, C. E., Theelen, J. P. G., Willemsen, R., van de Burgt, I., Hoogeveen, A. T., Oosterwijk, J. C., Oostra, B. A. <strong>Normal phenotype in two brothers with a full FMR1 mutation.</strong> Hum. Molec. Genet. 4: 2103-2108, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8589687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8589687</a>] [<a href="https://doi.org/10.1093/hmg/4.11.2103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8589687">Smeets et al. (1995)</a> found expanded CGG repeats in cytogenetically visible fragile sites. The FMR1 promoter was unmethylated and both RNA and protein could be detected. This indicated to the authors that inactivation of the FMR1 gene and not the repeat expansion itself resulted in the fragile X phenotype. <a href="#128" class="mim-tip-reference" title="Smeets, H. J. M., Smits, A. P. T., Verheij, C. E., Theelen, J. P. G., Willemsen, R., van de Burgt, I., Hoogeveen, A. T., Oosterwijk, J. C., Oostra, B. A. <strong>Normal phenotype in two brothers with a full FMR1 mutation.</strong> Hum. Molec. Genet. 4: 2103-2108, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8589687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8589687</a>] [<a href="https://doi.org/10.1093/hmg/4.11.2103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8589687">Smeets et al. (1995)</a> concluded that repeat expansion does not necessarily induce methylation and that methylation is not an absolute requirement for the induction of fragile sites. This fragile X family was ascertained through a mentally retarded boy who was the grandson of 1 of the 2 brothers through a daughter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8589687" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#91" class="mim-tip-reference" title="McConkie-Rosell, A., Lachiewicz, A. M., Spiridigliozzi, G. A., Tarleton, J., Schoenwald, S., Phelan, M. C., Goonewardena, P., Ding, X., Brown, W. T. <strong>Evidence that methylation of the FMR-1 locus is responsible for variable phenotypic expression of the fragile X syndrome.</strong> Am. J. Hum. Genet. 53: 800-809, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8213810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8213810</a>]" pmid="8213810">McConkie-Rosell et al. (1993)</a> reported an unusual family with 6 brothers, including 3 affected with fragile X syndrome, 2 nonpenetrant carriers, and 1 unaffected. Two of the affected brothers and the 2 'nonpenetrant' brothers were found to be methylation mosaics. A correlation was seen between the degree of methylation and the phenotypic expression identified in the 3 affected males. The 2 males initially classified as nonpenetrant were found to have mild phenotypic expression with minor cognitive deficits and a partial physical phenotype. These 2 males, who were negative on fragile X chromosome studies, were found on DNA analysis to have large, broad smears, with approximately 97% of the DNA unmethylated; they were mosaic for hypermethylation of an expansion of the CGG repeat in the premutation range (100-600 bp). The result indicated that some 'nonpenetrant' carrier males may have varying amounts of methylation of the FMR1 regions, which can result in mild expression of the fragile X syndrome. Expression of the syndrome may not be confined to males with the full mutation and large, hypermethylated expansions, but may instead have a gradient effect with a threshold for the full expression of the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8213810" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#74" class="mim-tip-reference" title="Kruyer, H., Mila, M., Glover, G., Carbonell, P., Ballesta, F., Estivill, X. <strong>Fragile X syndrome and the (CGG)n mutation: two families with discordant MZ twins.</strong> Am. J. Hum. Genet. 54: 437-442, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8116613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8116613</a>]" pmid="8116613">Kruyer et al. (1994)</a> reported 2 monozygotic twin sisters with the same number of FMR1 CGG repeats, but only 1 was mentally retarded. When the methylation status of the FMR1 CpG island was studied, <a href="#74" class="mim-tip-reference" title="Kruyer, H., Mila, M., Glover, G., Carbonell, P., Ballesta, F., Estivill, X. <strong>Fragile X syndrome and the (CGG)n mutation: two families with discordant MZ twins.</strong> Am. J. Hum. Genet. 54: 437-442, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8116613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8116613</a>]" pmid="8116613">Kruyer et al. (1994)</a> found that the majority of the normal chromosomes had been inactivated in the affected twin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8116613" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Chiurazzi, P., Pomponi, M. G., Willemsen, R., Oostra, B. A., Neri, G. <strong>In vitro reactivation of the FMR1 gene involved in fragile X syndrome.</strong> Hum. Molec. Genet. 7: 109-113, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9384610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9384610</a>] [<a href="https://doi.org/10.1093/hmg/7.1.109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9384610">Chiurazzi et al. (1998)</a> investigated whether FMR1 activity could be restored in vitro by inducing DNA demethylation with 5-azadeoxycytidine (5-azadC) lymphoblastoid cells derived from fragile X patients. Treatment with 5-azadC causes reactivation of fully mutated FMR1 genes with 300 to 800 repeats, as shown by the restoration of specific mRNA and protein production. This effect correlated with the extent of promoter demethylation, determined by restriction analysis with methylation-sensitive enzymes. <a href="#22" class="mim-tip-reference" title="Chiurazzi, P., Pomponi, M. G., Pietrobono, R., Bakker, C. E., Neri, G., Oostra, B. A. <strong>Synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of the FMR1 gene.</strong> Hum. Molec. Genet. 8: 2317-2323, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10545613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10545613</a>] [<a href="https://doi.org/10.1093/hmg/8.12.2317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10545613">Chiurazzi et al. (1999)</a> investigated the role of histone acetylation in regulating FMR1 expression by treating lymphoblastoid cell lines of nonmosaic full mutation patients with 3 drugs capable of inducing histone hyperacetylation. They observed a consistent, although modest, reactivation of the FMR1 gene with 4-phenylbutyrate, sodium butyrate, and the cytotoxic drug trichostatin A, as shown by RT-PCR. Combining these drugs with 5-azadC resulted in a 2- to 5-fold increase in FMR1 mRNA levels obtained with 5-azadC alone, thus showing a synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of FMR1 full mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9384610+10545613" 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="#111" class="mim-tip-reference" title="Pietrobono, R., Tabolacci, E., Zalfa, F., Zito, I., Terracciano, A., Moscato, U., Bagni, C., Oostra, B., Chiurazzi, P., Neri, G. <strong>Molecular dissection of the events leading to inactivation of the FMR1 gene.</strong> Hum. Molec. Genet. 14: 267-277, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15563507/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15563507</a>] [<a href="https://doi.org/10.1093/hmg/ddi024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15563507">Pietrobono et al. (2005)</a> analyzed lymphoblastoid cell DNA from a rare individual of normal intelligence with an unmethylated full mutation of the FMR1 gene. Lack of DNA methylation of the entire promoter region (including the expanded CGG repeat) correlated with methylation of lysine-4 residue on the N-tail of histone H3 (H3-K4), as in normal controls. Normal levels of FMR1 mRNA were detected by real-time RT-PCR, but mRNA translation was decreased by 40%, resulting in FMRP protein levels reduced by 30% compared to normal controls. These results confirmed that CGG repeat amplification per se does not prevent FMR1 transcription and FMRP production in the absence of DNA methylation. The cell line had deacetylated histones H3 and H4, as well as methylated lysine-9 on histone H3 (H3-K9) similar to fragile X cell lines, in both the promoter and exon 1. This suggested that histone deacetylation and H3-K9 methylation may be established in the absence of DNA methylation and do not interfere with active gene transcription. <a href="#111" class="mim-tip-reference" title="Pietrobono, R., Tabolacci, E., Zalfa, F., Zito, I., Terracciano, A., Moscato, U., Bagni, C., Oostra, B., Chiurazzi, P., Neri, G. <strong>Molecular dissection of the events leading to inactivation of the FMR1 gene.</strong> Hum. Molec. Genet. 14: 267-277, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15563507/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15563507</a>] [<a href="https://doi.org/10.1093/hmg/ddi024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15563507">Pietrobono et al. (2005)</a> suggested that the molecular pathways regulating DNA and H3-K4 methylation may be independent from those regulating histone acetylation and H3-K9 methylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15563507" 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="#101" class="mim-tip-reference" title="Naumann, A., Hochstein, N., Weber, S., Fanning, E., Doerfler, W. <strong>A distinct DNA-methylation boundary in the 5-prime-upstream sequence of the FMR1 promoter binds nuclear proteins and is lost in fragile X syndrome.</strong> Am. J. Hum. Genet. 85: 606-616, 2009. Note: Erratum: Am. J. Hum. Genet. 86: 98-100, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19853235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19853235</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19853235[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2009.09.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19853235">Naumann et al. (2009)</a> found that the methylation boundary upstream of the FMR1 gene was lost in FRAXA males. In the FRAXA genomes studied, methylation of upstream CpG pairs penetrated into the normally unmethylated promoter region of FMR1 and to the CGG repeat, resulting in inactivation of the FRAXA gene. The methylation pattern in DNA from premutation females was similar to that of normal females. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19853235" 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="#43" class="mim-tip-reference" title="Godler, D. E., Tassone, F., Loesch, D. Z., Taylor, A. K., Gehling, F., Hagerman, R. J., Burgess, T., Ganesamoorthy, D., Hennerich, D., Gordon, L., Evans, A., Choo, K. H., Slater, H. R. <strong>Methylation of novel markers of fragile X alleles is inversely correlated with FMRP expression and FMR1 activation ratio.</strong> Hum. Molec. Genet. 19: 1618-1632, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20118148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20118148</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20118148[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20118148">Godler et al. (2010)</a> identified epigenetic markers for fragile X syndrome using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS), naming the most informative fragile X-related epigenetic element 1 (FREE1) and 2 (FREE2). Methylation of both regions was correlated with that of the FMR1 CpG island detected using Southern blot and negatively correlated with lymphocyte expression of FMRP in blood of partially methylated 'high functioning' full mutation (FM) males. In blood of FM carrier females, methylation of both markers was inversely correlated with the FMR1 activation ratio. In a sample set of 49 controls, 18 gray zone (GZ 40-54 repeats), 22 premutation (PM 55-170 repeats), and 22 (affected) fragile X subjects, the FREE1 methylation pattern was consistent between blood and chorionic villi as a marker of methylated FM alleles and could be used to differentiate fragile X males and females from controls, as well as from carriers of GZ/PM alleles, but not between GZ and PM alleles and controls. <a href="#43" class="mim-tip-reference" title="Godler, D. E., Tassone, F., Loesch, D. Z., Taylor, A. K., Gehling, F., Hagerman, R. J., Burgess, T., Ganesamoorthy, D., Hennerich, D., Gordon, L., Evans, A., Choo, K. H., Slater, H. R. <strong>Methylation of novel markers of fragile X alleles is inversely correlated with FMRP expression and FMR1 activation ratio.</strong> Hum. Molec. Genet. 19: 1618-1632, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20118148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20118148</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20118148[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20118148">Godler et al. (2010)</a> suggested that FREE MALDI-TOF MS may be a tool in fragile X syndrome diagnostics and newborn population screening. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20118148" 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="#54" class="mim-tip-reference" title="Hecht, F., Cannizzaro, L. A., Hecht, B. K. <strong>Gene symbols for fragile sites: a proposal. (Letter)</strong> Hum. Genet. 82: 394, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2737673/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2737673</a>] [<a href="https://doi.org/10.1007/BF00274007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2737673">Hecht et al. (1989)</a> suggested a new system of gene symbols for fragile sites. Their suggestion for the fragile site discussed here was FRAXQ27*RFA, where R means 'rare' and FA indicates that it is of the 'folic acid type.' Thus, the fragile X syndrome locus is also referred to in the literature as FRAXA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2737673" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Nomenclature of Expanded Trinucleotide Repeats</em></strong></p><p>
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The repeat involved in the fragile X syndrome is variously referred to here as (CGG)n or (CCG)n. The identical repeat found in the cloned FRAXE gene (<a href="/entry/309548">309548</a>) was referred to as (GCC)n by <a href="#70" class="mim-tip-reference" title="Knight, S. J. L., Flannery, A. V., Hirst, M. C., Campbell, L., Christodoulou, Z., Phelps, S. R., Pointon, J., Middleton-Price, H. R., Barnicoat, A., Pembrey, M. E., Holland, J., Oostra, B. A., Bobrow, M., Davies, K. E. <strong>Trinucleotide repeat amplification and hypermethylation of a CpG island in FRAXE mental retardation.</strong> Cell 74: 127-134, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8334699/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8334699</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90300-f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8334699">Knight et al. (1993)</a>. There are only 10 different trinucleotide repeats, but each can be written in a number of ways. <a href="#133" class="mim-tip-reference" title="Sutherland, G. R. <strong>Personal Communication.</strong> Adelaide, Australia 11/3/1993."None>Sutherland (1993)</a> favored the convention that lists the motif in alphabetical order in the 5-prime to 3-prime direction. Consistent with this, he uses the (CCG)n designation. He preferred, furthermore, the designation (AGC)n for the other clinically significant dinucleotide repeat found in myotonic dystrophy (DM1; <a href="/entry/160900">160900</a>), Huntington disease (<a href="/entry/143100">143100</a>), Kennedy disease (SMAX1; <a href="/entry/313200">313200</a>), and SCA1 (<a href="/entry/164400">164400</a>); (CAG)n is the designation most often used. <a href="#133" class="mim-tip-reference" title="Sutherland, G. R. <strong>Personal Communication.</strong> Adelaide, Australia 11/3/1993."None>Sutherland (1993)</a> suggested that the same convention can apply to dinucleotides. He wrote: 'It must be very confusing for newcomers to the literature to find (AC)n, (CA)n, (GT)n, and (TG)n repeats, when the cognoscenti know these are synonyms.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8334699" 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="#147" class="mim-tip-reference" title="Wang, Y.-C., Lin, M.-L., Lin, S. J., Li, Y.-C., Li, S.-Y. <strong>Novel point mutation within intron 10 of FMR-1 gene causing fragile X syndrome.</strong> Hum. Mutat. 10: 393-399, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9375856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9375856</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)10:5<393::AID-HUMU10>3.0.CO;2-V" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9375856">Wang et al. (1997)</a> identified a splice site mutation in intron 10 of the FMR1 gene (IVS10+14C-T) in 3 unrelated patients with fragile X syndrome who did not have an expanded (CGG)n repeat. However, <a href="#143" class="mim-tip-reference" title="Vincent, J. B., Gurling, H. M. D. <strong>Point mutation in intron 10 of FMR1 is unlikely to be a cause of fragile X syndrome. (Letter)</strong> Hum. Mutat. 12: 431 only, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9829913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9829913</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)12:6<431::AID-HUMU10>3.0.CO;2-Y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9829913">Vincent and Gurling (1998)</a> and <a href="#146" class="mim-tip-reference" title="Wang, Y.-C., Li, S.-Y. <strong>Response to Vincent and Gurling. (Letter)</strong> Hum. Mutat. 12: 432 only, 1998."None>Wang and Li (1998)</a> confirmed that IVS10+14C-T is in fact a polymorphism and not a disorder-related mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9375856+9829913" 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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By mRNA in situ hybridization studies in mice, <a href="#56" class="mim-tip-reference" title="Hinds, H. L., Ashley, C. T., Sutcliffe, J. S., Nelson, D. L., Warren, S. T., Housman, D. E., Schalling, M. <strong>Tissue specific expression of FMR-1 provides evidence for a functional role in fragile X syndrome.</strong> Nature Genet. 3: 36-43, 1993. Note: Erratum: Nature Genet. 5: 312 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8490651/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8490651</a>] [<a href="https://doi.org/10.1038/ng0193-36" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8490651">Hinds et al. (1993)</a> demonstrated that expression of the Fmr1 gene was localized to several areas of the brain and the tubules of the testes in the adult mouse, whereas universal and very strong expression was observed in early mouse embryos. To identify transcribed sequences rapidly and efficiently, <a href="#52" class="mim-tip-reference" title="Hanzlik, A. J., Osemlak-Hanzlik, M. M., Hauser, M. A., Kurnit, D. M. <strong>A recombination-based assay demonstrates that the fragile X sequence is transcribed widely during development.</strong> Nature Genet. 3: 44-48, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8490653/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8490653</a>] [<a href="https://doi.org/10.1038/ng0193-44" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8490653">Hanzlik et al. (1993)</a> developed a recombination-based assay to screen bacteriophage lambda-libraries for sequences that share homology with a given probe. This strategy determined whether a given probe is transcribed in a given tissue at a given time of development and could also be used to isolate the transcribed sequence free of the screening probe. <a href="#52" class="mim-tip-reference" title="Hanzlik, A. J., Osemlak-Hanzlik, M. M., Hauser, M. A., Kurnit, D. M. <strong>A recombination-based assay demonstrates that the fragile X sequence is transcribed widely during development.</strong> Nature Genet. 3: 44-48, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8490653/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8490653</a>] [<a href="https://doi.org/10.1038/ng0193-44" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8490653">Hanzlik et al. (1993)</a> used the technique to demonstrate that the fragile X sequence is transcribed ubiquitously in an 11-week mouse fetus, in a variety of 20-week fetal tissues including brain, spinal cord, eye, liver, kidney, and skeletal muscle, and in adult jejunum. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8490653+8490651" 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 immunolocalization studies of murine Fmrp truncation and fusion constructs in COS-7 cells, <a href="#35" class="mim-tip-reference" title="Eberhart, D. E., Malter, H. E., Feng, Y., Warren, S. T. <strong>The fragile X mental retardation protein is a ribonucleoprotein containing both nuclear localization and nuclear export signals.</strong> Hum. Molec. Genet. 5: 1083-1091, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8842725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8842725</a>] [<a href="https://doi.org/10.1093/hmg/5.8.1083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8842725">Eberhart et al. (1996)</a> identified a nuclear localization signal in the amino terminus and a nuclear export signal encoded by exon 14. Fmrp was found in ribonucleoprotein (RNP) particles, consistent with nascent Fmrp protein entering the nucleus to assemble into RNP particles prior to export back into the cytoplasm. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8842725" 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="#82" class="mim-tip-reference" title="Li, Z., Zhang, Y., Ku, L., Wilkinson, K. D., Warren, S. T., Feng, Y. <strong>The fragile X mental retardation protein inhibits translation via interacting with mRNA.</strong> Nucleic Acids Res. 29: 2276-2283, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11376146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11376146</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11376146[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/nar/29.11.2276" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11376146">Li et al. (2001)</a> demonstrated that recombinant rat Fmrp caused dose-dependent translational inhibition of brain mRNA in rabbit reticulate lysate without accelerated mRNA degradation. Translation suppression by Fmrp was reversed in a trans-acting manner by the 3-prime untranslated portion of the Fmr1 message, which binds Fmrp, suggesting that Fmrp inhibits translation by interacting with mRNA. Consistently, Fmrp suppressed translation of the parathyroid hormone (PTH; <a href="/entry/168450">168450</a>) transcript, which binds Fmrp, but not the beta-globin (HBB; <a href="/entry/141900">141900</a>) transcript, which does not bind Fmrp. Similarly, removal of the Fmrp-binding site on a translation template abolished the inhibitory effect of Fmrp, supporting the hypothesis that FMRP inhibits translation by direct interaction with template mRNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11376146" 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>Human-murine homology at the FMR1 locus extends to the repeat region and promoter. The murine repeat region contains triplets ranging from 8 to 12 repeats. <a href="#14" class="mim-tip-reference" title="Bontekoe, C. J. M., Bakker, C. E., Nieuwenhuizen, I. M., van der Linde, H., Lans, H., de Lange, D., Hirst, M. C., Oostra, B. A. <strong>Instability of a (CGG)98 repeat in the Fmr1 promoter.</strong> Hum. Molec. Genet. 10: 1693-1699, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11487573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11487573</a>] [<a href="https://doi.org/10.1093/hmg/10.16.1693" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11487573">Bontekoe et al. (2001)</a> generated a knockin mouse Fmr1 gene in which the murine (CGG)8 repeat was exchanged with a human (CGG)98 repeat. Unlike other CGG transgenic models, this model showed moderate CGG repeat instability (2 contractions and 13 expansions among 155 transmissions) in both maternal and paternal transmission. An abnormal phenotype was not described. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11487573" 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="#156" class="mim-tip-reference" title="Wohrle, D., Salat, U., Hameister, H., Vogel, W., Steinbach, P. <strong>Demethylation, reactivation, and destabilization of human fragile X full-mutation alleles in mouse embryocarcinoma cells.</strong> Am. J. Hum. Genet. 69: 504-515, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11462172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11462172</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11462172[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/10.1086/322739" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11462172">Wohrle et al. (2001)</a> transferred hypermethylated and unmethylated full expansions of human fragile X chromosomes from murine A9 hybrids into murine embryocarcinoma cells, a model system of pluripotent embryonic cells. Full-expansion alleles that were fully methylated and stable in the donors' fibroblasts and in A9 became demethylated, reactivated, and destabilized in the undifferentiated embryocarcinoma hybrids. When destabilized expansions were reintroduced from embryocarcinoma cells into A9, instability was reversed to stability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11462172" 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 Drosophila, <a href="#60" class="mim-tip-reference" title="Ishizuka, A., Siomi, M. C., Siomi, H. <strong>A Drosophila fragile X protein interacts with components of RNAi and ribosomal proteins.</strong> Genes Dev. 16: 2497-2508, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12368261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12368261</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12368261[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/10.1101/gad.1022002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12368261">Ishizuka et al. (2002)</a> found that Fmr1 is a component of a large protein complex known as the RNA-induced silencing complex (RISC), which is a sequence-specific nuclease complex that mediates RNA interference (RNAi). Fmr1 was found to associate with argonaute-2 (Ago2; <a href="/entry/606229">606229</a>) and dicer (<a href="/entry/606241">606241</a>), 2 proteins normally present in the RISC. The findings suggested that defects in an RNAi-related machinery may underlie human disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12368261" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#90" class="mim-tip-reference" title="Mazroui, R., Huot, M.-E., Tremblay, S., Filion, C., Labelle, Y., Khandjian, E. W. <strong>Trapping of messenger RNA by fragile X mental retardation protein into cytoplasmic granules induces translation repression.</strong> Hum. Molec. Genet. 11: 3007-3017, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12417522/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12417522</a>] [<a href="https://doi.org/10.1093/hmg/11.24.3007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12417522">Mazroui et al. (2002)</a> established an immortal murine embryonic STEK Fmr1 knockout cell line, and showed by transfection assays with Fmr1-expressing vectors that newly synthesized Fmrp accumulated into cytoplasmic granules. These structures contained mRNAs and several other RNA-binding proteins. The formation of the cytoplasmic granules was dependent on determinants located in the RGG domain. The authors also presented evidence that FMRP acts as a translation repressor following cotransfection with reporter genes. The FMRP-containing mRNPs are dynamic structures that oscillate between polyribosomes and cytoplasmic granules reminiscent of the stress granules that contain repressed mRNAs. <a href="#90" class="mim-tip-reference" title="Mazroui, R., Huot, M.-E., Tremblay, S., Filion, C., Labelle, Y., Khandjian, E. W. <strong>Trapping of messenger RNA by fragile X mental retardation protein into cytoplasmic granules induces translation repression.</strong> Hum. Molec. Genet. 11: 3007-3017, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12417522/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12417522</a>] [<a href="https://doi.org/10.1093/hmg/11.24.3007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12417522">Mazroui et al. (2002)</a> suggested that, in neurons, FMRP may play a role as an mRNA repressor in incompetent mRNP granules that have to be translocated from the cell body to distal locations such as dendritic spines and synaptosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12417522" 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 mass spectrometry and site-directed mutagenesis, <a href="#19" class="mim-tip-reference" title="Ceman, S., O'Donnell, W. T., Reed, M., Patton, S., Pohl, J., Warren, S. T. <strong>Phosphorylation influences the translation state of FMRP-associated polyribosomes.</strong> Hum. Molec. Genet. 12: 3295-3305, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14570712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14570712</a>] [<a href="https://doi.org/10.1093/hmg/ddg350" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14570712">Ceman et al. (2003)</a> showed that Fmrp was phosphorylated between residues 483 and 521, N terminal to the RGG box, both in murine brain and in cultured cells. Primary phosphorylation occurred on the highly conserved ser499, which triggered hierarchical phosphorylation of nearby serines. Fmrp was phosphorylated within 2 to 4 hours of synthesis; however, phosphorylation had no effect on the half-life of the protein. In contrast to the Drosophila ortholog dFxr, the phosphorylation status of mammalian Fmrp did not influence its association with specific mRNAs in vivo. However, unphosphorylated Fmrp was associated with actively translating polyribosomes, while a fraction of phosphorylated FMRP was associated with apparently stalled polyribosomes. <a href="#19" class="mim-tip-reference" title="Ceman, S., O'Donnell, W. T., Reed, M., Patton, S., Pohl, J., Warren, S. T. <strong>Phosphorylation influences the translation state of FMRP-associated polyribosomes.</strong> Hum. Molec. Genet. 12: 3295-3305, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14570712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14570712</a>] [<a href="https://doi.org/10.1093/hmg/ddg350" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14570712">Ceman et al. (2003)</a> suggested that phosphorylation may regulate FMRP and that the release of FMRP-induced translational suppression may involve a dephosphorylation signal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14570712" 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="#144" class="mim-tip-reference" title="Wang, H., Ku, L., Osterhout, D. J., Li, W., Ahmadian, A., Liang, Z., Feng, Y. <strong>Developmentally-programmed FMRP expression in oligodendrocytes: a potential role of FMRP in regulating translation in oligodendroglia progenitors.</strong> Hum. Molec. Genet. 13: 79-89, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14613971/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14613971</a>] [<a href="https://doi.org/10.1093/hmg/ddh009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14613971">Wang et al. (2004)</a> detected Fmrp expression in oligodendroglia progenitor cells, immature oligodendrocytes, and oligodendroglia cell lines isolated from rat and mouse brain, where it interacted with a subgroup of oligodendrocyte-specific mRNAs, including myelin basic protein (MBP; <a href="/entry/159430">159430</a>) mRNA. Fmrp expression gradually declined as oligodendrocytes differentiated in vitro and in the developing brain. The decline of Fmrp expression during oligodendrocyte differentiation was associated with a vigorous upregulation of the MBP protein. The MBP 3-prime UTR was necessary and sufficient for binding Fmrp, and it mediated translation inhibition of a reporter gene by Fmrp specifically in oligodendrocytes. <a href="#144" class="mim-tip-reference" title="Wang, H., Ku, L., Osterhout, D. J., Li, W., Ahmadian, A., Liang, Z., Feng, Y. <strong>Developmentally-programmed FMRP expression in oligodendrocytes: a potential role of FMRP in regulating translation in oligodendroglia progenitors.</strong> Hum. Molec. Genet. 13: 79-89, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14613971/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14613971</a>] [<a href="https://doi.org/10.1093/hmg/ddh009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14613971">Wang et al. (2004)</a> hypothesized that Fmrp may participate in regulating translation of its bound mRNAs in oligodendroglia during early brain development in rodents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14613971" 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>MicroRNAs (miRNAs) are a class of noncoding RNAs that are believed to control translation of specific target mRNAs. In vitro, <a href="#63" class="mim-tip-reference" title="Jin, P., Zarnescu, D. C., Ceman, S., Nakamoto, M., Mowrey, J., Jongens, T. A., Nelson, D. L., Moses, K., Warren, S. T. <strong>Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway.</strong> Nature Neurosci. 7: 113-117, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14703574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14703574</a>] [<a href="https://doi.org/10.1038/nn1174" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14703574">Jin et al. (2004)</a> showed that mammalian FMRP interacts with AGO1 (<a href="/entry/606228">606228</a>), a downstream component of the miRNA pathway, and that AGO1 is required for the biologic functions of Fmr1 in vivo in Drosophila. The results suggested a mechanism by which Fmr1 regulates translational suppression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14703574" 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 Drosophila, Lgl (<a href="/entry/600966">600966</a>) encodes a cytoskeletal protein involved in cellular polarity and cytoplasmic transport. <a href="#158" class="mim-tip-reference" title="Zarnescu, D. C., Jin, P., Betschinger, J., Nakamoto, M., Wang, Y., Dockendorff, T. C., Feng, Y., Jongens, T. A., Sisson, J. C., Knoblich, J. A., Warren, S. T., Moses, K. <strong>Fragile X protein functions with lgl and the PAR complex in flies and mice.</strong> Dev. Cell 8: 43-52, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15621528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15621528</a>] [<a href="https://doi.org/10.1016/j.devcel.2004.10.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15621528">Zarnescu et al. (2005)</a> found that mouse Lgl was expressed at low levels in the cytoplasm along with Fmr1. Overexpression of fluorescence-tagged Fmr1 directed the assembly of endogenous Lgl into perinuclear and cytoplasmic granules. In a mouse catecholaminergic cell line, Fmr1 overexpression resulted in reorganization of endogenous Lgl into Fmr1-containing granules in the perinuclear region and within developing neurites. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15621528" 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="#145" class="mim-tip-reference" title="Wang, H., Wu, L.-J., Kim, S. S., Lee, F. J. S., Gong, B., Toyoda, H., Ren, M., Shang, Y.-Z., Xu, H., Liu, F., Zhao, M.-G., Zhuo, M. <strong>FMRP acts as a key messenger for dopamine modulation in the forebrain.</strong> Neuron 59: 634-647, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18760699/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18760699</a>] [<a href="https://doi.org/10.1016/j.neuron.2008.06.027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18760699">Wang et al. (2008)</a> provided evidence that Fmr1 acts as a messenger for dopamine modulation in the forebrain. Culture neurons from the prefrontal cortex and striatum of Fmr1-null mice showed decreased D1 receptor (DRD1; <a href="/entry/126449">126449</a>) agonist-induced effects, as evidenced by decreased D1 receptor-induced phosphorylation of the glutamate receptor (GRIA1; <a href="/entry/138248">138248</a>). Long-term potentiation was decreased in the Fmr1-null cells. Wildtype Fmrp was found to interact with Grk2 (<a href="/entry/109635">109635</a>). In Fmr1-null cells, exogenous expression of FMRP or inhibition of Grk2 rescued the deficits. A D1 receptor agonist partially rescued hyperactivity and enhanced the motor function of Fmr1-null mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18760699" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Callan, M. A., Cabernard, C., Heck, J., Luois, S., Doe, C. Q., Zarnescu, D. C. <strong>Fragile X protein controls neural stem cell proliferation in the Drosophila brain.</strong> Hum. Molec. Genet. 19: 3068-3079, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20504994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20504994</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20504994[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq213" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20504994">Callan et al. (2010)</a> compared Drosophila mutant Fmr1 brains to wildtype throughout larval development using cell cycle markers. Loss of Fmr1 led to significant increase in BrdU incorporation, and in the number of mitotic neuroblasts in the brain; this is consistent with FMRP controlling proliferation during neurogenesis. In developmental studies, FMRP inhibited neuroblast exit from quiescence in early larval brains, as indicated by misexpression of cyclin E (CCNE1; <a href="/entry/123837">123837</a>). By the third instar larval stage, the length of the cell cycle was unaffected, although more cells were found in S and G2/M in mutant Fmr1 brains compared with wildtype, indicating defective cell cycle progression. In addition, single mutant Fmr1 neuroblasts generated significantly more neurons than controls in the developing larval brain. The authors concluded that FMRP is required during brain development to control neuroblast exit from quiescence and proliferative capacity, as well as neuron production. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20504994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Animal Models of Fragile X Syndrome</em></strong></p><p>
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The <a href="#34" class="mim-tip-reference" title="Dutch-Belgian Fragile X Consortium. <strong>Fmr1 knockout mice: a model to study fragile X mental retardation.</strong> Cell 78: 23-33, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8033209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8033209</a>]" pmid="8033209">Dutch-Belgian Fragile X Consortium (1994)</a> created a knockout model for the fragile X syndrome in mice. The knockout mice lacked normal FMR1 protein and showed macroorchidism, learning deficits, and hyperactivity. Although brain MRI of fragile X patients has revealed abnormalities in the size of specific brain structures, including the cerebellar vermis, the hippocampus, and the ventricular system, <a href="#72" class="mim-tip-reference" title="Kooy, R. F., Reyniers, E., Verhoye, M., Sijbers, J., Bakker, C. E., Oostra, B. A., Willems, P. J., Van Der Linden, A. <strong>Neuroanatomy of the fragile X knockout mouse brain studied using in vivo high resolution magnetic resonance imaging.</strong> Europ. J. Hum. Genet. 7: 526-532, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10439957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10439957</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200348" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10439957">Kooy et al. (1999)</a> did not find evidence for size alterations in various brain regions of the fragile X mouse model. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10439957+8033209" 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="#108" class="mim-tip-reference" title="Peier, A. M., McIlwain, K. L., Kenneson, A., Warren, S. T., Paylor, R., Nelson, D. L. <strong>(Over)correction of FMR1 deficiency with YAC transgenics: behavioral and physical features.</strong> Hum. Molec. Genet. 9: 1145-1159, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10767339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10767339</a>] [<a href="https://doi.org/10.1093/hmg/9.8.1145" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10767339">Peier et al. (2000)</a> generated yeast artificial chromosome (YAC) transgenic mice to determine whether the Fmr1 knockout mouse phenotype could be rescued. The YAC transgene supported production of the human FMRP protein at levels 10 to 15 times that of endogenous protein; the protein was expressed in a cell- and tissue-specific manner. Macroorchidism was absent in knockout mice carrying the YAC transgene, indicating functional rescue by the human protein. While the knockout mice displayed reduced anxiety-related responses and increased exploratory behavior, the FMR1 YAC transgenic mice displayed opposing behavioral responses and other abnormal behaviors, presumably due to overexpression of FMRP. The authors suggested that overexpression of FMRP may harbor its own behavioral phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10767339" 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>Protein synthesis occurs in neuronal dendrites, often near synapses. Polyribosomal aggregates often appear in dendritic spines, particularly during development. Some protein synthesis appears to be regulated directly by synaptic activity. <a href="#45" class="mim-tip-reference" title="Greenough, W. T., Klintsova, A. Y., Irwin, S. A., Galvez, R., Bates, K. E., Weiler, I. J. <strong>Synaptic regulation of protein synthesis and the fragile X protein.</strong> Proc. Nat. Acad. Sci. 98: 7101-7106, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11416194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11416194</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11416194[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.141145998" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11416194">Greenough et al. (2001)</a> found that FMRP is one of the proteins that is synthesized in a preparation called synaptoneurosomes when stimulated with glutamate or group I metabotropic glutamate receptor agonists (e.g., <a href="/entry/604473">604473</a>). They also found that agonist-activated protein synthesis in synaptoneurosomes was dramatically reduced in a knockout mouse model of fragile X syndrome. Studies of autopsy samples from patients with fragile X syndrome indicated that dendritic spines may fail to assume a normal mature size and shape and that there are more spines per unit of dendrite length in the patient samples. Similar findings on spine size and shape had come from studies of the knockout mouse. Normal dendritic regression was also impaired in the knockout mouse. These findings suggested that FMRP may be required for the normal processes of maturation and elimination to occur in cerebral cortical development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11416194" 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="#161" class="mim-tip-reference" title="Zhang, Y. Q., Bailey, A. M., Matthies, H. J. G., Renden, R. B., Smith, M. A., Speese, S. D., Rubin, G. M., Broadie, K. <strong>Drosophila fragile X-related gene regulates the MAP1B homolog Futsch to control synaptic structure and function.</strong> Cell 107: 591-603, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11733059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11733059</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00589-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11733059">Zhang et al. (2001)</a> developed a Drosophila model of fragile X syndrome using loss-of-function mutants and overexpression of the FMR1 homolog, Dfxr (Drosophila fragile X-related gene). Dfxr nulls displayed enlarged synaptic terminals, whereas neuronal overexpression resulted in fewer and larger synaptic boutons. Synaptic structural defects were accompanied by altered neurotransmission, with synapse type-specific regulation in central and peripheral synapses. These phenotypes mimicked those observed in mutants of Futsch, a microtubule-associated protein with homology to mammalian MAP1B (<a href="/entry/157129">157129</a>). Immunoprecipitation of Dfxr showed association with Futsch mRNA, and Western blot analyses demonstrated that Dfxr inversely regulates Futsch expression. Dfxr-Futsch double mutants restored normal synaptic structure and function. <a href="#161" class="mim-tip-reference" title="Zhang, Y. Q., Bailey, A. M., Matthies, H. J. G., Renden, R. B., Smith, M. A., Speese, S. D., Rubin, G. M., Broadie, K. <strong>Drosophila fragile X-related gene regulates the MAP1B homolog Futsch to control synaptic structure and function.</strong> Cell 107: 591-603, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11733059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11733059</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00589-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11733059">Zhang et al. (2001)</a> proposed that Dfxr acts as a translational repressor of Futsch to regulate microtubule-dependent synaptic growth and function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11733059" 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 wildtype Drosophila and Drosophila mutant in Dfxr, <a href="#97" class="mim-tip-reference" title="Morales, J., Hiesinger, P. R., Schroeder, A. J., Kume, K., Verstreken, P., Jackson, F. R., Nelson, D. L., Hassan, B. A. <strong>Drosophila fragile X protein, DFXR, regulates neuronal morphology and function in the brain.</strong> Neuron 34: 961-972, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12086643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12086643</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00731-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12086643">Morales et al. (2002)</a> showed that the Dfxr protein is constitutively expressed in brain neuronal cell bodies and excluded from glia. The protein was found to be required for normal neurite extension, guidance, and branching, although different neuronal cell types appeared to be regulated differently, indicating diverse targets in the brain. Overexpression of the protein resulted in similar abnormalities, suggesting that the dose of Dfxr is strictly regulated and critical for normal function. Dfxr mutants exhibited abnormal circadian behavior and eclosion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12086643" 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="#59" class="mim-tip-reference" title="Irwin, S. A., Idupulapati, M., Gilberg, M. E., Harris, J. B., Chakravarti, A. B., Rogers, E. J., Crisostomo, R. A., Larsen, B. P., Mehta, A., Alcantara, C. J., Patel, B., Swain, R. A., Weiler, I. J., Oostra, B. A., Greenough, W. T. <strong>Dendritic spine and dendritic field characteristics of layer V pyramidal neurons in the visual cortex of fragile-X knockout mice.</strong> Am. J. Med. Genet. 111: 140-146, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12210340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12210340</a>] [<a href="https://doi.org/10.1002/ajmg.10500" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12210340">Irwin et al. (2002)</a> compared the dendritic spines on layer V pyramidal cells of visual cortices of wildtype and fragile-X knockout mice. The knockout mice had significantly more long dendritic spines, significantly fewer short dendritic spines, significantly more dendritic spines with an immature-like morphology, and significantly fewer dendritic spines with a more mature morphology. However, unlike the human patients, the knockout mice did not exhibit statistically significant dendritic spine density differences from controls. Fragile-X mice also did not demonstrate any significant differences from controls in dendritic tree complexity or dendritic arbor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12210340" 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 behavioral studies of Fmr1 knockout mice, <a href="#114" class="mim-tip-reference" title="Qin, M., Kang, J., Smith, C. B. <strong>Increased rates of cerebral glucose metabolism in a mouse model of fragile X mental retardation.</strong> Proc. Nat. Acad. Sci. 99: 15758-15763, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12427968/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12427968</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12427968[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.242377399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12427968">Qin et al. (2002)</a> observed hyperactivity and a higher rate of entrance into the center of an open field compared with controls, suggesting decreased levels of anxiety. Impaired performance of the knockout mice on a passive avoidance task suggested a deficit in learning and memory. To learn what brain regions are involved in the behavioral abnormalities of fragile X mental retardation, <a href="#114" class="mim-tip-reference" title="Qin, M., Kang, J., Smith, C. B. <strong>Increased rates of cerebral glucose metabolism in a mouse model of fragile X mental retardation.</strong> Proc. Nat. Acad. Sci. 99: 15758-15763, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12427968/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12427968</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12427968[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.242377399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12427968">Qin et al. (2002)</a> applied the carbon-labeled deoxyglucose method for determining regional cerebral metabolic rates of glucose. They found higher values in all 38 regions tested, as compared to control wildtype littermates; in 26 of the regions, differences were statistically significant. The greatest increases occurred in regions of the limbic system and primary sensory and posterior parietal cortical areas. The regions most affected were consistent with behavioral deficiencies and regions in which Fmrp expression is highest. <a href="#114" class="mim-tip-reference" title="Qin, M., Kang, J., Smith, C. B. <strong>Increased rates of cerebral glucose metabolism in a mouse model of fragile X mental retardation.</strong> Proc. Nat. Acad. Sci. 99: 15758-15763, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12427968/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12427968</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12427968[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.242377399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12427968">Qin et al. (2002)</a> suggested that the higher cerebral glucose metabolism in fragile X mice may be a function of abnormalities found in dendritic spines. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12427968" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#95" class="mim-tip-reference" title="Miyashiro, K. Y., Beckel-Mitchener, A., Purk, T. P., Becker, K. G., Barret, T., Liu, L., Carbonetto, S., Weiler, I. J., Greenough, W. T., Eberwine, J. <strong>RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null mice.</strong> Neuron 37: 417-431, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12575950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12575950</a>] [<a href="https://doi.org/10.1016/s0896-6273(03)00034-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12575950">Miyashiro et al. (2003)</a> determined that the RNA cargoes associated with Fmr1-mRNP complexes were altered in Fmr1 null mice. Some of these cargoes, as well as the proteins encoded by them, showed discrete changes in their abundance and/or subcellular distribution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12575950" 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="#152" class="mim-tip-reference" title="Weiler, I. J., Spangler, C. C., Klintsova, A. Y., Grossman, A. W., Kim, S. H., Bertaina-Anglade, V., Khaliq, H., de Vries, F. E., Lambers, F. A. E., Hatia, F., Base, C. K., Greenough, W. T. <strong>Fragile X mental retardation protein is necessary for neurotransmitter-activated protein translation at synapses.</strong> Proc. Nat. Acad. Sci. 101: 17504-17509, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15548614/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15548614</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15548614[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.0407533101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15548614">Weiler et al. (2004)</a> studied neurotransmitter-activated synaptic protein synthesis in Fmr1 knockout mice. Synaptoneurosomes from knockout mice did not manifest accelerated polyribosome assembly or protein synthesis as it occurs in wildtype mice upon stimulation of group I metabotropic glutamate receptors. Direct activation of protein kinase C (see <a href="/entry/176960">176960</a>) did not compensate in the knockout mice, indicating that the FMRP-dependent step is further along the signaling pathway. Visual cortices of young knockout mice exhibited a lower proportion of dendritic spine synapses containing polyribosomes than did the cortices of wildtype mice, corroborating this finding in vivo. This deficit in rapid neurotransmitter-controlled local translation of specific proteins may contribute to the morphologic and functional abnormalities observed in patients with fragile X syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15548614" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#117" class="mim-tip-reference" title="Restivo, L., Ferrari, F., Passino, E., Sgobio, C., Bock, J., Oostra, B. A., Bagni, C., Ammassari-Teule, M. <strong>Enriched environment promotes behavioral and morphological recovery in a mouse model for the fragile X syndrome.</strong> Proc. Nat. Acad. Sci. 102: 11557-11562, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16076950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16076950</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16076950[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.0504984102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16076950">Restivo et al. (2005)</a> reared Fmr1-null mice in an enriched environment and found that experience-dependent stimulation alleviated many behavioral and neuronal abnormalities associated with Fmr1 knockout. Enrichment did not affect hyperactivity of Fmr1-null mice, but it reduced the anxiety-like pattern of open field exploration to normal and restored habituation to objects. Enrichment increased basal dendrite length and branching and increased spine density along apical dendrites of layer 5 pyramidal neurons of the visual cortex in both knockout and wildtype mice, and it rescued the immature spine morphology in Fmr1-null mice. Rescue of the behavioral and neuronal defects was dependent on Glur1 (GRIA1; <a href="/entry/138248">138248</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16076950" 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>Neuronal dense granules transport mRNAs into dendrites for subsequent site-specific utilization at synapses. Some dense granules contain aggregates of translationally silent polysomes. During active protein synthesis, the structure of the granule relaxes into lighter translating polysomes. <a href="#5" class="mim-tip-reference" title="Aschrafi, A., Cunningham, B. A., Edelman, G. M., Vanderklish, P. W. <strong>The fragile X mental retardation protein and group I metabotropic glutamate receptors regulate levels of mRNA granules in brain.</strong> Proc. Nat. Acad. Sci. 102: 2180-2185, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15684045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15684045</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15684045[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.0409803102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15684045">Aschrafi et al. (2005)</a> found that Fmr1-knockout mouse brains showed a lower amount of dense granules than wildtype mouse brains. The Fmr1-knockout mice also showed elevated metabotropic GluR5 (GRM5; <a href="/entry/604102">604102</a>)-induced translation. Injection of a Grm5-specific inhibitor increased the dense granule peak in both wildtype and Fmr1-knockout mouse brains and blocked Grm5-induced activity in hippocampal slices. <a href="#5" class="mim-tip-reference" title="Aschrafi, A., Cunningham, B. A., Edelman, G. M., Vanderklish, P. W. <strong>The fragile X mental retardation protein and group I metabotropic glutamate receptors regulate levels of mRNA granules in brain.</strong> Proc. Nat. Acad. Sci. 102: 2180-2185, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15684045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15684045</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15684045[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.0409803102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15684045">Aschrafi et al. (2005)</a> concluded that GRM5-induced translation from neuronal granules occurs at a higher rate in the absence of FMR1. The results supported the hypothesis that elevated GRM5-dependent translation leads to changes in synaptic plasticity and fragile X symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15684045" 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="#100" class="mim-tip-reference" title="Nakamoto, M., Nalavadi, V., Epstein, M. P., Narayanan, U., Bassell, G. J., Warren, S. T. <strong>Fragile X mental retardation protein deficiency leads to excessive mGluR5-dependent internalization of AMPA receptors.</strong> Proc. Nat. Acad. Sci. 104: 15537-15542, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17881561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17881561</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17881561[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.0707484104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17881561">Nakamoto et al. (2007)</a> found that siRNA-mediated reduction of Fmrp in primary rat hippocampal cells resulted in internalization of the GluR1 (GRIA1; <a href="/entry/138248">138248</a>) AMPA receptor in dendrites. Aberrant GluR1 trafficking was rescued by pharmacologic inhibition of mGluR5. Since Fmrp acts as a negative regulator of translation at synapses and is thus a 'counterbalancing' signal, the findings suggested that the absence of Fmrp leads to an apparent excess of mGluR5 signaling in dendrites. The resultant hypersensitive AMPA receptor internalization reflects a cellular trafficking defect as well as a defect in synaptic plasticity, which may underlie the defects in learning and memory associated with mutations in the FMRP gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17881561" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Castren, M., Tervonen, T., Karkkainen, V., Heinonen, S., Castren, E., Larsson, K., Bakker, C. E., Oostra, B. A., Akerman, K. <strong>Altered differentiation of neural stem cells in fragile X chromosome.</strong> Proc. Nat. Acad. Sci. 102: 17834-17839, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16314562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16314562</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16314562[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.0508995102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16314562">Castren et al. (2005)</a> investigated the differentiation of neural stem cells generated from brains of Fmr1-knockout mice and from postmortem tissue of a fragile X fetus. Mouse and human FMRP-deficient neurospheres generated more tubulin beta-3 (TUBB3; <a href="/entry/602661">602661</a>)-positive cells than control neurospheres, and the number of GFAP (<a href="/entry/137780">137780</a>)-positive cells was reduced due to increased apoptotic cell death. Differentiation of fragile X neurospheres was abnormal, with fewer and shorter neurites and a smaller cell body volume. Differentiated FMRP-deficient cells showed an abnormal intense oscillatory Ca(2+) response to acetylcholine. <a href="#18" class="mim-tip-reference" title="Castren, M., Tervonen, T., Karkkainen, V., Heinonen, S., Castren, E., Larsson, K., Bakker, C. E., Oostra, B. A., Akerman, K. <strong>Altered differentiation of neural stem cells in fragile X chromosome.</strong> Proc. Nat. Acad. Sci. 102: 17834-17839, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16314562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16314562</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16314562[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.0508995102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16314562">Castren et al. (2005)</a> concluded that FMRP deficiency in fragile X syndrome causes substantial alterations in early maturation of neural stem cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16314562" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#71" class="mim-tip-reference" title="Koekkoek, S. K. E., Yamaguchi, K., Milojkovic, B. A., Dortland, B. R., Ruigrok, T. J. H., Maex, R., De Graaf, W., Smit, A. E., VanderWerf, F., Bakker, C. E., Willemsen, R., Ikeda, T., Kakizawa, S., Onodera, K., Nelson, D. L., Mientjes, E., Joosten, M., De Schutter, E., Oostra, B. A., Ito, M., De Zeeuw, C. I. <strong>Deletion of FMR1 in purkinje cells enhances parallel fiber LTD, enlarges spines, and attenuates cerebellar eyelid conditioning in fragile X syndrome.</strong> Neuron 47: 339-352, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16055059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16055059</a>] [<a href="https://doi.org/10.1016/j.neuron.2005.07.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16055059">Koekkoek et al. (2005)</a> found that Fmr1-null mice had deficits in classic delay eyeblink conditioning. Fmr1-null mouse cerebellar Purkinje cells showed elongated irregular dendritic spines and enhanced long-term depression induction at the parallel fiber synapses that innervate these spines. Patients with fragile X syndrome showed the same cerebellar deficits in eyeblink conditioning. The findings indicated that a lack of FMRP leads to cerebellar dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16055059" 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="#96" class="mim-tip-reference" title="Monzo, K., Papoulas, O., Cantin, G. T., Wang, Y., Yates, J. R., III, Sisson, J. C. <strong>Fragile X mental retardation protein controls trailer hitch expression and cleavage furrow formation in Drosophila embryos.</strong> Proc. Nat. Acad. Sci. 103: 18160-18165, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17110444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17110444</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17110444[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.0606508103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17110444">Monzo et al. (2006)</a> reported that Fmr1-null male Drosophila were sterile. Fmr1-null females produced morphologically normal eggs when crossed with wildtype males, but few of the embryos hatched. <a href="#96" class="mim-tip-reference" title="Monzo, K., Papoulas, O., Cantin, G. T., Wang, Y., Yates, J. R., III, Sisson, J. C. <strong>Fragile X mental retardation protein controls trailer hitch expression and cleavage furrow formation in Drosophila embryos.</strong> Proc. Nat. Acad. Sci. 103: 18160-18165, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17110444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17110444</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17110444[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.0606508103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17110444">Monzo et al. (2006)</a> determined that Fmr1 was required for cleavage furrow formation, and that Fmr1 functioned within dynamic cytoplasmic ribonucleoprotein bodies during the midblastula transition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17110444" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#93" class="mim-tip-reference" title="Meredith, R. M., Holmgren, C. D., Weidum, M., Burnashev, N., Mansvelder, H. D. <strong>Increased threshold for spike-timing-dependent plasticity is caused by unreliable calcium signaling in mice lacking fragile X gene FMR1.</strong> Neuron 54: 627-638, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17521574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17521574</a>] [<a href="https://doi.org/10.1016/j.neuron.2007.04.028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17521574">Meredith et al. (2007)</a> found an increased threshold for spike-timing-dependent long-term potentiation in the prefrontal cortex of Fmr1-null mice. The changes resulted from a defect in postsynaptic calcium signaling in dendrites and spines; in fact, there was absent activity of L-type calcium channels in dendritic spines. Long-term potentiation in these mice could be restored by increasing neuronal activity, which improved the reliability and amplitude of calcium signaling. Fmr1-null mice raised in enriched environments with enhanced sensory, cognitive, and motor stimulation, showed normalization of long-term potentiation back to wildtype levels. The results indicated that mechanisms for synaptic plasticity are in place in the absence of Fmr1, but require stronger neuronal activity to be triggered. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17521574" 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="#159" class="mim-tip-reference" title="Zhang, J., Fang, Z., Jud, C., Vansteensel, M. J., Kaasik, K., Lee, C. C., Albrecht, U., Tamanini, F., Meijer, J. H., Oostra, B. A., Nelson, D. L. <strong>Fragile X-related proteins regulate mammalian circadian behavioral rhythms.</strong> Am. J. Hum. Genet. 83: 43-52, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18589395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18589395</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18589395[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.06.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18589395">Zhang et al. (2008)</a> found that Fmr1/Fxr2 double-knockout mice and Fmr1-knockout/Fxr2-heterozygous mice exhibited a loss of rhythmic activity in a light-dark cycle, and that Fmr1- or Fxr2-knockout mice displayed a shorter free running period of locomotor activity in total darkness. Molecular analysis and in vitro electrophysiologic studies suggested essentially normal function of cells in the suprachiasmatic nucleus in Fmr1/Fxr2 double-knockout mice. However, the cyclical patterns of abundance of several core clock mRNAs were altered in the livers of double-knockout mice. Fxr2 alone or Fmr1 and Fxr2 together enhanced Per1 (<a href="/entry/602260">602260</a>)- or Per2 (<a href="/entry/603426">603426</a>)-mediated Bmal1 (ARNTL; <a href="/entry/602550">602550</a>)-Npas2 (<a href="/entry/603347">603347</a>) transcriptional activity in a dose-dependent manner. <a href="#159" class="mim-tip-reference" title="Zhang, J., Fang, Z., Jud, C., Vansteensel, M. J., Kaasik, K., Lee, C. C., Albrecht, U., Tamanini, F., Meijer, J. H., Oostra, B. A., Nelson, D. L. <strong>Fragile X-related proteins regulate mammalian circadian behavioral rhythms.</strong> Am. J. Hum. Genet. 83: 43-52, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18589395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18589395</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18589395[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.06.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18589395">Zhang et al. (2008)</a> concluded that FMR1 and FXR2 are required for rhythmic circadian behavior. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18589395" 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 mouse hippocampal slices, <a href="#58" class="mim-tip-reference" title="Hou, L., Antion, M. D., Hu, D., Spencer, C. M., Paylor, R., Klann, E. <strong>Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent long-term depression.</strong> Neuron 51: 441-454, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16908410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16908410</a>] [<a href="https://doi.org/10.1016/j.neuron.2006.07.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16908410">Hou et al. (2006)</a> found that GRM5 agonists caused rapid protein synthesis of FMRP followed by rapid degradation of FMRP in neuronal soma, nuclei, and proximal dendrites during long-term depression. FMRP degradation was mediated by the ubiquitin-proteasomal pathway. The lack of GRM5-dependent FMRP synthesis in Fmrp-null mice contributed to enhanced long-term depression. Absence of Fmrp also resulted in increased translation of other proteins, such as MAP1B (<a href="/entry/157129">157129</a>), indicating that FMRP normally acts as a translational repressor. These findings indicated that the translation, ubiquitination, and proteolysis of FMRP functions as a dynamic regulatory system for controlling synaptic plasticity. In addition, <a href="#58" class="mim-tip-reference" title="Hou, L., Antion, M. D., Hu, D., Spencer, C. M., Paylor, R., Klann, E. <strong>Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent long-term depression.</strong> Neuron 51: 441-454, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16908410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16908410</a>] [<a href="https://doi.org/10.1016/j.neuron.2006.07.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16908410">Hou et al. (2006)</a> concluded that disruption of FMRP alters the regulation of proteins affecting basic biochemical signaling mechanisms during synaptic plasticity in the hippocampus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16908410" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Dolen, G., Osterweil, E., Rao, B. S. S., Smith, G. B., Auerbach, B. D., Chattaji, S., Bear, M. F. <strong>Correction of fragile X syndrome in mice.</strong> Neuron 56: 955-962, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18093519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18093519</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18093519[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2007.12.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18093519">Dolen et al. (2007)</a> found that transgenic Fmr1-null mice with a 50% reduction of GRM5 expression showed amelioration of several Fmr1-null-related phenotypes, including experience-dependent synaptic modification (as measured by ocular dominant plasticity), altered dendritic spine density, altered hippocampal basal protein synthesis, inhibitory avoidance behavior, seizures susceptibility, and overall increased somatic growth. All of these features showed some rescue with decreased GRM5 activity. However, macroorchidism was not rescued. The findings were consistent with the hypothesis that the certain aspects of fragile X syndrome result from unchecked activation of the GRM5 receptor. <a href="#33" class="mim-tip-reference" title="Dolen, G., Osterweil, E., Rao, B. S. S., Smith, G. B., Auerbach, B. D., Chattaji, S., Bear, M. F. <strong>Correction of fragile X syndrome in mice.</strong> Neuron 56: 955-962, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18093519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18093519</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18093519[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2007.12.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18093519">Dolen et al. (2007)</a> concluded by suggesting that fragile X syndrome is a disorder of 'excess,' resulting from loss of putative repressor functions of FMRP. Suppression of at least 1 of the downstream effectors, GRM5, may alleviate some of these abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18093519" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#47" class="mim-tip-reference" title="Guo, W., Allan, A. M., Zong, R., Zhang, L., Johnson, E. B., Schaller, E. G., Murthy, A. C., Goggin, S. L., Eisch, A. J., Oostra, B. A., Nelson, D. L., Jin, P., Zhao, X. <strong>Ablation of Fmrp in adult neural stem cells disrupts hippocampus-dependent learning.</strong> Nature Med. 17: 559-565, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21516088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21516088</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21516088[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.2336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21516088">Guo et al. (2011)</a> found that mice with selective deletion of Fmrp from adult neural stem and progenitor cells showed increased production of neural stem cells in the hippocampus compared to controls, but these cells showed poorer survival and decreased differentiation. Mutant mice had decreased dendritic complexity of neurons as well as an increase in astrocyte number and differentiation. These findings were also observed in adult mouse neural stem cells in vitro. Mutant mice showed an impairment in challenging learning tasks, such as the trace conditioning task, that require adult hippocampal neurogenesis. Both the cellular neurogenesis defects and learning deficit could be rescued by conditional restoration of Fmrp. <a href="#47" class="mim-tip-reference" title="Guo, W., Allan, A. M., Zong, R., Zhang, L., Johnson, E. B., Schaller, E. G., Murthy, A. C., Goggin, S. L., Eisch, A. J., Oostra, B. A., Nelson, D. L., Jin, P., Zhao, X. <strong>Ablation of Fmrp in adult neural stem cells disrupts hippocampus-dependent learning.</strong> Nature Med. 17: 559-565, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21516088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21516088</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21516088[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.2336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21516088">Guo et al. (2011)</a> suggested that loss of functional FMRP specifically in adult neural stem cells may contribute to the cognitive defects in patients with fragile X syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21516088" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Animal Models of Fragile X Tremor/Ataxia Syndrome</em></strong></p><p>
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<a href="#153" class="mim-tip-reference" title="Willemsen, R., Hoogeveen-Westerveld, M., Reis, S., Holstege, J., Severijnen, L.-A. W. F. M., Nieuwenhuizen, I. M., Schrier, M., van Unen, L., Tassone, F., Hoogeveen, A. T., Hagerman, P. J., Mientjes, E. J., Oostra, B. A. <strong>The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor/ataxia syndrome.</strong> Hum. Molec. Genet. 12: 949-959, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12700164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12700164</a>] [<a href="https://doi.org/10.1093/hmg/ddg114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12700164">Willemsen et al. (2003)</a> described neurohistologic, biochemical, and molecular studies of the brains of transgenic mice with an expanded CGG repeat (102 to 110 repeats) in human FMR1, and reported elevated Fmr1 mRNA levels and intranuclear inclusions with ubiquitin, Hsp40 (see <a href="/entry/604572">604572</a>), and the 20S catalytic core complex of the proteasome as constituents. An increase was observed in both the number and the size of the inclusions during the course of life, which correlated with the progressive character of the cerebellar tremor/ataxia syndrome in humans. <a href="#153" class="mim-tip-reference" title="Willemsen, R., Hoogeveen-Westerveld, M., Reis, S., Holstege, J., Severijnen, L.-A. W. F. M., Nieuwenhuizen, I. M., Schrier, M., van Unen, L., Tassone, F., Hoogeveen, A. T., Hagerman, P. J., Mientjes, E. J., Oostra, B. A. <strong>The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor/ataxia syndrome.</strong> Hum. Molec. Genet. 12: 949-959, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12700164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12700164</a>] [<a href="https://doi.org/10.1093/hmg/ddg114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12700164">Willemsen et al. (2003)</a> concluded that the observations in expanded-repeat mice supported a direct role of the Fmr1 gene, by either CGG expansion per se or by mRNA level, in the formation of the inclusions and suggested a correlation between the presence of intranuclear inclusions in distinct regions of the brain and the clinical features in symptomatic premutation carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12700164" 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="#64" class="mim-tip-reference" title="Jin, P., Zarnescu, D. C., Zhang, F., Pearson, C. E., Lucchesi, J. C., Moses, K., Warren, S. T. <strong>RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in Drosophila.</strong> Neuron 39: 739-747, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12948442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12948442</a>] [<a href="https://doi.org/10.1016/s0896-6273(03)00533-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12948442">Jin et al. (2003)</a> expressed a human FMR1 premutation allele of 90 CGG repeats in Drosophila in a heterologous transcript (EGFP). The expanded RNA alone induced neuron-specific degeneration, as observed in retinal cells, characterized by Hsp70 (see <a href="/entry/140550">140550</a>)- and ubiquitin-positive inclusion bodies similar to those seen in patients with FXTAS. The findings suggested a role for a toxic RNA-mediated gain-of-function in FXTAS. <a href="#50" class="mim-tip-reference" title="Handa, V., Goldwater, D., Stiles, D., Cam, M., Poy, G., Kumari, D., Usdin, K. <strong>Long CGG-repeat tracts are toxic to human cells: implications for carriers of fragile X premutation alleles.</strong> FEBS Lett. 579: 2702-2708, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15862312/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15862312</a>] [<a href="https://doi.org/10.1016/j.febslet.2005.04.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15862312">Handa et al. (2005)</a> found that transcribed but untranslated expanded CGG premutation alleles were toxic to human cells, and microarray analysis detected altered expression of a wide variety of genes, including upregulation of CASP8 (<a href="/entry/601763">601763</a>), CYFIP1 (<a href="/entry/606322">606322</a>), NTS (<a href="/entry/162650">162650</a>), and UBE3A (<a href="/entry/601623">601623</a>), which was confirmed by RT-PCR analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15862312+12948442" 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="#53" class="mim-tip-reference" title="Hashem, V., Galloway, J. N., Mori, M., Willemsen, R., Oostra, B. A., Paylor, R., Nelson, D. L. <strong>Ectopic expression of CGG containing mRNA is neurotoxic in mammals.</strong> Hum. Molec. Genet. 18: 2443-2451, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19377084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19377084</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19377084[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp182" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19377084">Hashem et al. (2009)</a> generated mice expressing the human 90 CGG premutation in the context of the mouse Fmr1 5-prime UTR or the EGFP (enhanced green fluorescent protein) 5-prime UTR, specifically in Purkinje neurons, in order to segregate the effects of CGG repeat from alterations in Fmr1 and to provide evidence that CGG repeat is necessary and sufficient to cause pathology similar to human FXTAS. CGG(90)-EGFP was sufficient to produce ubiquitin-positive intranuclear inclusion formation. They also demonstrated CGG(90)-EGFP overexpression resulted in Purkinje neuron axonal swellings and neurotoxicity and in a mouse phenotype showing progressive age-dependent decline in neuromotor learning ability. <a href="#53" class="mim-tip-reference" title="Hashem, V., Galloway, J. N., Mori, M., Willemsen, R., Oostra, B. A., Paylor, R., Nelson, D. L. <strong>Ectopic expression of CGG containing mRNA is neurotoxic in mammals.</strong> Hum. Molec. Genet. 18: 2443-2451, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19377084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19377084</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19377084[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp182" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19377084">Hashem et al. (2009)</a> concluded that CGG expressed in Purkinje neurons outside the context of Fmr1 mRNA may result in neuronal pathology in a mammalian system, and that expanded CGG repeats in RNA are the likely cause of the neurodegeneration in FXTAS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19377084" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Chen, Y., Tassone, F., Berman, R. F., Hagerman, P. J., Hagerman, R. J., Willemsen, R., Pessah, I. N. <strong>Murine hippocampal neurons expressing Fmr1 gene premutations show early developmental deficits and late degeneration.</strong> Hum. Molec. Genet. 19: 196-208, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19846466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19846466</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19846466[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp479" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19846466">Chen et al. (2010)</a> reported that neurons cultured from heterozygous female mice with preCGG FMR1 repeats displayed shorter dendritic lengths and fewer branches between 7 to 21 days in vitro compared with cultured neurons from wildtype littermates. Although the numbers of synapsin and phalloidin puncta did not differ from wildtype, preCGG neurons possessed larger puncta. PreCGG neurons displayed lower viability, and expressed elevated stress protein as they matured. PreCGG neurons had inherently different patterns of growth, dendritic complexity, and synaptic architecture discernible early in the neuronal trajectory to maturation. <a href="#21" class="mim-tip-reference" title="Chen, Y., Tassone, F., Berman, R. F., Hagerman, P. J., Hagerman, R. J., Willemsen, R., Pessah, I. N. <strong>Murine hippocampal neurons expressing Fmr1 gene premutations show early developmental deficits and late degeneration.</strong> Hum. Molec. Genet. 19: 196-208, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19846466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19846466</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19846466[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp479" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19846466">Chen et al. (2010)</a> suggested that this may reflect a cellular basis for the developmental component of the spectrum of clinical involvement in carriers of premutation alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19846466" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By measuring cAMP levels in a single neuron, <a href="#89" class="mim-tip-reference" title="Maurin, T., Melancia, F., Jarjat, M., Castro, L., Costa, L., Delhaye, S., Khayachi, A., Castagnola, S., Mota, E., Di Giorgio, A., Servadio, M., Drozd, M., and 9 others. <strong>Involvement of phosphodiesterase 2A activity in the pathophysiology of fragile X syndrome.</strong> Cereb. Cortex 29: 3241-3252, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30137253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30137253</a>] [<a href="https://doi.org/10.1093/cercor/bhy192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30137253">Maurin et al. (2019)</a> showed that Pde2a (<a href="/entry/602658">602658</a>) dysregulation was involved in physiopathology of Fmr1-KO mice, a model of FXS. Fmr1-KO brain had increased Pde2a enzymatic activity, resulting in decreased levels of cAMP and cGMP. Blocking Pde2a rescued exaggerated long-term depression induced by activation of hippocampal metabotropic group I glutamate receptor in Fmr1-KO brain and abnormal immature dendritic spines in cultured Fmr1-KO cortical neurons, both of which are hallmarks of FXS in Fmr1-KO mice. Furthermore, inhibition of Pde2a activity rescued abnormal behavior in Fmr1-KO mice, as well as communication deficit in both Fmr1-KO mice and rats. The authors proposed that PDE2A may be a therapeutic target to treat FXS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30137253" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<p>This mutation in the FMR1 gene results in an ile304-to-asn (I304N) substitution (<a href="#124" class="mim-tip-reference" title="Siomi, H., Choi, M., Siomi, M. C., Nussbaum, R. L., Dreyfuss, G. <strong>Essential role for KH domains in RNA binding: impaired RNA binding by a mutation in the KH domain of FMR1 that causes fragile X syndrome.</strong> Cell 77: 33-39, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8156595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8156595</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90232-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8156595">Siomi et al., 1994</a>), although it was originally reported as I367N (<a href="#29" class="mim-tip-reference" title="De Boulle, K., Verkerk, A. J. M. H., Reyniers, E., Vits, L., Hendrickx, J., Van Roy, B., Van Den Bos, F., de Graaff, E., Oostra, B. A., Willems, P. J. <strong>A point mutation in the FMR-1 gene associated with fragile X mental retardation.</strong> Nature Genet. 3: 31-35, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8490650/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8490650</a>] [<a href="https://doi.org/10.1038/ng0193-31" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8490650">De Boulle et al., 1993</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8490650+8156595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="De Boulle, K., Verkerk, A. J. M. H., Reyniers, E., Vits, L., Hendrickx, J., Van Roy, B., Van Den Bos, F., de Graaff, E., Oostra, B. A., Willems, P. J. <strong>A point mutation in the FMR-1 gene associated with fragile X mental retardation.</strong> Nature Genet. 3: 31-35, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8490650/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8490650</a>] [<a href="https://doi.org/10.1038/ng0193-31" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8490650">De Boulle et al. (1993)</a> identified a T-to-A transversion in the FMR1 gene in a patient with a severe form of fragile X mental retardation (FXS; <a href="/entry/300624">300624</a>). The mutation was not found in the mother, brother, or nephews who had normal intellectual abilities and no stigmata of fragile X syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8490650" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#141" class="mim-tip-reference" title="Verheij, C., de Graaff, E., Bakker, C. E., Willemsen, R., Willems, P. J., Meijer, N., Galjaard, H., Reuser, A. J. J., Oostra, B. A., Hoogeveen, A. T. <strong>Characterization of FMR1 proteins isolated from different tissues.</strong> Hum. Molec. Genet. 4: 895-901, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7633450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7633450</a>] [<a href="https://doi.org/10.1093/hmg/4.5.895" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7633450">Verheij et al. (1995)</a> demonstrated that the ile367-to-asn substitution in the FMR1 protein did not alter the translation, processing, or localization of FMR1 proteins in lymphoblastoid cells from a patient carrying this mutation. All the high molecular mass FMR1 proteins isolated from normal lymphoblastoid cells and cells from the patient with this substitution were able to bind RNA. However, the FMR1 proteins of the patient had reduced affinity for RNA binding at high salt concentrations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7633450" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#38" class="mim-tip-reference" title="Feng, Y., Absher, D., Eberhart, D. E., Brown, V., Malter, H. E., Warren, S. T. <strong>FMRP associates with polyribosomes as an mRNP, and the I304N mutation of severe fragile X syndrome abolishes this association.</strong> Molec. Cell 1: 109-118, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9659908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9659908</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80012-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9659908">Feng et al. (1997)</a> demonstrated that normal FMRP associates with elongating polyribosomes via large mRNP particles. Despite normal expression and cytoplasmic mRNA association, the I304N FMRP was incorporated into abnormal mRNP particles that were not associated with polyribosomes. These data indicated that association of FMRP with polyribosomes must be functionally important and implied that the mechanism of the severe phenotype in the I304N patient lies in the sequestration of bound mRNAs in nontranslatable mRNP particles. In the absence of FMRP, these same mRNAs may be partially translated via alternate mRNPs, although perhaps abnormally localized or regulated, resulting in typical fragile X syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9659908" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Darnell, J. C., Fraser, C. E., Mostovetsky, O., Stefani, G., Jones, T. A., Eddy, S. R., Darnell, R. B. <strong>Kissing complex RNAs mediate interaction between the fragile-X mental retardation protein KH2 domain and brain polyribosomes.</strong> Genes Dev. 19: 903-918, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15805463/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15805463</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15805463[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/10.1101/gad.1276805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15805463">Darnell et al. (2005)</a> noted that the I304N mutation maps to a position within the second KH domain of FMR1 that is critical for stabilizing sequence-specific RNA-protein interactions. They found that the I304N mutation abrogates the association of the FMR1 KH2 domain with its target, kissing complex RNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15805463" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#84" class="mim-tip-reference" title="Linder, B., Plottner, O., Kroiss, M., Hartmann, E., Laggerbauer, B., Meister, G., Keidel, E., Fischer, U. <strong>Tdrd3 is a novel stress granule-associated protein interacting with the fragile-X syndrome protein FMRP.</strong> Hum. Molec. Genet. 17: 3236-3246, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18664458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18664458</a>] [<a href="https://doi.org/10.1093/hmg/ddn219" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18664458">Linder et al. (2008)</a> showed that the I304N substitution markedly reduced FMR1 homooligomerization. The mutation also abrogated the interaction between residual FMR1 oligomers with the stress granule protein TDRD3 (<a href="/entry/614392">614392</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18664458" 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">rs1569545562 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1569545562;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1569545562" 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=rs1569545562" 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=RCV000010649" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010649" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010649</a>
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<p>In a young male patient with fragile X syndrome (FXS; <a href="/entry/300624">300624</a>), <a href="#87" class="mim-tip-reference" title="Lugenbeel, K. A., Peier, A. M., Carson, N. L., Chudley, A. E., Nelson, D. L. <strong>Intragenic loss of function mutations demonstrate the primary role of FMR1 in fragile X syndrome.</strong> Nature Genet. 10: 483-485, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7670500/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7670500</a>] [<a href="https://doi.org/10.1038/ng0895-483" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7670500">Lugenbeel et al. (1995)</a> identified a de novo 1-bp deletion (373delA) in exon 5 of the FMR1 gene, resulting in a frameshift and premature termination of the protein at residue 159. Western blot analysis detected no Fmr1 protein. The finding provided strong evidence that absence of FMRP leads directly to fragile X syndrome and suggested that downregulation of other nearby genes is not likely to contribute to the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7670500" 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 an adult male with classic fragile X syndrome (FXS; <a href="/entry/300624">300624</a>), <a href="#87" class="mim-tip-reference" title="Lugenbeel, K. A., Peier, A. M., Carson, N. L., Chudley, A. E., Nelson, D. L. <strong>Intragenic loss of function mutations demonstrate the primary role of FMR1 in fragile X syndrome.</strong> Nature Genet. 10: 483-485, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7670500/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7670500</a>] [<a href="https://doi.org/10.1038/ng0895-483" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7670500">Lugenbeel et al. (1995)</a> identified a 2-bp change (23714GG-TA) spanning the intron/exon boundary of exon 2 of the FMR1 gene. RT-PCR and sequence analysis demonstrated 2 products of reduced size: a larger product created from splicing out exon 2 and a smaller product created by splicing out exons 2 and 3. Loss of exon 2 resulted in a frameshift and premature termination 4 amino acids into exon 3; loss of exons 2 and 3 removed 49 amino acids of the FMR protein but did not alter the reading frame. Although a protein of reduced size was predicted, no protein was recognized by Western blot. The same mutation was identified in the mother, who was described as mildly retarded. Other members of the family were either noncarriers or not available for study. The finding provided strong evidence that absence of FMRP leads directly to fragile X syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7670500" 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=RCV000010651 OR RCV000010652 OR RCV000010653" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010651, RCV000010652, RCV000010653" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010651...</a>
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<p><a href="#73" class="mim-tip-reference" title="Kremer, E. J., Pritchard, M., Lynch, M., Yu, S., Holman, K., Baker, E., Warren, S. T., Schlessinger, D., Sutherland, G. R., Richards, R. I. <strong>Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n.</strong> Science 252: 1711-1714, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1675488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1675488</a>] [<a href="https://doi.org/10.1126/science.1675488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1675488">Kremer et al. (1991)</a> demonstrated that the presence of an unstable expanded trinucleotide repeat sequence, designated p(CCG)n, in the 5-prime untranslated region of the FMR1 gene is the basis of fragile X syndrome (FXS; <a href="/entry/300624">300624</a>). The authors showed that normal X chromosomes have about 40 +/- 25 copies of p(CCG)n and that within these limits the sequence is a stable DNA polymorphism. The fragile X genotype was characterized by an increased amount of unstable DNA that maps to the repeat. The mutation causing fragile X syndrome contains over 200 CCG repeats (<a href="#30" class="mim-tip-reference" title="Devys, D., Biancalana, V., Rousseau, F., Boue, J., Mandel, J. L., Oberle, I. <strong>Analysis of full fragile X mutations in fetal tissues and monozygotic twins indicate that abnormal methylation and somatic heterogeneity are established early in development.</strong> Am. J. Med. Genet. 43: 208-216, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1605193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1605193</a>] [<a href="https://doi.org/10.1002/ajmg.1320430134" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1605193">Devys et al., 1992</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1605193+1675488" 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>Premutations</p><p>A premutation in the FMR1 gene is defined as an expansion of approximately 55 to 200 CGG repeats. <a href="#49" class="mim-tip-reference" title="Hagerman, R. J., Leehey, M., Heinrichs, W., Tassone, F., Wilson, R., Hills, J., Grigsby, J., Gage, B., Hagerman, P. J. <strong>Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X.</strong> Neurology 57: 127-130, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11445641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11445641</a>] [<a href="https://doi.org/10.1212/wnl.57.1.127" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11445641">Hagerman et al. (2001)</a> reported 5 men with an FMR1 premutation, ranging from 78 to 98 repeats, who presented in the sixth decade with progressive intention tremor, parkinsonism, cognitive decline, generalized atrophy on MRI, and impotence (FXTAS; <a href="/entry/300623">300623</a>). Levels of FMR1 mRNA were 2 to 4 times higher than normal, which the authors suggested resulted in a pathogenic gain-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11445641" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#99" class="mim-tip-reference" title="Murray, A., Webb, J., Grimley, S., Conway, G., Jacobs, P. <strong>Studies of FRAXA and FRAXE in women with premature ovarian failure.</strong> J. Med. Genet. 35: 637-640, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9719368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9719368</a>] [<a href="https://doi.org/10.1136/jmg.35.8.637" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9719368">Murray et al. (1998)</a> screened 147 women with idiopathic premature ovarian failure (POF1; <a href="/entry/311360">311360</a>) and found a significant association with premutations in the FMR1 gene, with 6 women having premutations, including 4 familial and 2 sporadic cases, but no women with full mutations in the FMR1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9719368" 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 an international collaborative study of 760 women from fragile X families, <a href="#2" class="mim-tip-reference" title="Allingham-Hawkins, D. J., Babul-Hirji, R., Chitayat, D., Holden, J. J. A., Yang, K. T., Lee, C., Hudson, R., Gorwill, H., Nolin, S. L., Glicksman, A., Jenkins, E. C., Brown, W. T., and 27 others. <strong>Fragile X premutation is a significant risk factor for premature ovarian failure: the international collaborative POF in fragile X study--preliminary data.</strong> Am. J. Med. Genet. 83: 322-325, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10208170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10208170</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10208170[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="10208170">Allingham-Hawkins et al. (1999)</a> found that 395 carried a premutation, 128 carried a full mutation, and 237 were noncarriers. In 63 (16%) of the premutation carriers, menopause occurred before the age of 40, compared with none of the full-mutation carriers and 1 (0.4%) of the controls, indicating a significant association between premature menopause and premutation carrier status. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10208170" 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 FRAGILE X SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1569545382 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1569545382;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1569545382" 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=rs1569545382" 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=RCV000022880" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022880" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022880</a>
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<p>In a man with classic features of fragile X syndrome (FXS; <a href="/entry/300624">300624</a>), <a href="#46" class="mim-tip-reference" title="Gronskov, K., Brondum-Nielsen, K., Dedic, A., Hjalgrim, H. <strong>A nonsense mutation in FMR1 causing fragile X syndrome.</strong> Europ. J. Hum. Genet. 19: 489-491, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21267007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21267007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21267007[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2010.223" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21267007">Gronskov et al. (2011)</a> identified an 80C-A transversion in exon 2 of the FMR1 gene, resulting in a ser27-to-ter (S27X) substitution. The patient had mental retardation, early-onset seizures, poor language development, and autistic tendencies. Dysmorphic features included an elongated face, high and broad forehead, low-set large ears, prognathia, and enlarged testes. Neurologic examination showed hypotonia and hypermobility, with hyperextensible joints. Western blot analysis of patient lymphoblastoid cells showed no FMRP protein expression. His mother, who also carried the mutation, had mild to moderate intellectual disability, hypermotor behavior, and automatisms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21267007" 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="#Laird1987" class="mim-tip-reference" title="Laird, C. D. <strong>Proposed mechanism of inheritance and expression of the human fragile X syndrome of mental retardation.</strong> Genetics 117: 587-599, 1987.">Laird (1987)</a>; <a href="#Rousseau1991" class="mim-tip-reference" title="Rousseau, F., Vincent, A., Rivella, S., Heitz, D., Triboli, C., Maestrini, E., Warren, S. T., Suthers, G. K., Goodfellow, P., Mandel, J. L., Toniolo, D., Oberle, I. <strong>Four chromosomal breakpoints and four new probes mark out a 10-cM region encompassing the fragile-X locus (FRAXA).</strong> Am. J. Hum. Genet. 48: 108-116, 1991.">Rousseau et al. (1991)</a>
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Abitbol, M., Menini, C., Delezoide, A.-L., Rhyner, T., Vekemans, M., Mallet, J.
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<strong>Nucleus basalis magnocellularis and hippocampus are the major sites of FMR-1 expression in the human fetal brain.</strong>
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Nature Genet. 4: 147-153, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8348153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8348153</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8348153" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng0693-147" target="_blank">Full Text</a>]
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Allingham-Hawkins, D. J., Babul-Hirji, R., Chitayat, D., Holden, J. J. A., Yang, K. T., Lee, C., Hudson, R., Gorwill, H., Nolin, S. L., Glicksman, A., Jenkins, E. C., Brown, W. T., and 27 others.
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<strong>Fragile X premutation is a significant risk factor for premature ovarian failure: the international collaborative POF in fragile X study--preliminary data.</strong>
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Am. J. Med. Genet. 83: 322-325, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10208170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10208170</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10208170[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=10208170" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Alpatov2014" class="mim-anchor"></a>
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Alpatov, R., Lesch, B. J., Nakamoto-Kinoshita, M., Blanco, A., Chen, S., Stutzer, A., Armache, K. J., Simon, M. D., Xu, C., Ali, M., Murn, J., Prisic, S., Kutateladze, T. G., Vakoc, C. R., Min, J., Kingston, R. E., Fischle, W., Warren, S. T., Page, D. C., Shi, Y.
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<strong>A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response.</strong>
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Cell 157: 869-881, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24813610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24813610</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24813610[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=24813610" 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.2014.03.040" target="_blank">Full Text</a>]
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Ascano, M., Jr., Mukherjee, N., Bandaru, P., Miller, J. B., Nusbaum, J. D., Corcoran, D. L., Langlois, C., Munschauer, M., Dewell, S., Hafner, M., Williams, Z., Ohler, U., Tuschl, T.
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<strong>FMRP targets distinct mRNA sequence elements to regulate protein expression.</strong>
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Nature 492: 382-386, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23235829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23235829</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23235829[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=23235829" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature11737" target="_blank">Full Text</a>]
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Aschrafi, A., Cunningham, B. A., Edelman, G. M., Vanderklish, P. W.
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<strong>The fragile X mental retardation protein and group I metabotropic glutamate receptors regulate levels of mRNA granules in brain.</strong>
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Proc. Nat. Acad. Sci. 102: 2180-2185, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15684045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15684045</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15684045[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=15684045" 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.0409803102" target="_blank">Full Text</a>]
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Ashley, C. T., Jr., Wilkinson, K. D., Reines, D., Warren, S. T.
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<strong>FMR1 protein: conserved RNP family domains and selective RNA binding.</strong>
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Science 262: 563-566, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7692601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7692601</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7692601" 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.7692601" target="_blank">Full Text</a>]
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Ashley, C. T., Sutcliffe, J. S., Kunst, C. B., Leiner, H. A., Eichler, E. E., Nelson, D. L., Warren, S. T.
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<strong>Human and murine FMR-1: alternative splicing and translational initiation downstream of the CGG-repeat.</strong>
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Nature Genet. 4: 244-251, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8358432/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8358432</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8358432" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng0793-244" target="_blank">Full Text</a>]
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Auerbach, B. D., Osterweil, E. K., Bear, M. F.
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<strong>Mutations causing syndromic autism define an axis of synaptic pathophysiology.</strong>
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Nature 480: 63-68, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22113615/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22113615</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22113615[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=22113615" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature10658" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/9.19.2909" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1101/gad.1276805" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(01)00566-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddm263" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng0193-31" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320430134" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.devcel.2008.04.003" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.neuron.2007.12.001" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/5.8.1083" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/2.8.1147" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0092-8674(91)90283-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp497" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nm.2336" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/386296" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.57.1.127" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00274007" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0092-8674(94)90232-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0092-8674(93)90420-u" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1128/MCB.16.7.3825" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/5.1.95" target="_blank">Full Text</a>]
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Zarnescu, D. C., Jin, P., Betschinger, J., Nakamoto, M., Wang, Y., Dockendorff, T. C., Feng, Y., Jongens, T. A., Sisson, J. C., Knoblich, J. A., Warren, S. T., Moses, K.
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<strong>Fragile X protein functions with lgl and the PAR complex in flies and mice.</strong>
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Dev. Cell 8: 43-52, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15621528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15621528</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15621528" 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.devcel.2004.10.020" target="_blank">Full Text</a>]
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<a id="Zhang2008" class="mim-anchor"></a>
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Zhang, J., Fang, Z., Jud, C., Vansteensel, M. J., Kaasik, K., Lee, C. C., Albrecht, U., Tamanini, F., Meijer, J. H., Oostra, B. A., Nelson, D. L.
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<strong>Fragile X-related proteins regulate mammalian circadian behavioral rhythms.</strong>
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Am. J. Hum. Genet. 83: 43-52, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18589395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18589395</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18589395[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=18589395" 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.ajhg.2008.06.003" target="_blank">Full Text</a>]
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Zhang, M., Wang, Q., Huang, Y.
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<strong>Fragile X mental retardation protein FMRP and the RNA export factor NXF2 associate with and destabilize Nxf1 mRNA in neuronal cells.</strong>
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Proc. Nat. Acad. Sci. 104: 10057-10062, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17548835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17548835</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17548835[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=17548835" 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.0700169104" target="_blank">Full Text</a>]
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Zhang, Y. Q., Bailey, A. M., Matthies, H. J. G., Renden, R. B., Smith, M. A., Speese, S. D., Rubin, G. M., Broadie, K.
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<strong>Drosophila fragile X-related gene regulates the MAP1B homolog Futsch to control synaptic structure and function.</strong>
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Cell 107: 591-603, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11733059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11733059</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11733059" 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/s0092-8674(01)00589-x" target="_blank">Full Text</a>]
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Zhong, N., Dobkin, C., Brown, W. T.
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<strong>A complex mutable polymorphism located within the fragile X gene.</strong>
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Nature Genet. 5: 248-253, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8275089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8275089</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8275089" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1193-248" target="_blank">Full Text</a>]
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Zuniga, A., Juan, J., Mila, M., Guerrero, A.
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<strong>Expansion of an intermediate allele of the FMR1 gene in only two generations. (Letter)</strong>
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Clin. Genet. 68: 471-473, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16207218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16207218</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16207218" 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/10.1111/j.1399-0004.2005.00514.x" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Bao Lige - updated : 03/05/2021
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Ada Hamosh - updated : 12/23/2019<br>Ada Hamosh - updated : 09/17/2018<br>Patricia A. Hartz - updated : 01/12/2018<br>Marla J. F. O'Neill - updated : 04/17/2017<br>Ada Hamosh - updated : 3/28/2014<br>Ada Hamosh - updated : 1/31/2014<br>Cassandra L. Kniffin - updated : 9/26/2013<br>George E. Tiller - updated : 8/30/2013<br>Ada Hamosh - updated : 1/30/2013<br>Ada Hamosh - updated : 10/24/2012<br>Patricia A. Hartz - updated : 11/23/2011<br>George E. Tiller - updated : 11/21/2011<br>George E. Tiller - updated : 11/14/2011<br>Cassandra L. Kniffin - updated : 6/7/2011<br>Cassandra L. Kniffin - updated : 5/11/2011<br>George E. Tiller - updated : 12/29/2010<br>George E. Tiller - updated : 11/12/2010<br>George E. Tiller - updated : 3/30/2010<br>Nara Sobreira - updated : 2/16/2010<br>Patricia A. Hartz - updated : 1/6/2010<br>Cassandra L. Kniffin - updated : 12/15/2009<br>Cassandra L. Kniffin - updated : 11/19/2009<br>Patricia A. Hartz - updated : 10/14/2009<br>Patricia A. Hartz - updated : 9/21/2009<br>Cassandra L. Kniffin - updated : 4/6/2009<br>Cassandra L. Kniffin - updated : 12/3/2008<br>George E. Tiller - updated : 11/18/2008<br>Patricia A. Hartz - updated : 8/21/2008<br>Patricia A. Hartz - updated : 8/14/2008<br>George E. Tiller - updated : 4/25/2008<br>Cassandra L. Kniffin - updated : 3/18/2008<br>George E. Tiller - updated : 11/30/2007<br>Cassandra L. Kniffin - updated : 10/16/2007<br>Patricia A. Hartz - updated : 8/24/2007<br>Marla J. F. O'Neill - updated : 6/6/2007<br>Patricia A. Hartz - updated : 2/12/2007<br>George E. Tiller - updated : 1/16/2007<br>George E. Tiller - updated : 11/28/2006<br>Cassandra L. Kniffin - reorganized : 11/27/2006<br>Cassandra L. Kniffin - updated : 8/29/2006<br>Ada Hamosh - updated : 7/31/2006<br>Patricia A. Hartz - updated : 4/20/2006<br>George E. Tiller - updated : 2/17/2006<br>George E. Tiller - updated : 2/3/2006<br>Patricia A. Hartz - updated : 1/27/2006<br>George E. Tiller - updated : 1/11/2006<br>Cassandra L. Kniffin - updated : 12/21/2005<br>Cassandra L. Kniffin - updated : 12/7/2005<br>Cassandra L. Kniffin - updated : 11/4/2005<br>Cassandra L. Kniffin - updated : 10/31/2005<br>George E. Tiller - updated : 10/21/2005<br>Cassandra L. Kniffin - updated : 9/23/2005<br>Cassandra L. Kniffin - updated : 8/23/2005<br>Cassandra L. Kniffin - updated : 8/17/2005<br>Patricia A. Hartz - updated : 7/8/2005<br>Cassandra L. Kniffin - updated : 6/20/2005<br>Patricia A. Hartz - updated : 6/8/2005<br>Victor A. McKusick - updated : 4/19/2005<br>Patricia A. Hartz - updated : 2/23/2005<br>Victor A. McKusick - updated : 1/27/2005<br>George E. Tiller - updated : 12/17/2004<br>Marla J. F. O'Neill - updated : 10/7/2004<br>Victor A. McKusick - updated : 9/22/2004<br>Marla J. F. O'Neill - updated : 5/19/2004<br>Victor A. McKusick - updated : 4/23/2004<br>Victor A. McKusick - updated : 4/14/2004<br>Cassandra L. Kniffin - updated : 3/1/2004<br>Cassandra L. Kniffin - updated : 1/22/2004<br>Victor A. McKusick - updated : 11/6/2003<br>Cassandra L. Kniffin - updated : 10/31/2003<br>Cassandra L. Kniffin - updated : 9/25/2003<br>Victor A. McKusick - updated : 8/1/2003<br>Victor A. McKusick - updated : 8/1/2003<br>Victor A. McKusick - updated : 7/18/2003<br>Patricia A. Hartz - updated : 7/8/2003<br>Cassandra L. Kniffin - updated : 5/28/2003<br>Victor A. McKusick - updated : 5/8/2003<br>Victor A. McKusick - updated : 4/11/2003<br>Victor A. McKusick - updated : 3/6/2003<br>Cassandra L. Kniffin - updated : 3/4/2003<br>Victor A. McKusick - updated : 1/31/2003<br>Victor A. McKusick - updated : 1/14/2003<br>Deborah L. Stone - updated : 11/15/2002<br>Patricia A. Hartz - updated : 11/11/2002<br>Cassandra L. Kniffin - updated : 10/15/2002<br>George E. Tiller - updated : 9/25/2002<br>Victor A. McKusick - updated : 9/19/2002<br>Victor A. McKusick - updated : 7/2/2002<br>Michael B. Petersen - updated : 2/28/2002<br>Victor A. McKusick - updated : 2/12/2002<br>Stylianos E. Antonarakis - updated : 1/10/2002<br>George E. Tiller - updated : 12/26/2001<br>George E. Tiller - updated : 12/6/2001<br>Stylianos E. Antonarakis - updated : 11/20/2001<br>Victor A. McKusick - updated : 9/20/2001<br>Deborah L. Stone - updated : 9/12/2001<br>Victor A. McKusick - updated : 8/30/2001<br>Victor A. McKusick - updated : 8/1/2001<br>George E. Tiller - updated : 4/25/2001<br>Sonja A. Rasmussen - updated : 4/23/2001<br>George E. Tiller - updated : 2/5/2001<br>Michael J. Wright - updated : 1/12/2001<br>Sonja A. Rasmussen - updated : 1/8/2001<br>Victor A. McKusick - updated : 12/19/2000<br>Sonja A. Rasmussen - updated : 12/12/2000<br>George E. Tiller - updated : 10/16/2000<br>Ada Hamosh - updated : 9/25/2000<br>Victor A. McKusick - updated : 9/11/2000<br>Sonja A. Rasmussen - updated : 7/13/2000<br>George E. Tiller - updated : 6/7/2000<br>George E. Tiller - updated : 5/2/2000<br>Stylianos E. Antonarakis - updated : 4/17/2000<br>Victor A. McKusick - updated : 3/31/2000<br>George E. Tiller - updated : 3/23/2000<br>Victor A. McKusick - updated : 11/24/1999<br>Sonja A. Rasmussen - updated : 11/16/1999<br>Sonja A. Rasmussen - updated : 10/5/1999<br>Victor A. McKusick - updated : 9/8/1999<br>Victor A. McKusick - updated : 6/30/1999<br>Victor A. McKusick - updated : 4/12/1999<br>Victor A. McKusick - updated : 2/18/1999<br>Victor A. McKusick - updated : 1/25/1999<br>Victor A. McKusick - updated : 1/12/1999<br>Michael J. Wright - updated : 11/16/1998<br>Victor A. McKusick - updated : 10/5/1998<br>Ada Hamosh - updated : 4/30/1998<br>Michael J. Wright - updated : 2/10/1998<br>Victor A. McKusick - updated : 11/26/1997<br>Victor A. McKusick - updated : 10/14/1997<br>Victor A. McKusick - updated : 9/2/1997<br>Victor A. McKusick - updated : 2/3/1997<br>Moyra Smith - updated : 1/31/1997<br>Moyra Smith - updated : 9/6/1996<br>Moyra Smith - updated : 8/27/1996<br>Mark H. Paalman - updated : 7/25/1996<br>Moyra Smith - updated : 3/26/1996
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Victor A. McKusick : 6/4/1986
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mgross : 03/05/2021<br>alopez : 12/23/2019<br>carol : 11/04/2019<br>carol : 11/01/2019<br>alopez : 09/17/2018<br>mgross : 01/12/2018<br>carol : 10/09/2017<br>carol : 05/09/2017<br>carol : 04/17/2017<br>carol : 04/03/2017<br>carol : 04/21/2016<br>alopez : 3/28/2014<br>alopez : 1/31/2014<br>tpirozzi : 10/10/2013<br>ckniffin : 9/26/2013<br>carol : 9/9/2013<br>tpirozzi : 8/30/2013<br>alopez : 2/8/2013<br>terry : 1/30/2013<br>alopez : 10/26/2012<br>terry : 10/24/2012<br>carol : 8/17/2012<br>terry : 5/29/2012<br>terry : 5/17/2012<br>alopez : 1/12/2012<br>alopez : 1/12/2012<br>terry : 11/23/2011<br>carol : 11/21/2011<br>terry : 11/21/2011<br>carol : 11/17/2011<br>terry : 11/14/2011<br>carol : 7/6/2011<br>wwang : 6/23/2011<br>ckniffin : 6/7/2011<br>wwang : 5/16/2011<br>ckniffin : 5/11/2011<br>wwang : 1/12/2011<br>terry : 12/29/2010<br>wwang : 11/19/2010<br>terry : 11/12/2010<br>wwang : 4/2/2010<br>terry : 3/30/2010<br>carol : 2/26/2010<br>carol : 2/16/2010<br>mgross : 1/21/2010<br>terry : 1/6/2010<br>carol : 12/23/2009<br>ckniffin : 12/15/2009<br>wwang : 12/10/2009<br>ckniffin : 11/19/2009<br>alopez : 11/3/2009<br>mgross : 10/23/2009<br>terry : 10/14/2009<br>mgross : 10/6/2009<br>mgross : 10/6/2009<br>mgross : 10/6/2009<br>mgross : 10/6/2009<br>terry : 9/21/2009<br>carol : 7/31/2009<br>wwang : 4/10/2009<br>ckniffin : 4/6/2009<br>wwang : 12/4/2008<br>ckniffin : 12/3/2008<br>wwang : 11/18/2008<br>mgross : 8/22/2008<br>terry : 8/21/2008<br>mgross : 8/14/2008<br>mgross : 8/14/2008<br>terry : 8/14/2008<br>ckniffin : 5/1/2008<br>wwang : 4/30/2008<br>terry : 4/25/2008<br>wwang : 3/28/2008<br>ckniffin : 3/18/2008<br>wwang : 11/30/2007<br>wwang : 11/19/2007<br>ckniffin : 10/16/2007<br>mgross : 8/29/2007<br>terry : 8/24/2007<br>carol : 6/6/2007<br>mgross : 2/12/2007<br>alopez : 1/17/2007<br>terry : 1/16/2007<br>carol : 11/28/2006<br>carol : 11/27/2006<br>ckniffin : 11/27/2006<br>carol : 11/27/2006<br>ckniffin : 11/22/2006<br>ckniffin : 11/16/2006<br>wwang : 8/31/2006<br>ckniffin : 8/29/2006<br>alopez : 8/1/2006<br>terry : 7/31/2006<br>mgross : 4/24/2006<br>terry : 4/20/2006<br>wwang : 3/7/2006<br>terry : 2/17/2006<br>wwang : 2/3/2006<br>mgross : 2/2/2006<br>terry : 1/27/2006<br>wwang : 1/24/2006<br>terry : 1/11/2006<br>wwang : 1/9/2006<br>ckniffin : 12/21/2005<br>wwang : 12/9/2005<br>ckniffin : 12/7/2005<br>wwang : 11/15/2005<br>ckniffin : 11/4/2005<br>wwang : 11/2/2005<br>ckniffin : 10/31/2005<br>alopez : 10/21/2005<br>wwang : 10/6/2005<br>ckniffin : 9/23/2005<br>wwang : 8/31/2005<br>carol : 8/23/2005<br>ckniffin : 8/23/2005<br>wwang : 8/22/2005<br>ckniffin : 8/17/2005<br>wwang : 7/15/2005<br>wwang : 7/8/2005<br>ckniffin : 6/20/2005<br>wwang : 6/17/2005<br>wwang : 6/9/2005<br>terry : 6/8/2005<br>alopez : 4/19/2005<br>mgross : 2/23/2005<br>wwang : 2/11/2005<br>wwang : 2/10/2005<br>wwang : 2/7/2005<br>terry : 1/27/2005<br>tkritzer : 12/17/2004<br>carol : 10/22/2004<br>carol : 10/8/2004<br>terry : 10/7/2004<br>tkritzer : 9/23/2004<br>terry : 9/22/2004<br>tkritzer : 8/26/2004<br>tkritzer : 8/24/2004<br>carol : 6/30/2004<br>carol : 5/19/2004<br>terry : 5/19/2004<br>tkritzer : 4/27/2004<br>terry : 4/23/2004<br>alopez : 4/16/2004<br>terry : 4/14/2004<br>joanna : 3/16/2004<br>tkritzer : 3/3/2004<br>ckniffin : 3/1/2004<br>tkritzer : 2/10/2004<br>ckniffin : 1/22/2004<br>tkritzer : 11/10/2003<br>terry : 11/6/2003<br>tkritzer : 10/31/2003<br>ckniffin : 10/31/2003<br>carol : 9/25/2003<br>ckniffin : 9/17/2003<br>terry : 8/20/2003<br>carol : 8/1/2003<br>terry : 8/1/2003<br>cwells : 7/29/2003<br>terry : 7/28/2003<br>terry : 7/28/2003<br>terry : 7/18/2003<br>mgross : 7/8/2003<br>tkritzer : 6/9/2003<br>ckniffin : 5/28/2003<br>tkritzer : 5/9/2003<br>terry : 5/8/2003<br>tkritzer : 4/17/2003<br>terry : 4/11/2003<br>carol : 3/7/2003<br>terry : 3/6/2003<br>carol : 3/6/2003<br>ckniffin : 3/4/2003<br>tkritzer : 2/4/2003<br>tkritzer : 2/3/2003<br>terry : 1/31/2003<br>carol : 1/23/2003<br>tkritzer : 1/17/2003<br>terry : 1/14/2003<br>carol : 11/15/2002<br>mgross : 11/11/2002<br>mgross : 11/11/2002<br>alopez : 10/21/2002<br>mgross : 10/18/2002<br>carol : 10/18/2002<br>ckniffin : 10/15/2002<br>cwells : 9/25/2002<br>tkritzer : 9/19/2002<br>tkritzer : 9/19/2002<br>carol : 9/11/2002<br>cwells : 7/17/2002<br>cwells : 7/15/2002<br>terry : 7/2/2002<br>mgross : 4/8/2002<br>cwells : 3/6/2002<br>cwells : 2/28/2002<br>terry : 2/12/2002<br>mgross : 1/10/2002<br>mgross : 1/10/2002<br>cwells : 1/4/2002<br>cwells : 12/26/2001<br>cwells : 12/18/2001<br>cwells : 12/6/2001<br>mgross : 11/21/2001<br>mgross : 11/20/2001<br>mcapotos : 10/8/2001<br>mcapotos : 10/1/2001<br>terry : 9/20/2001<br>carol : 9/12/2001<br>terry : 8/30/2001<br>terry : 8/30/2001<br>mcapotos : 8/16/2001<br>mcapotos : 8/2/2001<br>terry : 8/2/2001<br>terry : 8/1/2001<br>cwells : 5/9/2001<br>cwells : 5/1/2001<br>cwells : 4/25/2001<br>mcapotos : 4/23/2001<br>cwells : 2/5/2001<br>cwells : 1/30/2001<br>mcapotos : 1/29/2001<br>alopez : 1/12/2001<br>mcapotos : 1/8/2001<br>terry : 12/19/2000<br>mcapotos : 12/12/2000<br>alopez : 10/16/2000<br>alopez : 10/3/2000<br>terry : 9/25/2000<br>carol : 9/13/2000<br>terry : 9/11/2000<br>mcapotos : 7/14/2000<br>mcapotos : 7/13/2000<br>mcapotos : 7/13/2000<br>alopez : 6/7/2000<br>alopez : 5/2/2000<br>mgross : 4/17/2000<br>mgross : 4/11/2000<br>terry : 3/31/2000<br>alopez : 3/23/2000<br>alopez : 12/7/1999<br>carol : 11/29/1999<br>terry : 11/24/1999<br>mgross : 11/16/1999<br>carol : 10/5/1999<br>jlewis : 9/16/1999<br>terry : 9/8/1999<br>jlewis : 7/15/1999<br>terry : 6/30/1999<br>carol : 5/24/1999<br>terry : 5/20/1999<br>carol : 4/14/1999<br>terry : 4/12/1999<br>mgross : 3/10/1999<br>carol : 2/18/1999<br>terry : 2/18/1999<br>carol : 1/25/1999<br>carol : 1/19/1999<br>terry : 1/15/1999<br>terry : 1/12/1999<br>alopez : 12/7/1998<br>terry : 11/16/1998<br>carol : 10/8/1998<br>terry : 10/5/1998<br>terry : 6/4/1998<br>alopez : 5/21/1998<br>alopez : 5/11/1998<br>dholmes : 5/11/1998<br>dholmes : 4/30/1998<br>alopez : 2/18/1998<br>terry : 2/10/1998<br>alopez : 12/5/1997<br>alopez : 12/3/1997<br>alopez : 12/3/1997<br>dholmes : 12/1/1997<br>mark : 10/14/1997<br>terry : 9/12/1997<br>terry : 9/10/1997<br>jenny : 9/10/1997<br>terry : 9/2/1997<br>terry : 8/5/1997<br>alopez : 7/29/1997<br>alopez : 7/29/1997<br>mark : 7/16/1997<br>alopez : 7/10/1997<br>alopez : 7/8/1997<br>joanna : 7/7/1997<br>joanna : 6/24/1997<br>terry : 5/5/1997<br>jenny : 3/31/1997<br>mark : 2/3/1997<br>mark : 2/3/1997<br>mark : 1/31/1997<br>jamie : 1/16/1997<br>mark : 10/19/1996<br>terry : 9/20/1996<br>mark : 9/6/1996<br>terry : 9/3/1996<br>terry : 8/27/1996<br>mark : 7/25/1996<br>mark : 3/26/1996<br>terry : 3/19/1996<br>mark : 3/14/1996<br>terry : 3/14/1996<br>mark : 3/10/1996<br>terry : 3/5/1996<br>mark : 2/14/1996<br>terry : 2/9/1996<br>mark : 1/20/1996<br>mark : 1/19/1996<br>mark : 1/4/1996<br>terry : 12/29/1995<br>terry : 12/29/1995<br>terry : 11/16/1995<br>mark : 11/6/1995<br>pfoster : 7/6/1995<br>jason : 7/18/1994<br>mimadm : 5/17/1994<br>warfield : 4/20/1994
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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>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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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> 309550
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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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FRAGILE X MESSENGER RIBONUCLEOPROTEIN 1; FMR1
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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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</span>
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</p>
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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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FMRP TRANSLATIONAL REGULATOR 1<br />
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FRAGILE X MENTAL RETARDATION PROTEIN; FMRP
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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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<div>
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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FRAGILE SITE, FOLIC ACID TYPE, RARE, fraXq27.3, INCLUDED; FRAXA, INCLUDED
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</span>
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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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<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: FMR1</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 1332509007, 448045004, 613003;
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<strong>ICD10CM:</strong> Q99.2;
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<strong>ICD9CM:</strong> 759.83;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<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: Xq27.3
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Genomic coordinates <span class="small">(GRCh38)</span> : X:147,911,919-147,951,125 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="3">
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<span class="mim-font">
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Xq27.3
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</span>
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</td>
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<td>
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<span class="mim-font">
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Fragile X syndrome
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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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300624
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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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X-linked dominant
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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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<tr>
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<td>
|
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<span class="mim-font">
|
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Fragile X tremor/ataxia syndrome
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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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300623
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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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X-linked dominant
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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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<tr>
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<td>
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<span class="mim-font">
|
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Premature ovarian failure 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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311360
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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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X-linked
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
3
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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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">
|
|
<p>The selective RNA-binding protein FMRP forms a messenger ribonucleoprotein complex that associates with polyribosomes, suggesting that it is involved in translation (Jin 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">
|
|
<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">
|
|
<p>Warren et al. (1987, 1988, 1990) presented strategies for the molecular cloning of the fragile X syndrome (FXS; 300624) gene using mapping information from affected families. </p><p>Verkerk et al. (1991) identified the FMR1 gene within a 4-cosmid contig of YAC DNA spanning the fragile X syndrome breakpoint cluster region on Xq27-q28. The authors isolated cDNA clones corresponding to the gene from a human fetal brain cDNA library. The predicted sequence of the FMR1 protein contains a nuclear translocation signal. The gene-encoding region contains a CpG island previously shown to be hypermethylated in fragile X patients (Bell et al., 1991; Heitz et al., 1991). A 7.4-kb EcoRI fragment encompassing the region was identified in fragile X genomic DNA; the same fragment was 5.1 kb in normal X chromosomes, indicating that the region undergoes a variable increase in size in the fragile X chromosome. A CGG trinucleotide repeat, which is reiterated 30 times in the normal mRNA, was identified 250 bp distal to the well-known CpG island. Northern blot analysis detected a 4.8-kb mRNA in human brain. The findings suggested that the FMR1 gene is likely involved in fragile X syndrome. </p><p>Siomi et al. (1993) reported that the deduced 594-amino acid FMR1 protein has 2 tandem KH domains in its N-terminal half and an RGG box near its C terminus. The KH domains and RGG box are associated with RNA binding. </p><p>Using polyclonal antibodies to study sera from normal individuals, Verheij et al. (1993) identified 4 different FMR1 protein products, possibly resulting from alternative splicing. All these proteins were missing in cell lines from fragile X patients not expressing FMR1 mRNA. </p><p>Ashley et al. (1993) isolated and characterized cDNA clones encoding the murine homolog, Fmr1, which exhibits marked sequence identity with the human gene, including the conservation of the CGG repeat. A conserved ATG downstream of the CGG repeat in both human and mouse and an in-frame stop codon in other human 5-prime cDNA sequences demarcate the FMR1 coding region and confine the CGG repeat to the 5-prime untranslated region. Ashley et al. (1993) presented evidence for alternative splicing of the FMR1 gene in mouse and human brain and showed that one of these splicing events alters the FMR1 reading frame, predicting isoforms with novel carboxy termini. </p><p>Alpatov et al. (2014) identified an Agenet domain at the N terminus of FMRP. The Agenet domain consists of 2 adjacent Tudor domains referred to as 'N-terminal domain of FMRP 1' (NDF1) and NDF2. The Agenet domain of FMRP belongs to the Royal family of chromatin-binding proteins. Immunofluorescence analysis of chromosome spreads of adult mouse spermatocytes detected Fmrp puncta on condensed pachytene-stage chromosomes. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<span class="mim-text-font">
|
|
<p>Eichler et al. (1993) determined that the FMR1 gene contains 17 exons spanning 38 kb. Splice donors and acceptors located in the 5-prime portion of the gene demonstrated greater adherence to consensus than did those in the 3-prime end, providing a possible explanation for alternative splicing in FMR1. </p><p>Smith et al. (2004) examined the promoter region of the FMR1 gene and identified binding sites for several transcription factors, including AP2 (TFAP2A; 107580), NRF1 (600879), MYC (190080), and SP1 (189906). </p><p>Naumann et al. (2009) stated that the promoter region of the FMR1 gene lacks a typical TATAA box. </p><p><strong><em>DNA-Methylation Boundary in 5-prime Upstream Region</em></strong></p><p>
|
|
Naumann et al. (2009) identified 104 CpG dinucleotides in a 5.5-kb segment of the 5-prime upstream region of FMR1. These CpGs could be separated into a long, far upstream segment of methylated CpG pairs and a shorter, downstream segment of unmethylated CpG pairs covering the promoter region of FMR1 and extending to the CGG repeat region. The methylation boundary has a transition zone with a methylation mosaic on its downstream side. A similar methylation boundary is conserved in the mouse Fmr1 gene. Naumann et al. (2009) showed that the isolated transition sequence in the methylation boundary bound nuclear proteins from a human colorectal cell line. Competition studies showed that formation of these distinct protein-DNA complexes occurred in the presence or absence of DNA methylation. Naumann et al. (2009) proposed that the methylation boundary carries a specific chromatin structure that delineates a hypermethylated area in the genome from the unmethylated FMR1 promoter, protecting it from the spreading of DNA methylation. </p>
|
|
</span>
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
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<p>Poustka et al. (1991) described a physical map of the end of chromosome Xq encompassing the region from Xq27.2 to the telomere, inclusive of band Xq28. The map covered a total of 12 Mb of DNA and extended from the telomere to a location 3 Mb proximal to the most likely position of the fragile X mutation. The map determined order and position of loci throughout the Xq28 region and localized cell line breakpoints marking the fragile X region to an interval of 300-700 kb between 8 and 8.7 Mb proximal to the Xq telomere. </p><p>Faust et al. (1992) and Laval et al. (1992) determined the location of the corresponding gene on the mouse X chromosome by use of human cDNA clones in an interspecific backcross. Both groups found preservation of the order of loci, although no fragile site had been detected microscopically in that region of the mouse X chromosome. </p>
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<strong>Gene Function</strong>
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<p>By use of transient expression in COS-1 cells, Verheij et al. (1993) demonstrated intracellular localization of the FMR1 gene products. </p><p>Using monoclonal antibodies specific for the FMR1 protein, Devys et al. (1993) detected 4 or 5 protein bands in cells of normal males and of males carrying a premutation (an elongation of 70 to 200 bp), which were absent in affected males with a full mutation (FM). Immunohistochemistry showed a cytoplasmic localization of the FMR1 protein. The highest levels were observed in neurons, while glial cells contained very low levels. In epithelial tissues, levels of FMR1 were higher in dividing layers. In adult testes, FMR1 was detected only in spermatogonia. </p><p>Abitbol et al. (1993) used in situ hybridization to demonstrate that FMR1 mRNAs are expressed in human fetal brain from an early stage in proliferating and migrating cells of the nervous system and retina as well as cartilaginous structures, including branchial cartilage, and liver. In the brain of 25-week-old human fetuses, FMR1 mRNA was produced in highest levels in cholinergic neurons of the nucleus basalis magnocellularis and in pyramidal neurons of the hippocampus. The early transcription and distribution of the gene suggested that alterations of FMR1 gene expression contributes to the pathogenesis of the fragile X syndrome, especially the mental retardation. Bachner et al. (1993) presented evidence suggesting that the FMR1 gene serves a function in the mature testis, as reflected by high expression in spermatogonia and not in Sertoli cells. They suggested further that FMR1 expression in spermatogonia is necessary for germ cell proliferation. </p><p>Ashley et al. (1993) identified ribonucleoprotein particle domains within the FMR protein and showed that RNA bound in stoichiometric ratios, suggesting that there are 2 RNA binding sites per FMR protein molecule. The protein was able to bind to its own message with high affinity and interacted with approximately 4% of human fetal brain messages. Ashley et al. (1993) postulated that the absence of the normal interaction of the FMR protein with a subset of RNA molecules might result in the pleiotropic phenotype associated with the fragile X syndrome. </p><p>Siomi et al. (1993) demonstrated that the FMR1 protein contains 2 types of sequence motifs characteristic of RNA-binding proteins: an RGG box and 2 heterogeneous nuclear ribonucleoprotein (hnRNP) K homology (KH) domains. They also demonstrated that FMR1 binds RNA in vitro. Using antibodies to FMR1, they detected its expression in cells of unaffected humans but little or no FMR1 in patients with fragile X syndrome. It is noteworthy that a pathogenic point mutation (I304N; 309550.0001) described by de Boulle et al. (1993) is in one of the most highly conserved residues of one of these RNA-binding domains. The KH domain, a highly conserved domain originally described in the pre-mRNA-binding hnRNP K protein, contains approximately 50 amino acids found in a diverse group of RNA-binding proteins. Using mutagenesis of KH domains in hnRNP K and FMR1, Siomi et al. (1994) found that conserved residues of all 3 KH domains of hnRNP K were required for its wildtype RNA binding. The results demonstrated an essential role for KH domains in RNA binding and strengthened the connection between the fragile X syndrome and loss of RNA-binding activity of FMR1. </p><p>Khandjian et al. (1996) observed that the FMR protein cosediments with polyribosomes after centrifugation in sucrose density gradients. Specifically, it was associated with the ribosomal 60S subunit and possessed the characteristics of a nonintegral ribosomal protein. Immunofluorescent studies showed a tight colocalization of FMRP with cytoplasmic ribosomes in NIH 3T3 and HeLa cells and in primary cultures of neurons. The authors concluded that fragile X mental retardation may result from defects in the translational machinery due to absence of FMRP. </p><p>FMR1 protein and the fragile X-related proteins 1 (FXR1; 600819) and 2 (FXR2; 605339) form a family with functional similarities such as RNA binding, polyribosomal association, and nucleocytoplasmic shuttling. Using several FMR1 deletion mutants in coimmunoprecipitation experiments, Siomi et al. (1996) identified amino acids 359 to 472, which are encoded by exons 13 and 14, as the 60S ribosomal subunit-binding region. They found that amino acids 171 to 211 are sufficient for FMR1 interaction with FXR2 and that FMR1 is not required for the association of FXR1 or FXR2 with the 60S ribosomal subunit. FXR1 and FXR2 associated with 60S ribosomal subunits in cells lacking FMR1 and in cells derived from a fragile X syndrome patient. </p><p>Tamanini et al. (1999) found that FMR1 and FXR1 proteins shuttle between cytoplasm and nucleoplasm, while FXR2 protein shuttles between cytoplasm and nucleolus. </p><p>By immunofluorescence studies, Sittler et al. (1996) found that splice variants of FMR1 that exclude exon 14 sequences (and have alternate C-terminal regions) are nuclear. Analysis of various deletion mutants suggested the presence of a cytoplasmic retention domain encoded in exon 14 and of a nuclear association domain encoded within the first 8 exons that appeared, however, to lack a typical nuclear localization signal. </p><p>Feng et al. (1997) demonstrated that normal FMRP associates with elongating polyribosomes via large mRNP particles. </p><p>Lewis et al. (2000) determined the structure of the KH3 domain of NOVA2 (601991) interacting with single-stranded RNA at 2.4-angstrom resolution. The structure of the KH3 domain bound to a stem loop RNA resembled a molecular vise, with 5-prime-UCAC-3-prime pinioned between an invariant gly-X-X-gly motif and the variable loop. Tetranucleotide recognition was supported by an aliphatic alpha-helix/beta-sheet RNA-binding platform, which mimicked 5-prime-UG-3-prime by making Watson-Crick-like hydrogen bonds with 5-prime-CA-3-prime. Sequence conservation suggested that fragile X mental retardation results from perturbation of RNA binding by the KH2 domain of the FMR1 protein. </p><p>Darnell et al. (2001) used RNA selection to demonstrate that the FMRP RGG box binds intramolecular G quartets. These data allowed them to identify mRNAs encoding proteins involved in synaptic or developmental neurobiology that harbor FMRP-binding elements. The majority of these mRNAs had an altered polysome association in fragile X patient cells. These data demonstrated that G quartets serve as physiologically relevant targets for FMRP and identified mRNAs whose dysregulation may underlie human mental retardation. </p><p>Laggerbauer et al. (2001) showed that FMR1 strongly inhibited translation of various mRNAs at nanomolar concentrations in both rabbit reticulocyte lysate and microinjected Xenopus laevis oocytes. The effect was specific for FMR1, since other proteins with similar RNA-binding domains, including the autosomal homologs of FMR1, FXR1, and FXR2, failed to suppress translation in the same concentration range. Initial studies addressing the underlying mechanism of inhibition suggested that FMR1 may inhibit the assembly of 80S ribosomes on the target mRNAs. The I304N mutation rendered FMR1 incapable of interfering with translation in both test systems, and severely impaired homooligomerization of FMR1. The failure of FMR1 I304N to suppress translation was not due to its reduced affinity for mRNA or its interacting proteins FXR1 and FXR2. The authors hypothesized that inhibition of translation may be a function of FMR1 in vivo, and that failure of mutant FMR1 protein to oligomerize may contribute to the pathophysiologic events leading to fragile X syndrome. </p><p>Using microarray analysis, Brown et al. (2001) identified 432 associated mRNAs from mouse brain that coimmunoprecipitated mRNA with the FMRP ribonucleoprotein complex. Quantitative RT-PCR confirmed some to be more than 60-fold enriched in the immunoprecipitant. In parallel studies, mRNAs from polyribosomes of fragile X cells were used to probe microarrays. Despite equivalent cytoplasmic abundance, 251 mRNAs had an abnormal polyribosome profile in the absence of FMRP. Although this represented less than 2% of the total messages, 50% of the coimmunoprecipitated mRNAs with expressed human orthologs were found in this group. Nearly 70% of those transcripts found in both studies contained a G quartet structure, demonstrated as an in vitro FMRP target. Brown et al. (2001) concluded that translational dysregulation of mRNAs normally associated with FMRP may be the proximal cause of fragile X syndrome, and they identified candidate genes relevant to this phenotype. </p><p>Oostra and Chiurazzi (2001) reviewed the FMR1 gene and FMR1 protein function, including information on animal models for fragile X syndrome. </p><p>Using CpG methylation-deficient Drosophila cells, Smith et al. (2004) demonstrated in vivo that Nrf1 (600879) and Sp1 (189906) are strong, synergistic activators of an unmethylated human FMR1-driven reporter, while USF1/2 (191523, 600390) and Max (154950) repressed this activation. In addition, analyses of transcription factor activity upon DNA methylation of the reporter showed that Sp1 activity was largely intact when the promoter was densely methylated, but Nrf1 transactivation was very sensitive to dense methylation. Notably, Nrf1 transactivation was relatively insensitive to methylation of cytosines only at its binding site. FMR1 reporter activity was also reduced in HeLa cells after expression of a short interfering RNA directed against endogenous Nrf1. Sp1 and Nrf1 occupied the human FMR1 promoter in vivo, and these interactions were disrupted in fragile X patient cells. In addition, Max resided at the FMR1 promoter, and USF1/2, but not c-Myc (190080), were present at endogenous FMR1. </p><p>Using a mouse fibroblast model system, Castets et al. (2005) demonstrated that FMRP and the Rac1 (602048) pathway are connected. Rac1 activation induced relocalization of FMRP interactors CYFIP1 (606322), FXR1, NUFIP1 (604354), and NUFIP2 (609356) to actin ring areas. Moreover, Rac1-induced actin remodeling was altered in fibroblasts lacking FMRP or carrying a point mutation in the KH1 or in the KH2 RNA-binding domain. Absence of wildtype FMRP resulted in lowered levels of phospho-cofilin (CFL1; 601442), which is a major mediator of Rac1 signaling, and increased levels of the phospho-cofilin phosphatase PPP2CA (176915). FMRP bound with high affinity to the 5-prime-UTR of PPP2CA-beta mRNA and is a likely negative regulator of its translation. Castets et al. (2005) suggested a role for FMRP in modulation of actin dynamics, which is a key process in morphogenesis of dendritic spines. </p><p>To identify the RNA target for the KH2 domain of FMR1, Darnell et al. (2005) performed RNA selection with both full-length FMR1 and isolated KH2 domains. They determined that, unlike other characterized KH domains, the FMR1 KH2 domain bound to an RNA complex termed a loop-loop pseudoknot, or 'kissing complex.' The association of FMR1 with mouse brain polyribosomes was abrogated by competition with kissing complex RNAs, but not by G quartet RNAs. Darnell et al. (2005) concluded that kissing complex motifs are targets for FMR1 translational regulation. </p><p>Lim et al. (2005) tested the role of the transcription factor AP2-alpha (TFAP2A; 107580) in regulating Fmr1 expression. Chromatin immunoprecipitation showed that AP2-alpha associated with the Fmr1 promoter in vivo. Fmr1 transcript levels were reduced approximately 4-fold in homozygous null AP2-alpha mutant mice at embryonic day 18.5 when compared with normal littermates. AP2-alpha exhibited a strong gene dosage effect, with heterozygous mice showing an approximately 2-fold reduction in Fmr1 levels. Examination of conditional AP2-alpha mutant mice indicated that the transcription factor played a major role in regulating Fmr1 expression in embryos, but not in adults. Overexpression of a dominant-negative AP2-alpha in Xenopus embryos led to reduced Fmr1 levels. Exogenous wildtype AP2-alpha rescued Fmr1 expression in embryos where endogenous AP2-alpha had been suppressed. Lim et al. (2005) concluded that AP2-alpha associates with the Fmr1 promoter in vivo and selectively regulates Fmr1 transcription during embryonic development. </p><p>NXF1 (602647) and NXF2 (300315) belong to a family of evolutionarily conserved nuclear export factors. Using immunoprecipitation analysis and quantitative real-time RT-PCR, Zhang et al. (2007) showed that Fmrp and Nxf2 were present in Nxf1 mRNA-containing ribonucleoprotein particles in cultured mouse neuronal cells. Expression of Nxf2 led to destabilization of Nxf1 mRNA, and this effect was abolished when Fmrp expression was reduced by small interfering RNA. Zhang et al. (2007) concluded that FMRP and NXF2 collaborate to destabilize NXF1 mRNA. </p><p>Using yeast 2-hybrid analysis of a human fetal brain cDNA library, Davidovic et al. (2007) showed that the neurospecific kinesin KIF3C (602845) interacted directly with FMRP. Time-lapse videomicroscopy of cultured rat hippocampal neurons showed that a dominant-negative Kif3c mutant impeded the distal transport of Fmrp-containing RNA granules. Davidovic et al. (2007) concluded that FMRP acts as a molecular adaptor between mRNA granules and the molecular machinery that transports mRNAs along neuronal microtubules. </p><p>Dictenberg et al. (2008) showed that mouse Fmr1 had a role in rapid, activity-regulated transport of mRNAs important for synaptogenesis and neuronal plasticity. In hippocampal neurons derived from wildtype mice, Fmr1 acted as an adaptor for kinesin light chain (KLC1; 600025) to promote stimulus-induced mRNA transport. However, Fmr1-knockout (KO) brains showed widespread uncoupling of Fmr1 target mRNAs from kinesin. Acute suppression of Fmr1 transport in wildtype neurons resulted in diminished mRNA transport and a significant increase in the length and number of dendritic filopodia-spine protrusions that was similar to that observed in human fragile X syndrome and its mouse model. Dictenberg et al. (2008) proposed that altered stimulus-induced synaptic localization and transport kinetics of FMR1 target mRNAs may be involved in the translational and synaptic defects in fragile X syndrome. </p><p>Piazzon et al. (2008) found that FMRP and SMN (see SMN1; 600354), a protein complex essential for assembly of spliceosomal U small nuclear RNPs, partially colocalized in cell bodies and neural processes of transfected primary cultured rat hypothalamic neurons. Immunoprecipitation experiments revealed an association between FMRP and the SMN complex in human neuroblastoma and murine motor neuron cell lines. Site-directed mutagenesis and in vitro assays showed that the interaction involved the C-terminal region of FMRP and the conserved YG box and the region encoded by exon 7 of SMN1. </p><p>Pfeiffer et al. (2010) found that synapse elimination by the activity-dependent transcription factor MEF2 (600660) requires functional FMRP downstream. In wildtype murine neurons, postsynaptic activation of MEF2 led to a structural and functional elimination of synapses, whereas MEF2 activation in neurons derived from Fmr1-knockout mice had no effect on synapse structure or function. Postsynaptic expression of FMRP restored MEF2-dependent synapse elimination. Coimmunoprecipitation studies did not indicate an interaction between the 2 proteins, and Pfeiffer et al. (2010) suggested that FMRP may regulate the processing, transport, or translation of MEF2 transcripts or that transcripts of other genes are involved. </p><p>To identify the importance of methylation of RGG box arginines for FMRP function, Blackwell et al. (2010) examined their role in polyribosome and mRNA association. Arginines 533 and 538 were required for normal FMRP polyribosome association, whereas all 4 arginines played a role in RNA binding, depending on the identity of the RNA. The model G-quadruplex RNA sc1 required arginines 533 and 538 for normal association with FMRP, whereas AATYK (AATK; 605276) mRNA did not. In vitro methylation of FMRP-bearing arginine substitutions inhibited sc1 binding but not AATYK binding. In addition, PRMT1 (602950) coimmunoprecipitated with FMRP isolated from cells, and siRNAs directed against PRMT1 led to reduced FMRP methylation. </p><p>Auerbach et al. (2011) used electrophysiologic and biochemical assays of neuronal protein synthesis in the hippocampus of Tsc2 (191092) heterozygote and Fmr1-null male mice to show that synaptic dysfunction caused by these mutations falls at opposite ends of a physiologic spectrum. Synaptic, biochemical, and cognitive defects in these mutants were corrected by treatments that modulated metabotropic Grm5 (604102) in opposite directions, and deficits in the mutants disappeared in mice bred to carry both mutations. Auerbach et al. (2011) concluded that normal synaptic plasticity and cognition occur within an optimal range of metabotropic glutamate receptor-mediated protein synthesis, and deviations in either direction can lead to shared behavioral impairments. </p><p>Baudouin et al. (2012) discovered an unexpected convergence of synaptic pathophysiology in a nonsyndromic form of autism (due to mutation in the neuroligin-3 gene; 300336) with those in fragile X syndrome (due to silencing of the FMR1 gene). Neuroligin-3 knockout mice exhibited disrupted heterosynaptic competition and perturbed metabotropic glutamate receptor-dependent synaptic plasticity, a hallmark of fragile X. These phenotypes could be rescued by reexpression of neuroligin-3 in juvenile mice, highlighting the possibility of reverting neuronal circuit alterations in autism after the completion of development. </p><p>Ascano et al. (2012) reported the discovery of distinct RNA recognition elements that correspond to the 2 independent RNA-binding domains of FMRP, in addition to the binding sites within the mRNA targets for the wildtype and I304N mutant FMRP isoforms and the FMRP paralogs FXR1P and FXR2P, also known as FXR1 (600819) and FXR2 (605339), respectively. RNA recognition element frequency, ratio, and distribution determine the target mRNA association with FMRP. Among highly enriched targets, Ascano et al. (2012) identified many genes involved in autism spectrum disorder (see 209850) and showed that FMRP affects their protein levels in human cell culture, mouse ovaries, and human brain. Notably, Ascano et al. (2012) discovered that these targets are also dysregulated in Fmr1-null mouse ovaries showing signs of premature follicular overdevelopment. Ascano et al. (2012) concluded that FMRP targets share signaling pathways across different cellular contexts and that their results provided a ranked list of genes as basis for the pursuit of therapeutic targets for fragile X syndrome and autism spectrum disorder. </p><p>Using wildtype and knockout mutant mouse embryonic fibroblasts (MEFs) and wildtype and FMRP-knockdown HeLa cells, Alpatov et al. (2014) found that nuclear FMRP functions as a chromatin-binding protein that responds to DNA single-strand breaks. The N-terminal Agenet domain was required for this function and bound preferentially to methylated histone H3. FMRP was recruited to chromatin in response to replication stress, and loss of FMRP compromised subsequent phosphorylation of H2AX (H2AFX; 601772). However, Fmrp chromatin-binding defective mutant mice were not compromised in translation-dependent trafficking of Glur1 (GRIA1; 138248), indicating that nuclear and cytoplasmic functions of FMRP are independent. Fmrp was loaded onto chromosomes during meiosis in male mice and regulated placement of phosphorylated H2ax. A proportion of Fmrp mutant spermatocytes showed defective chromosome synapsis and defective resolution of single-strand intermediates during meiotic prophase. Alpatov et al. (2014) hypothesized that FMRP performs a docking function to regulate accessibility of DNA damage response protein to chromatin. </p><p>Greenblatt and Spradling (2018) analyzed quiescent Drosophila oocytes, which, like neural synapses, depend heavily on translating stored mRNA. Ribosome profiling revealed that Fmr1 enhances rather than represses the translation of mRNAs that overlap previously identified Fmr1 targets, and acts preferentially on large proteins. Human homologs of at least 20 targets were associated with dominant intellectual disability, and 30 others with recessive neurodevelopmental dysfunction. Unlike stored wildtype oocytes, stored oocytes lacking Fmr1 usually generate embryos with severe neural defects, which suggests that translation of multiple large proteins by stored mRNAs is defective in fragile X syndrome and possibly other autism spectrum disorders. </p><p>Using NMR spectroscopy of minimal condensates formed from the C-terminal disordered regions of 2 interacting translational regulators, FMRP and CAPRIN1 (601178), Kim et al. (2019) observed interactions involving arginine-rich and aromatic-rich regions. Kim et al. (2019) found that different FMRP serine/threonine and CAPRIN1 tyrosine phosphorylation patterns controlled phase separation propensity with RNA, including subcompartmentalization, and tuned deadenylation and translation rates in vitro. Kim et al. (2019) concluded that the resulting evidence for residue-specific interactions underlying co-phase separation, phosphorylation-modulated condensate architecture, and enzymatic activity within condensates had implications for how the integration of signaling pathways controls RNA processing and translation. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Fragile X Syndrome</em></strong></p><p>
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Kremer et al. (1991) demonstrated that an unstable expanded trinucleotide (CCG)n repeat sequence (309550.0004) in the 5-prime untranslated region of the FMR1 gene is the basis of fragile X syndrome (FXS; 300624). The authors showed that normal X chromosomes have about 40 +/- 25 copies of (CCG)n and that within these limits the sequence is a stable DNA polymorphism. The fragile X genotype was characterized by an increased amount of unstable DNA that maps to the repeat. </p><p>Devys et al. (1992) noted that there are 2 main types of mutations involved in fragile X syndrome. Premutations, which do not cause mental retardation, are characterized by an elongation of 70 to 500 bp with little or no somatic heterogeneity and without abnormal methylation. Full mutations are associated with high risk of mental retardation and consist of a 600 bp or more amplification, often with extensive somatic heterogeneity and abnormal DNA methylation. </p><p>By using microdissected markers close to the fragile site, Bell et al. (1991) demonstrated that the fragile X syndrome is not associated with large structural rearrangements in Xq27.3 but is associated with methylation of DNA sequences distal to the fragile site. Significant differences were observed in the pulsed field gel electrophoresis pattern observed after BssHII digestion of DNA from fragile X-positive, mentally retarded individuals compared with normal male controls. A 600-kb band was either absent or of reduced intensity in affected males. The pattern was normal in normal, fragile X-negative transmitting males, whereas their mentally retarded, fragile X-positive grandsons lacked the fragment. These observations suggested that the absence of the band is the result of methylation of the BssHII site. The findings were considered consistent with Laird's hypothesis of imprinting at this locus and with a 2-step process for the expression of the disease (Laird et al., 1987). </p><p>Oberle et al. (1991) found that probes adjacent to a single CpG island that was mapped at or very near the fragile site detected very localized DNA rearrangements that constitute the fragile X mutations. These rearrangements occurred in a 550-bp GC-rich fragment. Phenotypically normal, transmitting males had a 150- to 400-bp insertion that was inherited by their daughters either unchanged or with little change in size. Fragile X-positive persons in the next generation had much larger fragments that differed among sibs and showed a generally heterogeneous pattern indicating somatic mutation. The mutated allele appeared unmethylated in normal transmitting males, methylated only on the inactive X chromosome in their daughters, and totally methylated in most fragile X males. However, some males had a mosaic pattern. Expression of the fragile X syndrome thus appears to result from a 2-step mutation as well as highly localized methylation. </p><p>Rousseau et al. (1992) reviewed the 'unstable and methylatable mutations causing the fragile X syndrome.' They pointed out that the CGG repeat is in phase with the following protein coding sequence and, if translated, would code for a stretch of 6 to 54 arginines. </p><p>By studying chorionic villi from 10 fetuses with a full mutation, Devys et al. (1992) found that somatic heterogeneity of the full mutation is established during the very early stages of embryogenesis. Abnormal methylation was present in 8 of 9 villi analyzed. The pattern of mosaicism was strictly identical in 2 pairs of monozygotic twins, indicating that the somatic heterogeneity and abnormal methylation are established early in development. FMR1 mRNA was absent in those with the full mutation, with the exception of mosaics. </p><p>Smits et al. (1993) stated that they had been unable to demonstrate de novo FMR1 mutations in 84 probands referred to them to date. Interestingly, they also demonstrated the same FMR1 expansion mutation in 5 fragile X probands with common ancestors married in 1747. </p><p>In a survey of 222 unrelated mentally retarded individuals attending Spanish special schools, Mila et al. (1997) found 11 boys with full mutations in the FMR1 gene and 1 boy with a CCG repeat expansion in the FMR2 gene (see 309548). </p><p>Colak et al. (2014) demonstrated that FMR1 silencing is mediated by the FMR1 mRNA. The FMR1 mRNA contains the transcribed CGG-repeat tract as part of the 5-prime untranslated region, which hybridizes to the complementary CGG-repeat portion of the FMR1 gene to form an RNA/DNA duplex. Disrupting the interaction of the mRNA with the CGG-repeat portion of the FMR1 gene prevents promoter silencing. Colak et al. (2014) concluded that their data linked trinucleotide repeat expansion to a form of RNA-directed gene silencing mediated by direct interactions of the trinucleotide repeat RNA and DNA. </p><p><strong><em>Deletions in the FMR1 Gene</em></strong></p><p>
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In a fragile X-negative mentally retarded male who presented with the clinical phenotype of the fragile X syndrome, Wohrle et al. (1992) found a microdeletion of less than 250 kb, including the methylated island and at least 5 exons of the FMR1 gene. The data supported the hypothesis that loss of function of the FMR1 gene is responsible for the clinical phenotype of the fragile X syndrome and opened the possibility that pathogenetic mechanisms other than amplification of the CGG repeat can have the same phenotypic consequences. Wohrle et al. (1992) indicated that they had started a systematic screening of sporadic cases of the fragile X syndrome in which the individuals are cytogenetically negative. </p><p>Gedeon et al. (1992) described a patient with typical clinical features of the fragile X syndrome but without cytogenetic expression of the fragile X and without an amplified CCG trinucleotide repeat fragment. The patient had a previously uncharacterized submicroscopic deletion encompassing the CCG repeat, the entire FMR1 gene, and about 2.5 megabases of flanking sequences. Random X inactivation was found in the patient's mother, who was shown to be a carrier of the deletion. Tarleton et al. (1993) described a de novo deletion. </p><p>Meijer et al. (1994) reported a family in which 11 individuals had a 1.6-kb deletion proximal to the CGG repeat of the FMR1 gene as the cause of the fragile X syndrome. Although fragile X chromosomes were not cytologically detectable, all 4 affected males and 2 of the carrier females showed the characteristic clinical phenotype. Using RT-PCR, Meijer et al. (1994) demonstrated that FMR1 was not expressed in the affected males, strongly suggesting that the FMR1 promoter sequences 5-prime to the CGG repeat were missing. The deletion patients had approximately 45 CGG repeats in the FMR1 gene; however, these were not interspersed by AGG triplets that are usually present in both normal and expanded repeats. Meijer et al. (1994) hypothesized that an expansion of the repeat occurred prior to the occurrence of the deletion, and that the deletion removed the 5-prime part of the CGG repeat containing the AGG triplets. Transmission of the deletion through the family could be traced back to the deceased grandfather of the affected males, which supported the hypothesis that the FMR1 gene product is not required for spermatogenesis. </p><p>Hirst et al. (1995) reported 2 unrelated males with fragile X syndrome due to deletion of the FMR1 gene. </p><p>Quan et al. (1995) described a phenotypically atypical case of fragile X syndrome caused by a deletion that included the entire FMR1 gene and at least 9.0 Mb of flanking DNA. The proband was a 6-year-old mentally retarded male with obesity and anal atresia. The diagnosis of fragile X syndrome was established by the failure of the proband's DNA to hybridize to a restriction fragment specific for the 5-prime end of the FMR1 gene. The analysis of flanking markers in the interval Xq26.3-q28 indicated a deletion extending from between 160- to 500-kb distal, and 9.0-Mb proximal, to the FMR1 gene. High-resolution chromosome banding confirmed a deletion with breakpoints in Xq26.3 and Xq27.3. This deletion was maternally transmitted and arose as a new mutation on the grandpaternal X chromosome. </p><p>Quan et al. (1995) described a patient with mosaicism for expansion and deletion of the FMR1 CGG repeat. The deletion was in approximately 85% of the patient's cells. In addition to mental retardation, the affected male had cherubism (see 118400), although this was presumably unrelated. Previous work suggested that the expansion of the maternally derived allele occurs mitotically during early embryonic development. The failure to observe the expanded FMR1 alleles in the germline suggested that the expansion event occurred between days 5 and 20 of development, after the separation of the germline but before the divergence of tissue types. The findings of Quan et al. (1995) of mosaicism for expansion and deletion were consistent with this model of fragile X expansion. The detection of premutation-sized alleles in the proband was consistent with the transmission of a maternal premutation-sized FMR1 allele and postzygotic expansion. An unmethylated CpG island upstream of the FMR1 deletion indicated that the expansion and deletion of the CGG repeat occurred before FMR1 methylation. </p><p><strong><em>Premature Ovarian Failure and Premutation Alleles</em></strong></p><p>
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Fragile X premutations in female carriers appear to be a risk factor for premature ovarian failure (POF1; 311360), defined as menopause at age less than 40 years. Murray et al. (1998) screened 147 women with idiopathic premature ovarian failure and found a significant association with premutations in the FMR1 gene (309550.0004), with 6 women having premutations, including 4 familial and 2 sporadic cases, but no women with full mutations in the FMR1 gene. There were no pre- or full mutations of the FMR2 gene (309548), but there was an excess of small alleles with fewer than 11 repeats at this locus. Murray et al. (1998) concluded that premutations of FMR1 can affect ovarian development or function, or both. </p><p>In an international collaborative study of 760 women from fragile X families, Allingham-Hawkins et al. (1999) found that 395 carried a premutation, 128 carried a full mutation, and 237 were noncarriers. In 63 (16%) of the premutation carriers, menopause occurred before the age of 40, compared with none of the full-mutation carriers and 1 (0.4%) of the controls, indicating a significant association between premature menopause and premutation carrier status. </p><p><strong><em>Fragile X Tremor/Ataxia Syndrome (FXTAS) and Premutation Alleles</em></strong></p><p>
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Hagerman et al. (2001) reported 5 men with a fragile X premutation, ranging from 78 to 98 repeats, who presented in the sixth decade with progressive intention tremor, parkinsonism, cognitive decline, generalized atrophy on MRI, and impotence (FXTAS; 300623). Levels of FMR1 mRNA were 2 to 4 times higher than normal, which the authors suggested resulted in a pathogenic gain-of-function effect. Leehey et al. (2003) reported 2 unrelated men who presented with essential tremor at ages 58 and 49 years and were later found to carry a fragile X premutation (90 and 160 repeats, respectively). Besides the disabling intention tremor, both patients had tandem gait difficulties, generalized brain atrophy, and elevated FMR1 mRNA. </p><p>Garcia-Arocena et al. (2010) reported a cellular endophenotype involving increased stress response involving increase expression of HSP27 (HSPB1; 602195), HSP70 (HSPA1A; 140550) and CRYAB (123590) and altered lamin A/C (LMNA; 150330) expression/organization in cultured skin fibroblasts from 11 male carriers of premutation alleles of the FMR1 gene, including 6 patients with FXTAS and 5 premutation carriers with no clinical evidence of FXTAS, compared with 6 controls. A similar abnormal cellular phenotype was found in central nervous system tissue from 10 patients with FXTAS. There was an analogous abnormal cellular distribution of lamin A/C isoforms in knock-in mice bearing the expanded CGG repeat in the murine Fmr1 gene. These alterations were evident even in mouse embryonic fibroblasts, raising the possibility that, in humans, the expanded-repeat mRNA may trigger pathogenic mechanisms early in development. </p><p><strong><em>Additional Studies on Premutation/Intermediate Alleles</em></strong></p><p>
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Using fluorescence-based RT-PCR, Tassone et al. (2000) found that FMR1 mRNA levels were increased in peripheral blood lymphocytes from 16 male carriers of premutation alleles (55 to 192 repeats) compared to normal controls. The increase was approximately 5-fold in 7 carriers with over 100 repeats. No increase in FMRP mRNA stability was observed in a lymphoblastoid cell line with 160 repeats derived from a carrier male, indicating that the increased mRNA levels resulted from an increased rate of transcription. Cells from carriers of premutation alleles showed decreased immunostaining for the FMRP protein, suggesting a defect in translation. Tassone et al. (2000) postulated that diminished translation efficiency of FMRP mRNA in premutation carriers resulted in compensatory increased transcription. </p><p>Using a highly sensitive quantification assay, Kenneson et al. (2001) demonstrated significantly diminished levels of the FMRP protein in transformed cells derived from carriers of premutation alleles (105 to 130 repeats) and intermediate alleles (48 and 55 repeats). The protein levels were negatively correlated with repeat number. Despite reduced FMRP, these carrier alleles overexpressed FMR1 mRNA, resulting in a positive correlation between repeat number and FMR1 mRNA. Kenneson et al. (2001) concluded that biochemical abnormalities are already present in premutation FMR1 alleles, which may explain the phenotypic features reported in some of these carriers. </p><p>Chen et al. (2003) examined the influence of the CGG repeat on translation by transfecting human neural and kidney-derived cell lines with the FMR1 5-prime UTR of various CGG premutation repeat lengths (0 to 99) and a downstream reporter. For both cell types, the CGG element exerted distinct effects on reporter expression, depending on the length of the repeat. For lengths of 30 repeats or more, luciferase expression decreased with increasing repeat length, despite a slight increase in mRNA level for the larger repeats. However, for smaller alleles (0 to 30), reporter expression actually increased by nearly 2-fold with increasing repeat length in the absence of any change in mRNA level. Chen et al. (2003) concluded that the CGG repeat element can exert both positive (less than 30 repeats) and negative (greater than 30 repeats) effects on translation. </p><p>Beilina et al. (2004) used 5-prime-RLM-RACE to examine the influence of CGG repeat number on the utilization of transcription start sites in normal (less than 55) and premutation (greater than 54 and less than 200) cell lines of both nonneural (lymphoblastoid) and neural (primary astrocyte) origin. FMR1 transcription in both cell lines was initiated from several start sites within an approximately 50-nucleotide region that lies approximately 130 nucleotides upstream of the CGG repeat element. For normal alleles, most transcripts initiated from the downstream-most start site. As the size of the CGG repeat expanded into the premutation range, initiation shifted to the upstream sites, suggesting that the CGG element may act as a downstream enhancer/modulator of transcription. </p><p>From a screening study of 1,253 males attending Tasmanian schools, Loesch et al. (2007) identified 33 carriers of intermediate or 'gray zone' alleles, defined by the authors as 41 to 60 CGG repeats. Twenty carriers were special educational needs students attending regular schools, 10 were regular students, and 3 were brothers of special needs students previously identified as gray zone carriers. Loesch et al. (2007) found significantly increased transcriptional activity in intermediate carriers relative to carriers of common alleles of 5 to 40 repeats (p less than 0.001). Piecewise linear regression revealed that the threshold for onset of the increase in mRNA levels is at approximately 39 repeats, and that the reduction in the rate of this increase is at approximately 54 repeats. </p><p>Jenkins et al. (2008) quantified the telomere length in T lymphocytes from older male carriers of premutation FMR1 alleles, with or without FXTAS, and FXTAS with dementia. Shorter telomeres (relative to age-matched controls) were observed in 5 of 5 individuals with FXTAS and dementia, in 2 of 2 individuals with FXTAS without dementia, and in 3 of 3 individuals with the fragile X premutation only (p values ranged from less than 0.001 to less than 0.05; student's t-test), indicating that telomere shortening is associated with the FMR1 premutation expansion. A comparison of control, premutation, FXTAS, and FXTAS with dementia samples showed nearly equal degrees of shortening relative to controls among the 3 premutation sample groups. Jenkins et al. (2008) suggested that telomere shortening may serve as a biomarker for cellular dysregulation that may precede the development of the symptoms of FXTAS. </p><p><strong><em>Studies on Mechanisms of Repeat Instability</em></strong></p><p>
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The 'Sherman paradox' was applied to the following phenomenon observed in fragile X syndrome: 20% of males who carry a fragile X chromosome are phenotypically normal; their daughters, to whom they transmit the fragile X chromosome, are likewise normal, but their grandsons are often affected. The brothers of the clinically normal, transmitting males have a low risk, while grandsons and great-grandsons have much higher risks. Fu et al. (1991) demonstrated that the Sherman paradox is related to the particular structure of the (CGG)n repeat found in the coding sequence of the FMR1 gene. The range of allele sizes varied from 6 to 54 repeats in normal individuals. Premutations showing no phenotypic effect in fragile X families ranged in size from 52 to more than 200 repeats. All alleles with greater than 52 repeats, including those identified in a normal family, were meiotically unstable, with a mutation frequency of 1, while 75 meioses of alleles of 46 repeats and below showed no mutation. Demonstration of mosaicism suggested that premutation alleles are also mitotically unstable. Fu et al. (1991) showed that the risk of expansion during oogenesis to the full mutation increased with the number of repeats, thus explaining the Sherman paradox, which might be viewed as an example of the phenomenon of anticipation. Remarkably, the premutation expands to a full mutation only when it is transmitted by a female; consequently, daughters of normal transmitting males have only the premutation and never the full mutation, and never show mental retardation or cytogenetic expression of the fragile X syndrome. Furthermore, daughters of affected males do not express the fragile X syndrome at either the clinical or the cytogenetic level. </p><p>In a study of the sperm in 4 male fragile X patients, Reyniers et al. (1993) found that only the premutation was present, although the full mutation was present in peripheral lymphocytes. They concluded that expansion of the premutation to the full mutation in this disorder does not occur in meiosis but in a postzygotic stage. The same conclusion was supported by the finding of Kruyer et al. (1994) in 2 affected monozygotic brothers who differed in the number of CGG repeats, indicating mitotic instability. The work of Wohrle et al. (1993) also suggested that the expansion of an FMR1 premutation to a full mutation occurs mitotically during a postzygotic stage. </p><p>Zhong et al. (1993) described a second mutable sequence within the FMR1 gene. Richards et al. (1991) had described 2 polymorphic markers, designated AC1 and AC2, located within FMR1 and flanking the unstable (CGG)n repeat by approximately 10 kb. Zhong et al. (1993) confirmed linkage disequilibrium of the (CGG)n repeat with AC1 but found linkage equilibrium with AC2, which they also found was highly mutable. A mutation rate of 3.3% was observed but only among fragile X maternally-derived meioses. The finding of a second mutable locus within FMR1 suggested that the target for tandem repeat instability may not be confined to the (CGG)n repeat alone but may also involve microsatellites. Zhong et al. (1993) cited evidence that the AC sequence is located within intron 2 of the FMR1 gene and is adjacent to an Alu element. </p><p>In a daughter of a female carrier of the fragile X mutation, van den Ouweland et al. (1994) found a haplotype using flanking markers that predicted she had inherited the fragile X premutation chromosome. However, the CGG repeat sequence and the intragenic polymorphic marker FMRb showed the normal maternal alleles, while 2 other intragenic markers, FMRa and FRAXAC2, and other more distant markers, showed the risk haplotype. These observations were interpreted as indicating gene conversion and might represent back mutation at the FMR1 locus. </p><p>Nolin et al. (1996) examined transmission of the FMR1 (CGG)n repeat in 191 families with fragile X and in the general population. They reported that when fathers have (CGG)n expansions in the premutation range (greater than 80 repeats) the daughters frequently inherited smaller repeat expansions. A similar repeat number was inherited more often than expected by chance among a sibship segregating fragile X. They concluded that this familial clustering, observed in the offspring of both males and females with a premutation, implies that there may be an additional factor, independent of parental repeat size, that influences (CGG)n repeat instability. Nolin et al. (1996) found that gray-zone alleles (40 to 60 repeats) in families with no previous history of fragile X syndrome varied in their stability but that there was no repeat expansion to the full fragile X mutation in 1 generation. </p><p>It had been suggested that expansion of the CGG repeat in the FMR1 gene is a postzygotic event with the germline protected. From an analysis of intact ovaries of full-mutation fetuses, Malter et al. (1997) showed that only full-expansion alleles could be detected in oocyte, but in the unmethylated state. Similarly, the testis of a 13-week full-mutation fetus showed no evidence of premutations, while a 17-week full mutation fetus exhibited some germ cells with attributes of premutations. These data discounted the hypothesis that the germline is protected from full expansion and suggested that full-mutation contraction occurs in the immature testis. Thus, full expansion may already exist in the maternal oocyte, or postzygotic expansion, if it occurs, arises quite early in development prior to germline segregation. </p><p>Kunst et al. (1997) studied the influence of AGG interruptions on CGG repeat stability. In the sorted sperm of 2 donors, each with 39 total repeats but distinct AGG interruption patterns, there was approximately 15% variation in repeat length in each case. However, the male with 29 perfect repeats showed 3% expansion changes while the male with 19 perfect repeats had none. Kunst et al. (1997) also noted that all variant sperm showed expansion or contraction of the 3-prime end of the repeat array. Kunst et al. (1997) concluded that these data are consistent with the hypothesis that perfect repeat tracts influence repeat stability and that changes of the FMR1 repeat exhibit polarity. </p><p>Patients with hereditary nonpolyposis colon cancer (HNPCC; 120435) resulting from mutation in a mismatch repair gene such as MLH1 (120436) show instability of repeat sequences. Fulchignoni-Lataud et al. (1997) found that peripheral blood leukocytes from HNPCC patients showed roughly twice as great allele variation of the FMR1 CGG repeat as did controls, especially when patients carried mutations in MLH1. The findings suggested that instability within nonneoplastic cells of a subset of HNPCC patients might be a mechanism for transition from normal to the premutation range of the FMR1 CGG repeat. </p><p>Crawford et al. (2000) performed small pool (SP)-PCR on sperm and blood DNA from 7 unaffected males whose repeat sizes ranged from 20 to 33. Regression analyses suggested that components of the repeat structure, such as the number of interruptions and purity of the 3-prime end of the repeat, are important determinants of germline repeat instability. In contrast, elements other than repeat structure, such as haplotype background, seemed to have an impact on somatic repeat instability. The factors identified for either cell type, however, explained only a small portion of the variance, suggesting to the authors that other factors may be involved in this process. </p><p>Jin and Warren (2000) reviewed the molecular mechanism of CGG repeat expansion and physiologic functions of the FMR1 protein. Oostra and Willemsen (2003) reviewed expression of FMR1 in the context of trinucleotide repeat expansion and human disease states. </p><p>Laird et al. (1987) proposed that regions of late replicating DNA are present at fragile sites in human chromosomes. Hansen et al. (1993) found that cells derived from normal individuals replicated late in S phase, whereas cells from fragile X patients replicated later, with the major peak of replication occurring in G2/M phase. Delayed replication timing was observed on both sides of the expanded repeat, suggesting that the stalling of a replication fork at the expanded region was not the direct cause of replication delay. Subramanian et al. (1996) found that cells from individuals with a full FMR1 repeat expansion displayed a region of delayed replication timing; the apparent timing of the earlier-replicating allele in female cells in this region was intermediate between normal and affected alleles in male cells, a finding in accordance with expectations of a mixed population of cells resulting from random X inactivation. In this assay, relative times of replication of specific loci were inferred from the ratios of singlet and doublet fluorescence in situ hybridization signals in interphase nuclei. Trinucleotide repeat expansion thus may be acting in the Xq27.3-q28 region to alter long-range chromatin structure that could influence transcription of gene sequences within the affected domain. </p><p>Yeshaya et al. (1998) studied replication timing of the fragile X locus relative to the nontranscribed late replicating alpha-satellite region of chromosome X in lymphocytes and amniocytes from normal males, males with fragile X, and males who were premutation carriers. Three distinct populations were identified among the various samples. The first population had a high frequency of cells showing a doublet FMR1; this pattern, indicating early replication of FMR1, characterized cell populations of normal males. The second population had a high frequency of cells showing a singlet FMR1; this pattern, indicating very late replication of FMR1, characterized the population of fragile X patients. The third population had about one-half of the cells showing a singlet FMR1 and the other half with a doublet FMR1, indicating somatic variation in the replication timing of FMR1. This was the pattern seen in the population of premutation carriers. </p><p>Instability of the fragile X CGG repeat involves both maternally-derived expansions and deletions in the gametes of full-mutation males. Using an SV40 primate replication system, Nichol Edamura et al. (2005) investigated the effect of CGG tract length, DNA replication direction, location of replication initiation, and CpG methylation upon CGG stability. Replication-dependent deletions with 53 CGG repeats were observed when replication was initiated proximal to the repeat, with CGG as the lagging-strand template. When they initiated replication further from the repeat, while maintaining CGG as the lagging-strand template or using CCG as the lagging-strand template, significant instability was not observed. CpG methylation of the unstable template stabilized the repeat, decreasing both the frequency and the magnitude of deletion events. Furthermore, CpG methylation slowed the efficiency of replication for all templates. Interestingly, replication forks displayed no evidence of a block at the CGG repeat tract, regardless of replication direction or CpG methylation status. Templates with 20 CGG repeats were stable under all circumstances. These results showed that CGG deletions occur during replication and are sensitive to replication-fork dynamics, tract length, and CpG methylation. </p><p>Terracciano et al. (2004) reported a family in which unstable transmission of an intermediate 44 CGG fragile X allele from the maternal grandfather occurred, with expansion first to a premutated allele of 61 CGGs in a daughter and then to a fully mutated allele in her child, representing a rare progression from intermediate to full mutation in just 2 generations. Zuniga et al. (2005) reported another family in which an intermediate fragile X allele expanded to a fully mutated allele in 2 generations. The maternal grandmother carried an intermediate fragile X allele with 45 CGG repeats, which expanded to premutated alleles of 80 and 90 repeats in her 2 daughters, respectively, and then to fully mutated alleles in each daughter's son. Sequencing showed absence of AGG interruptions that are believed to ensure repeat stability from 1 generation to another. </p><p>Nolin et al. (2008) found that leukocyte samples from individuals with full expansion FMR1 alleles showed only 1 to 4 major alleles per individual when analyzed in the absence of ethidium bromide. In contrast, full mutations in chorionic villi exhibited greater heterogeneity. Analysis of 9 mother-offspring pairs showed expansion of the allele in the offspring. The findings suggested that extensive heterogeneity of full mutation fragments often reported as 'smears' by Southern analysis is an artifact, and that somatic instability in the FMR1 CGG repeat is limited to early embryogenesis. </p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>Using the G6PD Mediterranean variant as a marker, Rocchi et al. (1990) investigated the number of somatic cells (fibroblasts or red cells) with an active fragile X chromosome. They found a significant inverse correlation between IQ level in heterozygotes and the percentage of fibroblasts with the fragile X as the active chromosome. In contrast, no significant correlation was found between IQ and the red cell data, suggesting somatic selection against hematopoietic stem cells with an active fragile X. In studies of peripheral lymphocytes, Webb and Jacobs (1990) found that the number of active fra(X) chromosomes was consistently higher in retarded heterozygous females than in mentally normal heterozygous females. A review of the findings in the literature showed the same result. Khalifa et al. (1990) found no evidence that DNA methylation in the vicinity of the fragile X site influences the phenotype of the syndrome. </p><p>Rousseau et al. (1994) reported the results of a 14-center collaborative study of genotype-phenotype correlations in the fragile X syndrome involving 318 affected families comprising 539 individuals with a fragile X premutation and 693 with a typical full fragile X mutation. Mental status of those with a premutation did not differ from those with a normal genotype. Both abnormal methylation of the FMR1 site and size of the expansion were highly correlated with cytogenetics, facial dysmorphism, macroorchidism, and mental retardation. There was a significantly higher prevalence of 'mosaic' cases among males with a full mutation (12%) than among females with a full mutation (6%); the mosaic males had a larger expansion than did the mosaic females. 'Mosaics' are individuals carrying the full mutation who also have some premutations in some of their cells. Among 164 independent couples, 3 unrelated husbands carried a premutation, suggesting that the prevalence of fragile X premutations in the general population is approximately 0.9% of the X chromosomes. The data validated the use of direct DNA testing for fragile X diagnosis and carrier identification. </p><p>Kirchgessner et al. (1995) determined that the FMR1 gene is subject to X inactivation by studying inactive X chromosomes in somatic cell hybrids that contained an active or inactive human X chromosome and in a female patient with a large deletion surrounding the FMR1 gene. The findings were consistent with the results of previous studies of DNA methylation of FMR1 and supported the involvement of X inactivation in the variable phenotype of females with full mutations of the FMR1 gene. </p><p>Sun and Baumer (1999) studied a fibroblast culture from a 20-week female fetus who was diagnosed as a full mutation heterozygote. Higher passage cells showed a complete absence of cells in which the normal X chromosome would be inactivated. Studies of a control fibroblast culture derived from a female fetus with normal FMR1 alleles showed no selection. The study indicated nonrandom X inactivation and suggested a selection process that is dependent on the activation status of the X chromosome carrying an FMR1 full mutation. </p><p>Primerano et al. (2002) noted that lymphoblastoid cells from patients with the full fragile X mutation (greater than 200 CGG repeats) have essentially absent levels of FMR1 mRNA and FMR1 protein, consistent with hypermethylation of the FMR1 gene and complete transcriptional silencing of the gene. In cells from 3 patients with premutation alleles (97, 170, and 195 CGG repeats), Primerano et al. (2002) found significantly increased levels of FMR1 mRNA compared with normal controls, and the level of mRNA increased with longer CGG repeats in the premutation range. However, overexpression of the mRNA from the premutation expanded alleles was not associated with increased levels of FMRP protein, suggesting a defect in translation. An analysis of polysomes and mRNA showed that the association of mRNA with polysomes progressively decreased with increasing allele expansion. Thus, in cases with premutation, impaired FMR1 translation leads to lower FMRP levels and clinical involvement. </p><p>In a boy with speech and developmental delay and low normal IQ measures, Tarleton et al. (2002) identified a G-to-C point mutation within the CGG repeat region of FMR1. The patient had a 31-repeat segment, within the normal range, but was originally thought to have a deletion in the FMR1 gene. Peripheral blood analysis showed a 24% reduction in the FMR protein. Tarleton et al. (2002) suggested that the mild phenotype resulted from the mild change in FMRP expression. </p><p>Hagerman and Hagerman (2004) pointed out that carriers of premutation alleles (55 to 200 CGG repeats) of the FMR1 gene can present with 1 or more of 3 distinct clinical disorders: mild cognitive and/or behavioral deficits on the fragile X spectrum; premature ovarian failure; and fragile X tremor/ataxia syndrome (FXTAS). </p><p>Among 621 children, Loat et al. (2006) observed an inverse association between between FMR1 allele length and cognitive ability in boys. There was a significant negative correlation between nonverbal ability at age 4 years (p = 0.048) and academic achievement in math (p = 0.003) and English (p = 0.011) at 7 years. There was also a negative correlation between repeat size and IQ in a cohort of 122 students with high IQ. However, only 35 (3.5%) of 1,016 X chromosomes harbored more than 40 CGG repeats, and there was no difference in the incidence of alleles with greater than 40 repeats between the groups of children with high, control, and low cognitive ability. </p><p>Murray et al. (2014) studied FMR1 CGG repeat number in more than 2,000 women from the Breakthrough Generations Study who underwent menopause before the age of 46. The authors determined the prevalence of premutation FMR1 alleles (55-200 CGG repeats) and intermediate (45-54 CGG repeats) alleles in 254 women with primary ovarian failure (311360), defined as menopause prior to the age of 40, and 1,881 with early menopause, defined as menopause between the ages of 40 and 45. The prevalence of the premutation was 2.0% in primary ovarian failure and 0.7% in early menopause compared with 0.4% in controls, corresponding to odds ratios of 5.4 (95% CI = 1.7-17.4; p = 0.004) for primary ovarian failure and 2.0 (95% CI = 0.8-5.1; p = 0.12) for early menopause. Intermediate alleles were not significant risk factors for either early menopause or primary ovarian failure. </p><p><strong><em>Methylation</em></strong></p><p>
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In 2 clinically normal brothers, Smeets et al. (1995) found expanded CGG repeats in cytogenetically visible fragile sites. The FMR1 promoter was unmethylated and both RNA and protein could be detected. This indicated to the authors that inactivation of the FMR1 gene and not the repeat expansion itself resulted in the fragile X phenotype. Smeets et al. (1995) concluded that repeat expansion does not necessarily induce methylation and that methylation is not an absolute requirement for the induction of fragile sites. This fragile X family was ascertained through a mentally retarded boy who was the grandson of 1 of the 2 brothers through a daughter. </p><p>McConkie-Rosell et al. (1993) reported an unusual family with 6 brothers, including 3 affected with fragile X syndrome, 2 nonpenetrant carriers, and 1 unaffected. Two of the affected brothers and the 2 'nonpenetrant' brothers were found to be methylation mosaics. A correlation was seen between the degree of methylation and the phenotypic expression identified in the 3 affected males. The 2 males initially classified as nonpenetrant were found to have mild phenotypic expression with minor cognitive deficits and a partial physical phenotype. These 2 males, who were negative on fragile X chromosome studies, were found on DNA analysis to have large, broad smears, with approximately 97% of the DNA unmethylated; they were mosaic for hypermethylation of an expansion of the CGG repeat in the premutation range (100-600 bp). The result indicated that some 'nonpenetrant' carrier males may have varying amounts of methylation of the FMR1 regions, which can result in mild expression of the fragile X syndrome. Expression of the syndrome may not be confined to males with the full mutation and large, hypermethylated expansions, but may instead have a gradient effect with a threshold for the full expression of the phenotype. </p><p>Kruyer et al. (1994) reported 2 monozygotic twin sisters with the same number of FMR1 CGG repeats, but only 1 was mentally retarded. When the methylation status of the FMR1 CpG island was studied, Kruyer et al. (1994) found that the majority of the normal chromosomes had been inactivated in the affected twin. </p><p>Chiurazzi et al. (1998) investigated whether FMR1 activity could be restored in vitro by inducing DNA demethylation with 5-azadeoxycytidine (5-azadC) lymphoblastoid cells derived from fragile X patients. Treatment with 5-azadC causes reactivation of fully mutated FMR1 genes with 300 to 800 repeats, as shown by the restoration of specific mRNA and protein production. This effect correlated with the extent of promoter demethylation, determined by restriction analysis with methylation-sensitive enzymes. Chiurazzi et al. (1999) investigated the role of histone acetylation in regulating FMR1 expression by treating lymphoblastoid cell lines of nonmosaic full mutation patients with 3 drugs capable of inducing histone hyperacetylation. They observed a consistent, although modest, reactivation of the FMR1 gene with 4-phenylbutyrate, sodium butyrate, and the cytotoxic drug trichostatin A, as shown by RT-PCR. Combining these drugs with 5-azadC resulted in a 2- to 5-fold increase in FMR1 mRNA levels obtained with 5-azadC alone, thus showing a synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of FMR1 full mutations. </p><p>Pietrobono et al. (2005) analyzed lymphoblastoid cell DNA from a rare individual of normal intelligence with an unmethylated full mutation of the FMR1 gene. Lack of DNA methylation of the entire promoter region (including the expanded CGG repeat) correlated with methylation of lysine-4 residue on the N-tail of histone H3 (H3-K4), as in normal controls. Normal levels of FMR1 mRNA were detected by real-time RT-PCR, but mRNA translation was decreased by 40%, resulting in FMRP protein levels reduced by 30% compared to normal controls. These results confirmed that CGG repeat amplification per se does not prevent FMR1 transcription and FMRP production in the absence of DNA methylation. The cell line had deacetylated histones H3 and H4, as well as methylated lysine-9 on histone H3 (H3-K9) similar to fragile X cell lines, in both the promoter and exon 1. This suggested that histone deacetylation and H3-K9 methylation may be established in the absence of DNA methylation and do not interfere with active gene transcription. Pietrobono et al. (2005) suggested that the molecular pathways regulating DNA and H3-K4 methylation may be independent from those regulating histone acetylation and H3-K9 methylation. </p><p>Naumann et al. (2009) found that the methylation boundary upstream of the FMR1 gene was lost in FRAXA males. In the FRAXA genomes studied, methylation of upstream CpG pairs penetrated into the normally unmethylated promoter region of FMR1 and to the CGG repeat, resulting in inactivation of the FRAXA gene. The methylation pattern in DNA from premutation females was similar to that of normal females. </p><p>Godler et al. (2010) identified epigenetic markers for fragile X syndrome using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS), naming the most informative fragile X-related epigenetic element 1 (FREE1) and 2 (FREE2). Methylation of both regions was correlated with that of the FMR1 CpG island detected using Southern blot and negatively correlated with lymphocyte expression of FMRP in blood of partially methylated 'high functioning' full mutation (FM) males. In blood of FM carrier females, methylation of both markers was inversely correlated with the FMR1 activation ratio. In a sample set of 49 controls, 18 gray zone (GZ 40-54 repeats), 22 premutation (PM 55-170 repeats), and 22 (affected) fragile X subjects, the FREE1 methylation pattern was consistent between blood and chorionic villi as a marker of methylated FM alleles and could be used to differentiate fragile X males and females from controls, as well as from carriers of GZ/PM alleles, but not between GZ and PM alleles and controls. Godler et al. (2010) suggested that FREE MALDI-TOF MS may be a tool in fragile X syndrome diagnostics and newborn population screening. </p>
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<strong>Nomenclature</strong>
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<p>Hecht et al. (1989) suggested a new system of gene symbols for fragile sites. Their suggestion for the fragile site discussed here was FRAXQ27*RFA, where R means 'rare' and FA indicates that it is of the 'folic acid type.' Thus, the fragile X syndrome locus is also referred to in the literature as FRAXA. </p><p><strong><em>Nomenclature of Expanded Trinucleotide Repeats</em></strong></p><p>
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The repeat involved in the fragile X syndrome is variously referred to here as (CGG)n or (CCG)n. The identical repeat found in the cloned FRAXE gene (309548) was referred to as (GCC)n by Knight et al. (1993). There are only 10 different trinucleotide repeats, but each can be written in a number of ways. Sutherland (1993) favored the convention that lists the motif in alphabetical order in the 5-prime to 3-prime direction. Consistent with this, he uses the (CCG)n designation. He preferred, furthermore, the designation (AGC)n for the other clinically significant dinucleotide repeat found in myotonic dystrophy (DM1; 160900), Huntington disease (143100), Kennedy disease (SMAX1; 313200), and SCA1 (164400); (CAG)n is the designation most often used. Sutherland (1993) suggested that the same convention can apply to dinucleotides. He wrote: 'It must be very confusing for newcomers to the literature to find (AC)n, (CA)n, (GT)n, and (TG)n repeats, when the cognoscenti know these are synonyms.' </p>
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<strong>History</strong>
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<p>Wang et al. (1997) identified a splice site mutation in intron 10 of the FMR1 gene (IVS10+14C-T) in 3 unrelated patients with fragile X syndrome who did not have an expanded (CGG)n repeat. However, Vincent and Gurling (1998) and Wang and Li (1998) confirmed that IVS10+14C-T is in fact a polymorphism and not a disorder-related mutation. </p>
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<strong>Animal Model</strong>
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<p><strong><em>FMR Protein Function in Animal Models</em></strong></p><p>
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By mRNA in situ hybridization studies in mice, Hinds et al. (1993) demonstrated that expression of the Fmr1 gene was localized to several areas of the brain and the tubules of the testes in the adult mouse, whereas universal and very strong expression was observed in early mouse embryos. To identify transcribed sequences rapidly and efficiently, Hanzlik et al. (1993) developed a recombination-based assay to screen bacteriophage lambda-libraries for sequences that share homology with a given probe. This strategy determined whether a given probe is transcribed in a given tissue at a given time of development and could also be used to isolate the transcribed sequence free of the screening probe. Hanzlik et al. (1993) used the technique to demonstrate that the fragile X sequence is transcribed ubiquitously in an 11-week mouse fetus, in a variety of 20-week fetal tissues including brain, spinal cord, eye, liver, kidney, and skeletal muscle, and in adult jejunum. </p><p>Using immunolocalization studies of murine Fmrp truncation and fusion constructs in COS-7 cells, Eberhart et al. (1996) identified a nuclear localization signal in the amino terminus and a nuclear export signal encoded by exon 14. Fmrp was found in ribonucleoprotein (RNP) particles, consistent with nascent Fmrp protein entering the nucleus to assemble into RNP particles prior to export back into the cytoplasm. </p><p>Li et al. (2001) demonstrated that recombinant rat Fmrp caused dose-dependent translational inhibition of brain mRNA in rabbit reticulate lysate without accelerated mRNA degradation. Translation suppression by Fmrp was reversed in a trans-acting manner by the 3-prime untranslated portion of the Fmr1 message, which binds Fmrp, suggesting that Fmrp inhibits translation by interacting with mRNA. Consistently, Fmrp suppressed translation of the parathyroid hormone (PTH; 168450) transcript, which binds Fmrp, but not the beta-globin (HBB; 141900) transcript, which does not bind Fmrp. Similarly, removal of the Fmrp-binding site on a translation template abolished the inhibitory effect of Fmrp, supporting the hypothesis that FMRP inhibits translation by direct interaction with template mRNA. </p><p>Human-murine homology at the FMR1 locus extends to the repeat region and promoter. The murine repeat region contains triplets ranging from 8 to 12 repeats. Bontekoe et al. (2001) generated a knockin mouse Fmr1 gene in which the murine (CGG)8 repeat was exchanged with a human (CGG)98 repeat. Unlike other CGG transgenic models, this model showed moderate CGG repeat instability (2 contractions and 13 expansions among 155 transmissions) in both maternal and paternal transmission. An abnormal phenotype was not described. </p><p>Wohrle et al. (2001) transferred hypermethylated and unmethylated full expansions of human fragile X chromosomes from murine A9 hybrids into murine embryocarcinoma cells, a model system of pluripotent embryonic cells. Full-expansion alleles that were fully methylated and stable in the donors' fibroblasts and in A9 became demethylated, reactivated, and destabilized in the undifferentiated embryocarcinoma hybrids. When destabilized expansions were reintroduced from embryocarcinoma cells into A9, instability was reversed to stability. </p><p>In Drosophila, Ishizuka et al. (2002) found that Fmr1 is a component of a large protein complex known as the RNA-induced silencing complex (RISC), which is a sequence-specific nuclease complex that mediates RNA interference (RNAi). Fmr1 was found to associate with argonaute-2 (Ago2; 606229) and dicer (606241), 2 proteins normally present in the RISC. The findings suggested that defects in an RNAi-related machinery may underlie human disease. </p><p>Mazroui et al. (2002) established an immortal murine embryonic STEK Fmr1 knockout cell line, and showed by transfection assays with Fmr1-expressing vectors that newly synthesized Fmrp accumulated into cytoplasmic granules. These structures contained mRNAs and several other RNA-binding proteins. The formation of the cytoplasmic granules was dependent on determinants located in the RGG domain. The authors also presented evidence that FMRP acts as a translation repressor following cotransfection with reporter genes. The FMRP-containing mRNPs are dynamic structures that oscillate between polyribosomes and cytoplasmic granules reminiscent of the stress granules that contain repressed mRNAs. Mazroui et al. (2002) suggested that, in neurons, FMRP may play a role as an mRNA repressor in incompetent mRNP granules that have to be translocated from the cell body to distal locations such as dendritic spines and synaptosomes. </p><p>Using mass spectrometry and site-directed mutagenesis, Ceman et al. (2003) showed that Fmrp was phosphorylated between residues 483 and 521, N terminal to the RGG box, both in murine brain and in cultured cells. Primary phosphorylation occurred on the highly conserved ser499, which triggered hierarchical phosphorylation of nearby serines. Fmrp was phosphorylated within 2 to 4 hours of synthesis; however, phosphorylation had no effect on the half-life of the protein. In contrast to the Drosophila ortholog dFxr, the phosphorylation status of mammalian Fmrp did not influence its association with specific mRNAs in vivo. However, unphosphorylated Fmrp was associated with actively translating polyribosomes, while a fraction of phosphorylated FMRP was associated with apparently stalled polyribosomes. Ceman et al. (2003) suggested that phosphorylation may regulate FMRP and that the release of FMRP-induced translational suppression may involve a dephosphorylation signal. </p><p>Wang et al. (2004) detected Fmrp expression in oligodendroglia progenitor cells, immature oligodendrocytes, and oligodendroglia cell lines isolated from rat and mouse brain, where it interacted with a subgroup of oligodendrocyte-specific mRNAs, including myelin basic protein (MBP; 159430) mRNA. Fmrp expression gradually declined as oligodendrocytes differentiated in vitro and in the developing brain. The decline of Fmrp expression during oligodendrocyte differentiation was associated with a vigorous upregulation of the MBP protein. The MBP 3-prime UTR was necessary and sufficient for binding Fmrp, and it mediated translation inhibition of a reporter gene by Fmrp specifically in oligodendrocytes. Wang et al. (2004) hypothesized that Fmrp may participate in regulating translation of its bound mRNAs in oligodendroglia during early brain development in rodents. </p><p>MicroRNAs (miRNAs) are a class of noncoding RNAs that are believed to control translation of specific target mRNAs. In vitro, Jin et al. (2004) showed that mammalian FMRP interacts with AGO1 (606228), a downstream component of the miRNA pathway, and that AGO1 is required for the biologic functions of Fmr1 in vivo in Drosophila. The results suggested a mechanism by which Fmr1 regulates translational suppression. </p><p>In Drosophila, Lgl (600966) encodes a cytoskeletal protein involved in cellular polarity and cytoplasmic transport. Zarnescu et al. (2005) found that mouse Lgl was expressed at low levels in the cytoplasm along with Fmr1. Overexpression of fluorescence-tagged Fmr1 directed the assembly of endogenous Lgl into perinuclear and cytoplasmic granules. In a mouse catecholaminergic cell line, Fmr1 overexpression resulted in reorganization of endogenous Lgl into Fmr1-containing granules in the perinuclear region and within developing neurites. </p><p>Wang et al. (2008) provided evidence that Fmr1 acts as a messenger for dopamine modulation in the forebrain. Culture neurons from the prefrontal cortex and striatum of Fmr1-null mice showed decreased D1 receptor (DRD1; 126449) agonist-induced effects, as evidenced by decreased D1 receptor-induced phosphorylation of the glutamate receptor (GRIA1; 138248). Long-term potentiation was decreased in the Fmr1-null cells. Wildtype Fmrp was found to interact with Grk2 (109635). In Fmr1-null cells, exogenous expression of FMRP or inhibition of Grk2 rescued the deficits. A D1 receptor agonist partially rescued hyperactivity and enhanced the motor function of Fmr1-null mice. </p><p>Callan et al. (2010) compared Drosophila mutant Fmr1 brains to wildtype throughout larval development using cell cycle markers. Loss of Fmr1 led to significant increase in BrdU incorporation, and in the number of mitotic neuroblasts in the brain; this is consistent with FMRP controlling proliferation during neurogenesis. In developmental studies, FMRP inhibited neuroblast exit from quiescence in early larval brains, as indicated by misexpression of cyclin E (CCNE1; 123837). By the third instar larval stage, the length of the cell cycle was unaffected, although more cells were found in S and G2/M in mutant Fmr1 brains compared with wildtype, indicating defective cell cycle progression. In addition, single mutant Fmr1 neuroblasts generated significantly more neurons than controls in the developing larval brain. The authors concluded that FMRP is required during brain development to control neuroblast exit from quiescence and proliferative capacity, as well as neuron production. </p><p><strong><em>Animal Models of Fragile X Syndrome</em></strong></p><p>
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The Dutch-Belgian Fragile X Consortium (1994) created a knockout model for the fragile X syndrome in mice. The knockout mice lacked normal FMR1 protein and showed macroorchidism, learning deficits, and hyperactivity. Although brain MRI of fragile X patients has revealed abnormalities in the size of specific brain structures, including the cerebellar vermis, the hippocampus, and the ventricular system, Kooy et al. (1999) did not find evidence for size alterations in various brain regions of the fragile X mouse model. </p><p>Peier et al. (2000) generated yeast artificial chromosome (YAC) transgenic mice to determine whether the Fmr1 knockout mouse phenotype could be rescued. The YAC transgene supported production of the human FMRP protein at levels 10 to 15 times that of endogenous protein; the protein was expressed in a cell- and tissue-specific manner. Macroorchidism was absent in knockout mice carrying the YAC transgene, indicating functional rescue by the human protein. While the knockout mice displayed reduced anxiety-related responses and increased exploratory behavior, the FMR1 YAC transgenic mice displayed opposing behavioral responses and other abnormal behaviors, presumably due to overexpression of FMRP. The authors suggested that overexpression of FMRP may harbor its own behavioral phenotype. </p><p>Protein synthesis occurs in neuronal dendrites, often near synapses. Polyribosomal aggregates often appear in dendritic spines, particularly during development. Some protein synthesis appears to be regulated directly by synaptic activity. Greenough et al. (2001) found that FMRP is one of the proteins that is synthesized in a preparation called synaptoneurosomes when stimulated with glutamate or group I metabotropic glutamate receptor agonists (e.g., 604473). They also found that agonist-activated protein synthesis in synaptoneurosomes was dramatically reduced in a knockout mouse model of fragile X syndrome. Studies of autopsy samples from patients with fragile X syndrome indicated that dendritic spines may fail to assume a normal mature size and shape and that there are more spines per unit of dendrite length in the patient samples. Similar findings on spine size and shape had come from studies of the knockout mouse. Normal dendritic regression was also impaired in the knockout mouse. These findings suggested that FMRP may be required for the normal processes of maturation and elimination to occur in cerebral cortical development. </p><p>Zhang et al. (2001) developed a Drosophila model of fragile X syndrome using loss-of-function mutants and overexpression of the FMR1 homolog, Dfxr (Drosophila fragile X-related gene). Dfxr nulls displayed enlarged synaptic terminals, whereas neuronal overexpression resulted in fewer and larger synaptic boutons. Synaptic structural defects were accompanied by altered neurotransmission, with synapse type-specific regulation in central and peripheral synapses. These phenotypes mimicked those observed in mutants of Futsch, a microtubule-associated protein with homology to mammalian MAP1B (157129). Immunoprecipitation of Dfxr showed association with Futsch mRNA, and Western blot analyses demonstrated that Dfxr inversely regulates Futsch expression. Dfxr-Futsch double mutants restored normal synaptic structure and function. Zhang et al. (2001) proposed that Dfxr acts as a translational repressor of Futsch to regulate microtubule-dependent synaptic growth and function. </p><p>Using wildtype Drosophila and Drosophila mutant in Dfxr, Morales et al. (2002) showed that the Dfxr protein is constitutively expressed in brain neuronal cell bodies and excluded from glia. The protein was found to be required for normal neurite extension, guidance, and branching, although different neuronal cell types appeared to be regulated differently, indicating diverse targets in the brain. Overexpression of the protein resulted in similar abnormalities, suggesting that the dose of Dfxr is strictly regulated and critical for normal function. Dfxr mutants exhibited abnormal circadian behavior and eclosion. </p><p>Irwin et al. (2002) compared the dendritic spines on layer V pyramidal cells of visual cortices of wildtype and fragile-X knockout mice. The knockout mice had significantly more long dendritic spines, significantly fewer short dendritic spines, significantly more dendritic spines with an immature-like morphology, and significantly fewer dendritic spines with a more mature morphology. However, unlike the human patients, the knockout mice did not exhibit statistically significant dendritic spine density differences from controls. Fragile-X mice also did not demonstrate any significant differences from controls in dendritic tree complexity or dendritic arbor. </p><p>In behavioral studies of Fmr1 knockout mice, Qin et al. (2002) observed hyperactivity and a higher rate of entrance into the center of an open field compared with controls, suggesting decreased levels of anxiety. Impaired performance of the knockout mice on a passive avoidance task suggested a deficit in learning and memory. To learn what brain regions are involved in the behavioral abnormalities of fragile X mental retardation, Qin et al. (2002) applied the carbon-labeled deoxyglucose method for determining regional cerebral metabolic rates of glucose. They found higher values in all 38 regions tested, as compared to control wildtype littermates; in 26 of the regions, differences were statistically significant. The greatest increases occurred in regions of the limbic system and primary sensory and posterior parietal cortical areas. The regions most affected were consistent with behavioral deficiencies and regions in which Fmrp expression is highest. Qin et al. (2002) suggested that the higher cerebral glucose metabolism in fragile X mice may be a function of abnormalities found in dendritic spines. </p><p>Miyashiro et al. (2003) determined that the RNA cargoes associated with Fmr1-mRNP complexes were altered in Fmr1 null mice. Some of these cargoes, as well as the proteins encoded by them, showed discrete changes in their abundance and/or subcellular distribution. </p><p>Weiler et al. (2004) studied neurotransmitter-activated synaptic protein synthesis in Fmr1 knockout mice. Synaptoneurosomes from knockout mice did not manifest accelerated polyribosome assembly or protein synthesis as it occurs in wildtype mice upon stimulation of group I metabotropic glutamate receptors. Direct activation of protein kinase C (see 176960) did not compensate in the knockout mice, indicating that the FMRP-dependent step is further along the signaling pathway. Visual cortices of young knockout mice exhibited a lower proportion of dendritic spine synapses containing polyribosomes than did the cortices of wildtype mice, corroborating this finding in vivo. This deficit in rapid neurotransmitter-controlled local translation of specific proteins may contribute to the morphologic and functional abnormalities observed in patients with fragile X syndrome. </p><p>Restivo et al. (2005) reared Fmr1-null mice in an enriched environment and found that experience-dependent stimulation alleviated many behavioral and neuronal abnormalities associated with Fmr1 knockout. Enrichment did not affect hyperactivity of Fmr1-null mice, but it reduced the anxiety-like pattern of open field exploration to normal and restored habituation to objects. Enrichment increased basal dendrite length and branching and increased spine density along apical dendrites of layer 5 pyramidal neurons of the visual cortex in both knockout and wildtype mice, and it rescued the immature spine morphology in Fmr1-null mice. Rescue of the behavioral and neuronal defects was dependent on Glur1 (GRIA1; 138248). </p><p>Neuronal dense granules transport mRNAs into dendrites for subsequent site-specific utilization at synapses. Some dense granules contain aggregates of translationally silent polysomes. During active protein synthesis, the structure of the granule relaxes into lighter translating polysomes. Aschrafi et al. (2005) found that Fmr1-knockout mouse brains showed a lower amount of dense granules than wildtype mouse brains. The Fmr1-knockout mice also showed elevated metabotropic GluR5 (GRM5; 604102)-induced translation. Injection of a Grm5-specific inhibitor increased the dense granule peak in both wildtype and Fmr1-knockout mouse brains and blocked Grm5-induced activity in hippocampal slices. Aschrafi et al. (2005) concluded that GRM5-induced translation from neuronal granules occurs at a higher rate in the absence of FMR1. The results supported the hypothesis that elevated GRM5-dependent translation leads to changes in synaptic plasticity and fragile X symptoms. </p><p>Nakamoto et al. (2007) found that siRNA-mediated reduction of Fmrp in primary rat hippocampal cells resulted in internalization of the GluR1 (GRIA1; 138248) AMPA receptor in dendrites. Aberrant GluR1 trafficking was rescued by pharmacologic inhibition of mGluR5. Since Fmrp acts as a negative regulator of translation at synapses and is thus a 'counterbalancing' signal, the findings suggested that the absence of Fmrp leads to an apparent excess of mGluR5 signaling in dendrites. The resultant hypersensitive AMPA receptor internalization reflects a cellular trafficking defect as well as a defect in synaptic plasticity, which may underlie the defects in learning and memory associated with mutations in the FMRP gene. </p><p>Castren et al. (2005) investigated the differentiation of neural stem cells generated from brains of Fmr1-knockout mice and from postmortem tissue of a fragile X fetus. Mouse and human FMRP-deficient neurospheres generated more tubulin beta-3 (TUBB3; 602661)-positive cells than control neurospheres, and the number of GFAP (137780)-positive cells was reduced due to increased apoptotic cell death. Differentiation of fragile X neurospheres was abnormal, with fewer and shorter neurites and a smaller cell body volume. Differentiated FMRP-deficient cells showed an abnormal intense oscillatory Ca(2+) response to acetylcholine. Castren et al. (2005) concluded that FMRP deficiency in fragile X syndrome causes substantial alterations in early maturation of neural stem cells. </p><p>Koekkoek et al. (2005) found that Fmr1-null mice had deficits in classic delay eyeblink conditioning. Fmr1-null mouse cerebellar Purkinje cells showed elongated irregular dendritic spines and enhanced long-term depression induction at the parallel fiber synapses that innervate these spines. Patients with fragile X syndrome showed the same cerebellar deficits in eyeblink conditioning. The findings indicated that a lack of FMRP leads to cerebellar dysfunction. </p><p>Monzo et al. (2006) reported that Fmr1-null male Drosophila were sterile. Fmr1-null females produced morphologically normal eggs when crossed with wildtype males, but few of the embryos hatched. Monzo et al. (2006) determined that Fmr1 was required for cleavage furrow formation, and that Fmr1 functioned within dynamic cytoplasmic ribonucleoprotein bodies during the midblastula transition. </p><p>Meredith et al. (2007) found an increased threshold for spike-timing-dependent long-term potentiation in the prefrontal cortex of Fmr1-null mice. The changes resulted from a defect in postsynaptic calcium signaling in dendrites and spines; in fact, there was absent activity of L-type calcium channels in dendritic spines. Long-term potentiation in these mice could be restored by increasing neuronal activity, which improved the reliability and amplitude of calcium signaling. Fmr1-null mice raised in enriched environments with enhanced sensory, cognitive, and motor stimulation, showed normalization of long-term potentiation back to wildtype levels. The results indicated that mechanisms for synaptic plasticity are in place in the absence of Fmr1, but require stronger neuronal activity to be triggered. </p><p>Zhang et al. (2008) found that Fmr1/Fxr2 double-knockout mice and Fmr1-knockout/Fxr2-heterozygous mice exhibited a loss of rhythmic activity in a light-dark cycle, and that Fmr1- or Fxr2-knockout mice displayed a shorter free running period of locomotor activity in total darkness. Molecular analysis and in vitro electrophysiologic studies suggested essentially normal function of cells in the suprachiasmatic nucleus in Fmr1/Fxr2 double-knockout mice. However, the cyclical patterns of abundance of several core clock mRNAs were altered in the livers of double-knockout mice. Fxr2 alone or Fmr1 and Fxr2 together enhanced Per1 (602260)- or Per2 (603426)-mediated Bmal1 (ARNTL; 602550)-Npas2 (603347) transcriptional activity in a dose-dependent manner. Zhang et al. (2008) concluded that FMR1 and FXR2 are required for rhythmic circadian behavior. </p><p>In mouse hippocampal slices, Hou et al. (2006) found that GRM5 agonists caused rapid protein synthesis of FMRP followed by rapid degradation of FMRP in neuronal soma, nuclei, and proximal dendrites during long-term depression. FMRP degradation was mediated by the ubiquitin-proteasomal pathway. The lack of GRM5-dependent FMRP synthesis in Fmrp-null mice contributed to enhanced long-term depression. Absence of Fmrp also resulted in increased translation of other proteins, such as MAP1B (157129), indicating that FMRP normally acts as a translational repressor. These findings indicated that the translation, ubiquitination, and proteolysis of FMRP functions as a dynamic regulatory system for controlling synaptic plasticity. In addition, Hou et al. (2006) concluded that disruption of FMRP alters the regulation of proteins affecting basic biochemical signaling mechanisms during synaptic plasticity in the hippocampus. </p><p>Dolen et al. (2007) found that transgenic Fmr1-null mice with a 50% reduction of GRM5 expression showed amelioration of several Fmr1-null-related phenotypes, including experience-dependent synaptic modification (as measured by ocular dominant plasticity), altered dendritic spine density, altered hippocampal basal protein synthesis, inhibitory avoidance behavior, seizures susceptibility, and overall increased somatic growth. All of these features showed some rescue with decreased GRM5 activity. However, macroorchidism was not rescued. The findings were consistent with the hypothesis that the certain aspects of fragile X syndrome result from unchecked activation of the GRM5 receptor. Dolen et al. (2007) concluded by suggesting that fragile X syndrome is a disorder of 'excess,' resulting from loss of putative repressor functions of FMRP. Suppression of at least 1 of the downstream effectors, GRM5, may alleviate some of these abnormalities. </p><p>Guo et al. (2011) found that mice with selective deletion of Fmrp from adult neural stem and progenitor cells showed increased production of neural stem cells in the hippocampus compared to controls, but these cells showed poorer survival and decreased differentiation. Mutant mice had decreased dendritic complexity of neurons as well as an increase in astrocyte number and differentiation. These findings were also observed in adult mouse neural stem cells in vitro. Mutant mice showed an impairment in challenging learning tasks, such as the trace conditioning task, that require adult hippocampal neurogenesis. Both the cellular neurogenesis defects and learning deficit could be rescued by conditional restoration of Fmrp. Guo et al. (2011) suggested that loss of functional FMRP specifically in adult neural stem cells may contribute to the cognitive defects in patients with fragile X syndrome. </p><p><strong><em>Animal Models of Fragile X Tremor/Ataxia Syndrome</em></strong></p><p>
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Willemsen et al. (2003) described neurohistologic, biochemical, and molecular studies of the brains of transgenic mice with an expanded CGG repeat (102 to 110 repeats) in human FMR1, and reported elevated Fmr1 mRNA levels and intranuclear inclusions with ubiquitin, Hsp40 (see 604572), and the 20S catalytic core complex of the proteasome as constituents. An increase was observed in both the number and the size of the inclusions during the course of life, which correlated with the progressive character of the cerebellar tremor/ataxia syndrome in humans. Willemsen et al. (2003) concluded that the observations in expanded-repeat mice supported a direct role of the Fmr1 gene, by either CGG expansion per se or by mRNA level, in the formation of the inclusions and suggested a correlation between the presence of intranuclear inclusions in distinct regions of the brain and the clinical features in symptomatic premutation carriers. </p><p>Jin et al. (2003) expressed a human FMR1 premutation allele of 90 CGG repeats in Drosophila in a heterologous transcript (EGFP). The expanded RNA alone induced neuron-specific degeneration, as observed in retinal cells, characterized by Hsp70 (see 140550)- and ubiquitin-positive inclusion bodies similar to those seen in patients with FXTAS. The findings suggested a role for a toxic RNA-mediated gain-of-function in FXTAS. Handa et al. (2005) found that transcribed but untranslated expanded CGG premutation alleles were toxic to human cells, and microarray analysis detected altered expression of a wide variety of genes, including upregulation of CASP8 (601763), CYFIP1 (606322), NTS (162650), and UBE3A (601623), which was confirmed by RT-PCR analysis. </p><p>Hashem et al. (2009) generated mice expressing the human 90 CGG premutation in the context of the mouse Fmr1 5-prime UTR or the EGFP (enhanced green fluorescent protein) 5-prime UTR, specifically in Purkinje neurons, in order to segregate the effects of CGG repeat from alterations in Fmr1 and to provide evidence that CGG repeat is necessary and sufficient to cause pathology similar to human FXTAS. CGG(90)-EGFP was sufficient to produce ubiquitin-positive intranuclear inclusion formation. They also demonstrated CGG(90)-EGFP overexpression resulted in Purkinje neuron axonal swellings and neurotoxicity and in a mouse phenotype showing progressive age-dependent decline in neuromotor learning ability. Hashem et al. (2009) concluded that CGG expressed in Purkinje neurons outside the context of Fmr1 mRNA may result in neuronal pathology in a mammalian system, and that expanded CGG repeats in RNA are the likely cause of the neurodegeneration in FXTAS. </p><p>Chen et al. (2010) reported that neurons cultured from heterozygous female mice with preCGG FMR1 repeats displayed shorter dendritic lengths and fewer branches between 7 to 21 days in vitro compared with cultured neurons from wildtype littermates. Although the numbers of synapsin and phalloidin puncta did not differ from wildtype, preCGG neurons possessed larger puncta. PreCGG neurons displayed lower viability, and expressed elevated stress protein as they matured. PreCGG neurons had inherently different patterns of growth, dendritic complexity, and synaptic architecture discernible early in the neuronal trajectory to maturation. Chen et al. (2010) suggested that this may reflect a cellular basis for the developmental component of the spectrum of clinical involvement in carriers of premutation alleles. </p><p>By measuring cAMP levels in a single neuron, Maurin et al. (2019) showed that Pde2a (602658) dysregulation was involved in physiopathology of Fmr1-KO mice, a model of FXS. Fmr1-KO brain had increased Pde2a enzymatic activity, resulting in decreased levels of cAMP and cGMP. Blocking Pde2a rescued exaggerated long-term depression induced by activation of hippocampal metabotropic group I glutamate receptor in Fmr1-KO brain and abnormal immature dendritic spines in cultured Fmr1-KO cortical neurons, both of which are hallmarks of FXS in Fmr1-KO mice. Furthermore, inhibition of Pde2a activity rescued abnormal behavior in Fmr1-KO mice, as well as communication deficit in both Fmr1-KO mice and rats. The authors proposed that PDE2A may be a therapeutic target to treat FXS. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>5 Selected Examples):</strong>
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<strong>.0001 FRAGILE X SYNDROME</strong>
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FMR1, ILE304ASN
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SNP: rs121434622,
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<p>This mutation in the FMR1 gene results in an ile304-to-asn (I304N) substitution (Siomi et al., 1994), although it was originally reported as I367N (De Boulle et al., 1993). </p><p>De Boulle et al. (1993) identified a T-to-A transversion in the FMR1 gene in a patient with a severe form of fragile X mental retardation (FXS; 300624). The mutation was not found in the mother, brother, or nephews who had normal intellectual abilities and no stigmata of fragile X syndrome. </p><p>Verheij et al. (1995) demonstrated that the ile367-to-asn substitution in the FMR1 protein did not alter the translation, processing, or localization of FMR1 proteins in lymphoblastoid cells from a patient carrying this mutation. All the high molecular mass FMR1 proteins isolated from normal lymphoblastoid cells and cells from the patient with this substitution were able to bind RNA. However, the FMR1 proteins of the patient had reduced affinity for RNA binding at high salt concentrations. </p><p>Feng et al. (1997) demonstrated that normal FMRP associates with elongating polyribosomes via large mRNP particles. Despite normal expression and cytoplasmic mRNA association, the I304N FMRP was incorporated into abnormal mRNP particles that were not associated with polyribosomes. These data indicated that association of FMRP with polyribosomes must be functionally important and implied that the mechanism of the severe phenotype in the I304N patient lies in the sequestration of bound mRNAs in nontranslatable mRNP particles. In the absence of FMRP, these same mRNAs may be partially translated via alternate mRNPs, although perhaps abnormally localized or regulated, resulting in typical fragile X syndrome. </p><p>Darnell et al. (2005) noted that the I304N mutation maps to a position within the second KH domain of FMR1 that is critical for stabilizing sequence-specific RNA-protein interactions. They found that the I304N mutation abrogates the association of the FMR1 KH2 domain with its target, kissing complex RNA. </p><p>Linder et al. (2008) showed that the I304N substitution markedly reduced FMR1 homooligomerization. The mutation also abrogated the interaction between residual FMR1 oligomers with the stress granule protein TDRD3 (614392). </p>
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<strong>.0002 FRAGILE X SYNDROME</strong>
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FMR1, 1-BP DEL, 373A
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<p>In a young male patient with fragile X syndrome (FXS; 300624), Lugenbeel et al. (1995) identified a de novo 1-bp deletion (373delA) in exon 5 of the FMR1 gene, resulting in a frameshift and premature termination of the protein at residue 159. Western blot analysis detected no Fmr1 protein. The finding provided strong evidence that absence of FMRP leads directly to fragile X syndrome and suggested that downregulation of other nearby genes is not likely to contribute to the phenotype. </p>
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 FRAGILE X SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FMR1, IVS2AS1, G-T, -1 AND G-A, +1
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<br />
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SNP: rs1557176576,
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ClinVar: RCV000010650
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an adult male with classic fragile X syndrome (FXS; 300624), Lugenbeel et al. (1995) identified a 2-bp change (23714GG-TA) spanning the intron/exon boundary of exon 2 of the FMR1 gene. RT-PCR and sequence analysis demonstrated 2 products of reduced size: a larger product created from splicing out exon 2 and a smaller product created by splicing out exons 2 and 3. Loss of exon 2 resulted in a frameshift and premature termination 4 amino acids into exon 3; loss of exons 2 and 3 removed 49 amino acids of the FMR protein but did not alter the reading frame. Although a protein of reduced size was predicted, no protein was recognized by Western blot. The same mutation was identified in the mother, who was described as mildly retarded. Other members of the family were either noncarriers or not available for study. The finding provided strong evidence that absence of FMRP leads directly to fragile X syndrome. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 FRAGILE X SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FRAGILE X TREMOR/ATAXIA SYNDROME, INCLUDED<br />
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PREMATURE OVARIAN FAILURE 1, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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FMR1, (CGG)n REPEAT EXPANSION
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<br />
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ClinVar: RCV000010651, RCV000010652, RCV000010653
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Kremer et al. (1991) demonstrated that the presence of an unstable expanded trinucleotide repeat sequence, designated p(CCG)n, in the 5-prime untranslated region of the FMR1 gene is the basis of fragile X syndrome (FXS; 300624). The authors showed that normal X chromosomes have about 40 +/- 25 copies of p(CCG)n and that within these limits the sequence is a stable DNA polymorphism. The fragile X genotype was characterized by an increased amount of unstable DNA that maps to the repeat. The mutation causing fragile X syndrome contains over 200 CCG repeats (Devys et al., 1992). </p><p>Premutations</p><p>A premutation in the FMR1 gene is defined as an expansion of approximately 55 to 200 CGG repeats. Hagerman et al. (2001) reported 5 men with an FMR1 premutation, ranging from 78 to 98 repeats, who presented in the sixth decade with progressive intention tremor, parkinsonism, cognitive decline, generalized atrophy on MRI, and impotence (FXTAS; 300623). Levels of FMR1 mRNA were 2 to 4 times higher than normal, which the authors suggested resulted in a pathogenic gain-of-function effect. </p><p>Murray et al. (1998) screened 147 women with idiopathic premature ovarian failure (POF1; 311360) and found a significant association with premutations in the FMR1 gene, with 6 women having premutations, including 4 familial and 2 sporadic cases, but no women with full mutations in the FMR1 gene. </p><p>In an international collaborative study of 760 women from fragile X families, Allingham-Hawkins et al. (1999) found that 395 carried a premutation, 128 carried a full mutation, and 237 were noncarriers. In 63 (16%) of the premutation carriers, menopause occurred before the age of 40, compared with none of the full-mutation carriers and 1 (0.4%) of the controls, indicating a significant association between premature menopause and premutation carrier status. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 FRAGILE X SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FMR1, SER27TER
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<br />
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SNP: rs1569545382,
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ClinVar: RCV000022880
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a man with classic features of fragile X syndrome (FXS; 300624), Gronskov et al. (2011) identified an 80C-A transversion in exon 2 of the FMR1 gene, resulting in a ser27-to-ter (S27X) substitution. The patient had mental retardation, early-onset seizures, poor language development, and autistic tendencies. Dysmorphic features included an elongated face, high and broad forehead, low-set large ears, prognathia, and enlarged testes. Neurologic examination showed hypotonia and hypermobility, with hyperextensible joints. Western blot analysis of patient lymphoblastoid cells showed no FMRP protein expression. His mother, who also carried the mutation, had mild to moderate intellectual disability, hypermotor behavior, and automatisms. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Laird (1987); Rousseau et al. (1991)
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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">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<strong>Nucleus basalis magnocellularis and hippocampus are the major sites of FMR-1 expression in the human fetal brain.</strong>
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Allingham-Hawkins, D. J., Babul-Hirji, R., Chitayat, D., Holden, J. J. A., Yang, K. T., Lee, C., Hudson, R., Gorwill, H., Nolin, S. L., Glicksman, A., Jenkins, E. C., Brown, W. T., and 27 others.
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<strong>Fragile X premutation is a significant risk factor for premature ovarian failure: the international collaborative POF in fragile X study--preliminary data.</strong>
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Alpatov, R., Lesch, B. J., Nakamoto-Kinoshita, M., Blanco, A., Chen, S., Stutzer, A., Armache, K. J., Simon, M. D., Xu, C., Ali, M., Murn, J., Prisic, S., Kutateladze, T. G., Vakoc, C. R., Min, J., Kingston, R. E., Fischle, W., Warren, S. T., Page, D. C., Shi, Y.
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<strong>A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response.</strong>
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Aschrafi, A., Cunningham, B. A., Edelman, G. M., Vanderklish, P. W.
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Ashley, C. T., Jr., Wilkinson, K. D., Reines, D., Warren, S. T.
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Science 262: 563-566, 1993.
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<strong>Human and murine FMR-1: alternative splicing and translational initiation downstream of the CGG-repeat.</strong>
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Nature Genet. 4: 244-251, 1993.
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Auerbach, B. D., Osterweil, E. K., Bear, M. F.
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Bachner, D., Steinbach, P., Wohrle, D., Just, W., Vogel, W., Hameister, H., Manca, A., Poustka, A.
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Baudouin, S. J., Gaudias, J., Gerharz, S., Hatstatt, L., Zhou, K., Punnakkal, P., Tanaka, K. F., Spooren, W., Hen, R., De Zeeuw, C. I., Vogt, K., Scheiffele, P.
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Beilina, A., Tassone, F., Schwartz, P. H., Sahota, P., Hagerman, P. J.
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Bell, M. V., Hirst, M. C., Nakahori, Y., MacKinnon, R. N., Roche, A., Flint, T. J., Jacobs, P. A., Tommerup, N., Tranebjaerg, L., Froster-Iskenius, U., Kerr, B., Turner, G., Lindenbaum, R. H., Winter, R., Pembrey, M., Thibodeau, S., Davies, K. E.
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<p class="mim-text-font">
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Bontekoe, C. J. M., Bakker, C. E., Nieuwenhuizen, I. M., van der Linde, H., Lans, H., de Lange, D., Hirst, M. C., Oostra, B. A.
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<strong>Instability of a (CGG)98 repeat in the Fmr1 promoter.</strong>
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[PubMed: 11487573]
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Brown, V., Jin, P., Ceman, S., Darnell, J. C., O'Donnell, W. T., Tenenbaum, S. A., Jin, X., Feng, Y., Wilkinson, K. D., Keene, J. D., Darnell, R. B., Warren, S. T.
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<p class="mim-text-font">
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Callan, M. A., Cabernard, C., Heck, J., Luois, S., Doe, C. Q., Zarnescu, D. C.
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<strong>Fragile X protein controls neural stem cell proliferation in the Drosophila brain.</strong>
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[PubMed: 20504994]
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<p class="mim-text-font">
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Castets, M., Schaeffer, C., Bechara, E., Schenck, A., Khandjian, E. W., Luche, S., Moine, H., Rabilloud, T., Mandel, J.-L., Bardoni, B.
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<strong>FMRP interferes with the Rac1 pathway and controls actin cytoskeleton dynamics in murine fibroblasts.</strong>
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Hum. Molec. Genet. 14: 835-844, 2005.
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[PubMed: 15703194]
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[Full Text: https://doi.org/10.1093/hmg/ddi077]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Castren, M., Tervonen, T., Karkkainen, V., Heinonen, S., Castren, E., Larsson, K., Bakker, C. E., Oostra, B. A., Akerman, K.
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<strong>Altered differentiation of neural stem cells in fragile X chromosome.</strong>
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Proc. Nat. Acad. Sci. 102: 17834-17839, 2005.
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[PubMed: 16314562]
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[Full Text: https://doi.org/10.1073/pnas.0508995102]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Ceman, S., O'Donnell, W. T., Reed, M., Patton, S., Pohl, J., Warren, S. T.
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<strong>Phosphorylation influences the translation state of FMRP-associated polyribosomes.</strong>
|
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Hum. Molec. Genet. 12: 3295-3305, 2003.
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[PubMed: 14570712]
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[Full Text: https://doi.org/10.1093/hmg/ddg350]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Chen, L.-S., Tassone, F., Sahota, P., Hagerman, P. J.
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<strong>The (CGG)n repeat element within the 5-prime untranslated region on the FMR1 message provides both positive and negative cis effects on in vivo translation of a downstream reporter.</strong>
|
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Hum. Molec. Genet. 12: 3067-3074, 2003.
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[PubMed: 14519687]
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[Full Text: https://doi.org/10.1093/hmg/ddg331]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Chen, Y., Tassone, F., Berman, R. F., Hagerman, P. J., Hagerman, R. J., Willemsen, R., Pessah, I. N.
|
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<strong>Murine hippocampal neurons expressing Fmr1 gene premutations show early developmental deficits and late degeneration.</strong>
|
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Hum. Molec. Genet. 19: 196-208, 2010.
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[PubMed: 19846466]
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[Full Text: https://doi.org/10.1093/hmg/ddp479]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Chiurazzi, P., Pomponi, M. G., Pietrobono, R., Bakker, C. E., Neri, G., Oostra, B. A.
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Wohrle, D., Kotzot, D., Hirst, M. C., Manca, A., Korn, B., Schmidt, A., Barbi, G., Rott, H.-D., Poustka, A., Davies, K. E., Steinbach, P.
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<strong>A microdeletion of less than 250 kb, including the proximal part of the FMR-1 gene and the fragile-X site, in a male with the clinical phenotype of fragile-X syndrome.</strong>
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Wohrle, D., Salat, U., Hameister, H., Vogel, W., Steinbach, P.
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<strong>Demethylation, reactivation, and destabilization of human fragile X full-mutation alleles in mouse embryocarcinoma cells.</strong>
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Zarnescu, D. C., Jin, P., Betschinger, J., Nakamoto, M., Wang, Y., Dockendorff, T. C., Feng, Y., Jongens, T. A., Sisson, J. C., Knoblich, J. A., Warren, S. T., Moses, K.
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<strong>Fragile X protein functions with lgl and the PAR complex in flies and mice.</strong>
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Zhang, J., Fang, Z., Jud, C., Vansteensel, M. J., Kaasik, K., Lee, C. C., Albrecht, U., Tamanini, F., Meijer, J. H., Oostra, B. A., Nelson, D. L.
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<strong>Drosophila fragile X-related gene regulates the MAP1B homolog Futsch to control synaptic structure and function.</strong>
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<strong>A complex mutable polymorphism located within the fragile X gene.</strong>
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<strong>Expansion of an intermediate allele of the FMR1 gene in only two generations. (Letter)</strong>
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Contributors:
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</span>
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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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Bao Lige - updated : 03/05/2021<br>Ada Hamosh - updated : 12/23/2019<br>Ada Hamosh - updated : 09/17/2018<br>Patricia A. Hartz - updated : 01/12/2018<br>Marla J. F. O'Neill - updated : 04/17/2017<br>Ada Hamosh - updated : 3/28/2014<br>Ada Hamosh - updated : 1/31/2014<br>Cassandra L. Kniffin - updated : 9/26/2013<br>George E. Tiller - updated : 8/30/2013<br>Ada Hamosh - updated : 1/30/2013<br>Ada Hamosh - updated : 10/24/2012<br>Patricia A. Hartz - updated : 11/23/2011<br>George E. Tiller - updated : 11/21/2011<br>George E. Tiller - updated : 11/14/2011<br>Cassandra L. Kniffin - updated : 6/7/2011<br>Cassandra L. Kniffin - updated : 5/11/2011<br>George E. Tiller - updated : 12/29/2010<br>George E. Tiller - updated : 11/12/2010<br>George E. Tiller - updated : 3/30/2010<br>Nara Sobreira - updated : 2/16/2010<br>Patricia A. Hartz - updated : 1/6/2010<br>Cassandra L. Kniffin - updated : 12/15/2009<br>Cassandra L. Kniffin - updated : 11/19/2009<br>Patricia A. Hartz - updated : 10/14/2009<br>Patricia A. Hartz - updated : 9/21/2009<br>Cassandra L. Kniffin - updated : 4/6/2009<br>Cassandra L. Kniffin - updated : 12/3/2008<br>George E. Tiller - updated : 11/18/2008<br>Patricia A. Hartz - updated : 8/21/2008<br>Patricia A. Hartz - updated : 8/14/2008<br>George E. Tiller - updated : 4/25/2008<br>Cassandra L. Kniffin - updated : 3/18/2008<br>George E. Tiller - updated : 11/30/2007<br>Cassandra L. Kniffin - updated : 10/16/2007<br>Patricia A. Hartz - updated : 8/24/2007<br>Marla J. F. O'Neill - updated : 6/6/2007<br>Patricia A. Hartz - updated : 2/12/2007<br>George E. Tiller - updated : 1/16/2007<br>George E. Tiller - updated : 11/28/2006<br>Cassandra L. Kniffin - reorganized : 11/27/2006<br>Cassandra L. Kniffin - updated : 8/29/2006<br>Ada Hamosh - updated : 7/31/2006<br>Patricia A. Hartz - updated : 4/20/2006<br>George E. Tiller - updated : 2/17/2006<br>George E. Tiller - updated : 2/3/2006<br>Patricia A. Hartz - updated : 1/27/2006<br>George E. Tiller - updated : 1/11/2006<br>Cassandra L. Kniffin - updated : 12/21/2005<br>Cassandra L. Kniffin - updated : 12/7/2005<br>Cassandra L. Kniffin - updated : 11/4/2005<br>Cassandra L. Kniffin - updated : 10/31/2005<br>George E. Tiller - updated : 10/21/2005<br>Cassandra L. Kniffin - updated : 9/23/2005<br>Cassandra L. Kniffin - updated : 8/23/2005<br>Cassandra L. Kniffin - updated : 8/17/2005<br>Patricia A. Hartz - updated : 7/8/2005<br>Cassandra L. Kniffin - updated : 6/20/2005<br>Patricia A. Hartz - updated : 6/8/2005<br>Victor A. McKusick - updated : 4/19/2005<br>Patricia A. Hartz - updated : 2/23/2005<br>Victor A. McKusick - updated : 1/27/2005<br>George E. Tiller - updated : 12/17/2004<br>Marla J. F. O'Neill - updated : 10/7/2004<br>Victor A. McKusick - updated : 9/22/2004<br>Marla J. F. O'Neill - updated : 5/19/2004<br>Victor A. McKusick - updated : 4/23/2004<br>Victor A. McKusick - updated : 4/14/2004<br>Cassandra L. Kniffin - updated : 3/1/2004<br>Cassandra L. Kniffin - updated : 1/22/2004<br>Victor A. McKusick - updated : 11/6/2003<br>Cassandra L. Kniffin - updated : 10/31/2003<br>Cassandra L. Kniffin - updated : 9/25/2003<br>Victor A. McKusick - updated : 8/1/2003<br>Victor A. McKusick - updated : 8/1/2003<br>Victor A. McKusick - updated : 7/18/2003<br>Patricia A. Hartz - updated : 7/8/2003<br>Cassandra L. Kniffin - updated : 5/28/2003<br>Victor A. McKusick - updated : 5/8/2003<br>Victor A. McKusick - updated : 4/11/2003<br>Victor A. McKusick - updated : 3/6/2003<br>Cassandra L. Kniffin - updated : 3/4/2003<br>Victor A. McKusick - updated : 1/31/2003<br>Victor A. McKusick - updated : 1/14/2003<br>Deborah L. Stone - updated : 11/15/2002<br>Patricia A. Hartz - updated : 11/11/2002<br>Cassandra L. Kniffin - updated : 10/15/2002<br>George E. Tiller - updated : 9/25/2002<br>Victor A. McKusick - updated : 9/19/2002<br>Victor A. McKusick - updated : 7/2/2002<br>Michael B. Petersen - updated : 2/28/2002<br>Victor A. McKusick - updated : 2/12/2002<br>Stylianos E. Antonarakis - updated : 1/10/2002<br>George E. Tiller - updated : 12/26/2001<br>George E. Tiller - updated : 12/6/2001<br>Stylianos E. Antonarakis - updated : 11/20/2001<br>Victor A. McKusick - updated : 9/20/2001<br>Deborah L. Stone - updated : 9/12/2001<br>Victor A. McKusick - updated : 8/30/2001<br>Victor A. McKusick - updated : 8/1/2001<br>George E. Tiller - updated : 4/25/2001<br>Sonja A. Rasmussen - updated : 4/23/2001<br>George E. Tiller - updated : 2/5/2001<br>Michael J. Wright - updated : 1/12/2001<br>Sonja A. Rasmussen - updated : 1/8/2001<br>Victor A. McKusick - updated : 12/19/2000<br>Sonja A. Rasmussen - updated : 12/12/2000<br>George E. Tiller - updated : 10/16/2000<br>Ada Hamosh - updated : 9/25/2000<br>Victor A. McKusick - updated : 9/11/2000<br>Sonja A. Rasmussen - updated : 7/13/2000<br>George E. Tiller - updated : 6/7/2000<br>George E. Tiller - updated : 5/2/2000<br>Stylianos E. Antonarakis - updated : 4/17/2000<br>Victor A. McKusick - updated : 3/31/2000<br>George E. Tiller - updated : 3/23/2000<br>Victor A. McKusick - updated : 11/24/1999<br>Sonja A. Rasmussen - updated : 11/16/1999<br>Sonja A. Rasmussen - updated : 10/5/1999<br>Victor A. McKusick - updated : 9/8/1999<br>Victor A. McKusick - updated : 6/30/1999<br>Victor A. McKusick - updated : 4/12/1999<br>Victor A. McKusick - updated : 2/18/1999<br>Victor A. McKusick - updated : 1/25/1999<br>Victor A. McKusick - updated : 1/12/1999<br>Michael J. Wright - updated : 11/16/1998<br>Victor A. McKusick - updated : 10/5/1998<br>Ada Hamosh - updated : 4/30/1998<br>Michael J. Wright - updated : 2/10/1998<br>Victor A. McKusick - updated : 11/26/1997<br>Victor A. McKusick - updated : 10/14/1997<br>Victor A. McKusick - updated : 9/2/1997<br>Victor A. McKusick - updated : 2/3/1997<br>Moyra Smith - updated : 1/31/1997<br>Moyra Smith - updated : 9/6/1996<br>Moyra Smith - updated : 8/27/1996<br>Mark H. Paalman - updated : 7/25/1996<br>Moyra Smith - updated : 3/26/1996
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</span>
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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 : 6/4/1986
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Edit History:
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</span>
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</div>
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carol : 04/05/2022<br>mgross : 03/05/2021<br>alopez : 12/23/2019<br>carol : 11/04/2019<br>carol : 11/01/2019<br>alopez : 09/17/2018<br>mgross : 01/12/2018<br>carol : 10/09/2017<br>carol : 05/09/2017<br>carol : 04/17/2017<br>carol : 04/03/2017<br>carol : 04/21/2016<br>alopez : 3/28/2014<br>alopez : 1/31/2014<br>tpirozzi : 10/10/2013<br>ckniffin : 9/26/2013<br>carol : 9/9/2013<br>tpirozzi : 8/30/2013<br>alopez : 2/8/2013<br>terry : 1/30/2013<br>alopez : 10/26/2012<br>terry : 10/24/2012<br>carol : 8/17/2012<br>terry : 5/29/2012<br>terry : 5/17/2012<br>alopez : 1/12/2012<br>alopez : 1/12/2012<br>terry : 11/23/2011<br>carol : 11/21/2011<br>terry : 11/21/2011<br>carol : 11/17/2011<br>terry : 11/14/2011<br>carol : 7/6/2011<br>wwang : 6/23/2011<br>ckniffin : 6/7/2011<br>wwang : 5/16/2011<br>ckniffin : 5/11/2011<br>wwang : 1/12/2011<br>terry : 12/29/2010<br>wwang : 11/19/2010<br>terry : 11/12/2010<br>wwang : 4/2/2010<br>terry : 3/30/2010<br>carol : 2/26/2010<br>carol : 2/16/2010<br>mgross : 1/21/2010<br>terry : 1/6/2010<br>carol : 12/23/2009<br>ckniffin : 12/15/2009<br>wwang : 12/10/2009<br>ckniffin : 11/19/2009<br>alopez : 11/3/2009<br>mgross : 10/23/2009<br>terry : 10/14/2009<br>mgross : 10/6/2009<br>mgross : 10/6/2009<br>mgross : 10/6/2009<br>mgross : 10/6/2009<br>terry : 9/21/2009<br>carol : 7/31/2009<br>wwang : 4/10/2009<br>ckniffin : 4/6/2009<br>wwang : 12/4/2008<br>ckniffin : 12/3/2008<br>wwang : 11/18/2008<br>mgross : 8/22/2008<br>terry : 8/21/2008<br>mgross : 8/14/2008<br>mgross : 8/14/2008<br>terry : 8/14/2008<br>ckniffin : 5/1/2008<br>wwang : 4/30/2008<br>terry : 4/25/2008<br>wwang : 3/28/2008<br>ckniffin : 3/18/2008<br>wwang : 11/30/2007<br>wwang : 11/19/2007<br>ckniffin : 10/16/2007<br>mgross : 8/29/2007<br>terry : 8/24/2007<br>carol : 6/6/2007<br>mgross : 2/12/2007<br>alopez : 1/17/2007<br>terry : 1/16/2007<br>carol : 11/28/2006<br>carol : 11/27/2006<br>ckniffin : 11/27/2006<br>carol : 11/27/2006<br>ckniffin : 11/22/2006<br>ckniffin : 11/16/2006<br>wwang : 8/31/2006<br>ckniffin : 8/29/2006<br>alopez : 8/1/2006<br>terry : 7/31/2006<br>mgross : 4/24/2006<br>terry : 4/20/2006<br>wwang : 3/7/2006<br>terry : 2/17/2006<br>wwang : 2/3/2006<br>mgross : 2/2/2006<br>terry : 1/27/2006<br>wwang : 1/24/2006<br>terry : 1/11/2006<br>wwang : 1/9/2006<br>ckniffin : 12/21/2005<br>wwang : 12/9/2005<br>ckniffin : 12/7/2005<br>wwang : 11/15/2005<br>ckniffin : 11/4/2005<br>wwang : 11/2/2005<br>ckniffin : 10/31/2005<br>alopez : 10/21/2005<br>wwang : 10/6/2005<br>ckniffin : 9/23/2005<br>wwang : 8/31/2005<br>carol : 8/23/2005<br>ckniffin : 8/23/2005<br>wwang : 8/22/2005<br>ckniffin : 8/17/2005<br>wwang : 7/15/2005<br>wwang : 7/8/2005<br>ckniffin : 6/20/2005<br>wwang : 6/17/2005<br>wwang : 6/9/2005<br>terry : 6/8/2005<br>alopez : 4/19/2005<br>mgross : 2/23/2005<br>wwang : 2/11/2005<br>wwang : 2/10/2005<br>wwang : 2/7/2005<br>terry : 1/27/2005<br>tkritzer : 12/17/2004<br>carol : 10/22/2004<br>carol : 10/8/2004<br>terry : 10/7/2004<br>tkritzer : 9/23/2004<br>terry : 9/22/2004<br>tkritzer : 8/26/2004<br>tkritzer : 8/24/2004<br>carol : 6/30/2004<br>carol : 5/19/2004<br>terry : 5/19/2004<br>tkritzer : 4/27/2004<br>terry : 4/23/2004<br>alopez : 4/16/2004<br>terry : 4/14/2004<br>joanna : 3/16/2004<br>tkritzer : 3/3/2004<br>ckniffin : 3/1/2004<br>tkritzer : 2/10/2004<br>ckniffin : 1/22/2004<br>tkritzer : 11/10/2003<br>terry : 11/6/2003<br>tkritzer : 10/31/2003<br>ckniffin : 10/31/2003<br>carol : 9/25/2003<br>ckniffin : 9/17/2003<br>terry : 8/20/2003<br>carol : 8/1/2003<br>terry : 8/1/2003<br>cwells : 7/29/2003<br>terry : 7/28/2003<br>terry : 7/28/2003<br>terry : 7/18/2003<br>mgross : 7/8/2003<br>tkritzer : 6/9/2003<br>ckniffin : 5/28/2003<br>tkritzer : 5/9/2003<br>terry : 5/8/2003<br>tkritzer : 4/17/2003<br>terry : 4/11/2003<br>carol : 3/7/2003<br>terry : 3/6/2003<br>carol : 3/6/2003<br>ckniffin : 3/4/2003<br>tkritzer : 2/4/2003<br>tkritzer : 2/3/2003<br>terry : 1/31/2003<br>carol : 1/23/2003<br>tkritzer : 1/17/2003<br>terry : 1/14/2003<br>carol : 11/15/2002<br>mgross : 11/11/2002<br>mgross : 11/11/2002<br>alopez : 10/21/2002<br>mgross : 10/18/2002<br>carol : 10/18/2002<br>ckniffin : 10/15/2002<br>cwells : 9/25/2002<br>tkritzer : 9/19/2002<br>tkritzer : 9/19/2002<br>carol : 9/11/2002<br>cwells : 7/17/2002<br>cwells : 7/15/2002<br>terry : 7/2/2002<br>mgross : 4/8/2002<br>cwells : 3/6/2002<br>cwells : 2/28/2002<br>terry : 2/12/2002<br>mgross : 1/10/2002<br>mgross : 1/10/2002<br>cwells : 1/4/2002<br>cwells : 12/26/2001<br>cwells : 12/18/2001<br>cwells : 12/6/2001<br>mgross : 11/21/2001<br>mgross : 11/20/2001<br>mcapotos : 10/8/2001<br>mcapotos : 10/1/2001<br>terry : 9/20/2001<br>carol : 9/12/2001<br>terry : 8/30/2001<br>terry : 8/30/2001<br>mcapotos : 8/16/2001<br>mcapotos : 8/2/2001<br>terry : 8/2/2001<br>terry : 8/1/2001<br>cwells : 5/9/2001<br>cwells : 5/1/2001<br>cwells : 4/25/2001<br>mcapotos : 4/23/2001<br>cwells : 2/5/2001<br>cwells : 1/30/2001<br>mcapotos : 1/29/2001<br>alopez : 1/12/2001<br>mcapotos : 1/8/2001<br>terry : 12/19/2000<br>mcapotos : 12/12/2000<br>alopez : 10/16/2000<br>alopez : 10/3/2000<br>terry : 9/25/2000<br>carol : 9/13/2000<br>terry : 9/11/2000<br>mcapotos : 7/14/2000<br>mcapotos : 7/13/2000<br>mcapotos : 7/13/2000<br>alopez : 6/7/2000<br>alopez : 5/2/2000<br>mgross : 4/17/2000<br>mgross : 4/11/2000<br>terry : 3/31/2000<br>alopez : 3/23/2000<br>alopez : 12/7/1999<br>carol : 11/29/1999<br>terry : 11/24/1999<br>mgross : 11/16/1999<br>carol : 10/5/1999<br>jlewis : 9/16/1999<br>terry : 9/8/1999<br>jlewis : 7/15/1999<br>terry : 6/30/1999<br>carol : 5/24/1999<br>terry : 5/20/1999<br>carol : 4/14/1999<br>terry : 4/12/1999<br>mgross : 3/10/1999<br>carol : 2/18/1999<br>terry : 2/18/1999<br>carol : 1/25/1999<br>carol : 1/19/1999<br>terry : 1/15/1999<br>terry : 1/12/1999<br>alopez : 12/7/1998<br>terry : 11/16/1998<br>carol : 10/8/1998<br>terry : 10/5/1998<br>terry : 6/4/1998<br>alopez : 5/21/1998<br>alopez : 5/11/1998<br>dholmes : 5/11/1998<br>dholmes : 4/30/1998<br>alopez : 2/18/1998<br>terry : 2/10/1998<br>alopez : 12/5/1997<br>alopez : 12/3/1997<br>alopez : 12/3/1997<br>dholmes : 12/1/1997<br>mark : 10/14/1997<br>terry : 9/12/1997<br>terry : 9/10/1997<br>jenny : 9/10/1997<br>terry : 9/2/1997<br>terry : 8/5/1997<br>alopez : 7/29/1997<br>alopez : 7/29/1997<br>mark : 7/16/1997<br>alopez : 7/10/1997<br>alopez : 7/8/1997<br>joanna : 7/7/1997<br>joanna : 6/24/1997<br>terry : 5/5/1997<br>jenny : 3/31/1997<br>mark : 2/3/1997<br>mark : 2/3/1997<br>mark : 1/31/1997<br>jamie : 1/16/1997<br>mark : 10/19/1996<br>terry : 9/20/1996<br>mark : 9/6/1996<br>terry : 9/3/1996<br>terry : 8/27/1996<br>mark : 7/25/1996<br>mark : 3/26/1996<br>terry : 3/19/1996<br>mark : 3/14/1996<br>terry : 3/14/1996<br>mark : 3/10/1996<br>terry : 3/5/1996<br>mark : 2/14/1996<br>terry : 2/9/1996<br>mark : 1/20/1996<br>mark : 1/19/1996<br>mark : 1/4/1996<br>terry : 12/29/1995<br>terry : 12/29/1995<br>terry : 11/16/1995<br>mark : 11/6/1995<br>pfoster : 7/6/1995<br>jason : 7/18/1994<br>mimadm : 5/17/1994<br>warfield : 4/20/1994
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