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Entry
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- *609390 - FIG4 PHOSPHOINOSITIDE 5-PHOSPHATASE; FIG4
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- OMIM
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</nav>
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<div id="mimSearch" class="hidden-print">
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<div class="container">
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<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
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<div class="input-group">
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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<div class="input-group-btn">
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<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
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<button type="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
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<ul class="dropdown-menu dropdown-menu-right">
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<li class="dropdown-header">
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Advanced Search
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<li role="separator" class="divider"></li>
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<a href="/history"> Search History </a>
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</form>
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<p />
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<div class="row">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*609390</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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="#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/609390">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
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</span>
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</span>
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</div>
|
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
|
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000112367;t=ENST00000230124" 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=9896" 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=609390" 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=ENSG00000112367;t=ENST00000230124" 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_014845,XM_011536281" 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_014845" 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=609390" 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=11073&isoform_id=11073_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/FIG4" 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/2497367,7662034,27370598,62897023,119568717,158256774,194373667,767943968,929653855,2462611625" 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/Q92562" 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=9896" 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=ENSG00000112367;t=ENST00000230124" 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=FIG4" 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=FIG4" 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+9896" 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/FIG4" 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:9896" 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/9896" 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=chr6&hgg_gene=ENST00000230124.8&hgg_start=109691296&hgg_end=109825426&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/genes/HGNC:16873" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=609390[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=609390[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/FIG4/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/ENSG00000112367" 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=FIG4" 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=FIG4" 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=FIG4" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=FIG4&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/PA162388528" 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:16873" 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/FBgn0031611.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:2143585" 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/FIG4#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:2143585" 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/9896/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=9896" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00007912;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-130213-1" 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="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">
|
|
<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://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:9896" 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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<div><a href="https://reactome.org/content/query?q=FIG4&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> 720638000<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>
|
|
609390
|
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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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FIG4 PHOSPHOINOSITIDE 5-PHOSPHATASE; FIG4
|
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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>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
FIG4, S. CEREVISIAE, HOMOLOG OF<br />
|
|
SAC DOMAIN-CONTAINING INOSITOL PHOSPHATASE 3; SAC3<br />
|
|
KIAA0274
|
|
</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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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=FIG4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FIG4</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>
|
|
Cytogenetic location: <a href="/geneMap/6/769?start=-3&limit=10&highlight=769">6q21</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr6:109691296-109825426&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'})">6:109,691,296-109,825,426</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover 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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<a href="/clinicalSynopsis/table?mimNumber=612691,612577,611228,216340" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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<a href="/geneMap/6/769?start=-3&limit=10&highlight=769">
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6q21
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?Polymicrogyria, bilateral temporooccipital
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<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
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<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
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<a href="/entry/612691"> 612691 </a>
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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Amyotrophic lateral sclerosis 11
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<a href="/entry/612577"> 612577 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</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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Charcot-Marie-Tooth disease, type 4J
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<a href="/entry/611228"> 611228 </a>
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</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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Yunis-Varon syndrome
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<a href="/entry/216340"> 216340 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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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/609390" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/609390" 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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<strong>Description</strong>
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<p>The content of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) in endosomal membranes changes dynamically with fission and fusion events that generate or absorb intracellular transport vesicles. FIG4 is a PtdIns(3,5)P2 5-phosphatase that functions in a trimolecular complex that tightly regulates the level of PtdIns(3,5)P2. Other components of this complex are the PtdIns(3,5)P2-synthesizing enzyme PIKFYVE (<a href="/entry/609414">609414</a>) and its activator, VAC14 (<a href="/entry/604632">604632</a>) (<a href="#16" class="mim-tip-reference" title="Sbrissa, D., Ikonomov, O. C., Fu, Z., Ijuin, T., Gruenberg, J., Takenawa, T., Shisheva, A. <strong>Core protein machinery for mammalian phosphatidylinositol 3,5-bisphosphate synthesis and turnover that regulates the progression of endosomal transport: novel Sac phosphatase joins the ArPIKfyve-PIKfyve complex.</strong> J. Biol. Chem. 282: 23878-23891, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17556371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17556371</a>] [<a href="https://doi.org/10.1074/jbc.M611678200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17556371">Sbrissa et al., 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17556371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Cloning and Expression</strong>
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<p>By sequencing clones obtained from a size-fractionated brain cDNA library, <a href="#13" class="mim-tip-reference" title="Nagase, T., Seki, N., Ishikawa, K., Ohira, M., Kawarabayasi, Y., Ohara, O., Tanaka, A., Kotani, H., Miyajima, N., Nomura, N. <strong>Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain.</strong> DNA Res. 3: 321-329, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9039502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9039502</a>] [<a href="https://doi.org/10.1093/dnares/3.5.321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9039502">Nagase et al. (1996)</a> cloned full-length FIG4, which they called KIAA0274. The deduced protein contains 907 amino acids. Northern blot analysis detected expression in all tissues examined, with highest expression in testis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9039502" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="Sbrissa, D., Ikonomov, O. C., Fu, Z., Ijuin, T., Gruenberg, J., Takenawa, T., Shisheva, A. <strong>Core protein machinery for mammalian phosphatidylinositol 3,5-bisphosphate synthesis and turnover that regulates the progression of endosomal transport: novel Sac phosphatase joins the ArPIKfyve-PIKfyve complex.</strong> J. Biol. Chem. 282: 23878-23891, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17556371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17556371</a>] [<a href="https://doi.org/10.1074/jbc.M611678200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17556371">Sbrissa et al. (2007)</a> stated that the full-length 907-amino acid SAC3 protein contains an N-terminal SAC phosphatase domain of about 400 amino acids. SAC3 also has multiple sites for serine/threonine and tyrosine phosphorylation and numerous motifs for interaction with intracellular transport and sorting molecules. Western blot analysis of HEK293 human embryonic kidney cells and other mammalian cell lines detected SAC3 at an apparent molecular mass of 97 kD. The presence of a broad band suggested posttranslational modification of the protein. Fractionation of HEK293 cells showed that SAC3 associated with both cytosol and membranes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17556371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Gene Structure</strong>
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<p><a href="#4" class="mim-tip-reference" title="Chow, C. Y., Zhang, Y., Dowling, J. J., Jin, N., Adamska, M., Shiga, K., Szigeti, K., Shy, M. E., Li, J., Zhang, X., Lupski, J. R., Weisman, L. S., Meisler, M. H. <strong>Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J.</strong> Nature 448: 68-72, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17572665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17572665</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17572665[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/nature05876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17572665">Chow et al. (2007)</a> determined that the human FIG4 gene comprises 23 coding exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17572665" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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<a id="mapping" class="mim-anchor"></a>
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p>By radiation hybrid analysis, <a href="#13" class="mim-tip-reference" title="Nagase, T., Seki, N., Ishikawa, K., Ohira, M., Kawarabayasi, Y., Ohara, O., Tanaka, A., Kotani, H., Miyajima, N., Nomura, N. <strong>Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain.</strong> DNA Res. 3: 321-329, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9039502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9039502</a>] [<a href="https://doi.org/10.1093/dnares/3.5.321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9039502">Nagase et al. (1996)</a> mapped the KIAA0274 gene to chromosome 6. <a href="#4" class="mim-tip-reference" title="Chow, C. Y., Zhang, Y., Dowling, J. J., Jin, N., Adamska, M., Shiga, K., Szigeti, K., Shy, M. E., Li, J., Zhang, X., Lupski, J. R., Weisman, L. S., Meisler, M. H. <strong>Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J.</strong> Nature 448: 68-72, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17572665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17572665</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17572665[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/nature05876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17572665">Chow et al. (2007)</a> localized the gene to chromosome 6q21. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17572665+9039502" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 coimmunoprecipitation analysis, <a href="#16" class="mim-tip-reference" title="Sbrissa, D., Ikonomov, O. C., Fu, Z., Ijuin, T., Gruenberg, J., Takenawa, T., Shisheva, A. <strong>Core protein machinery for mammalian phosphatidylinositol 3,5-bisphosphate synthesis and turnover that regulates the progression of endosomal transport: novel Sac phosphatase joins the ArPIKfyve-PIKfyve complex.</strong> J. Biol. Chem. 282: 23878-23891, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17556371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17556371</a>] [<a href="https://doi.org/10.1074/jbc.M611678200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17556371">Sbrissa et al. (2007)</a> showed that endogenous SAC3, PIKFYVE, and ARPIKFYVE (VAC14) formed a stable ternary complex in HEK293 cells and other mammalian cell lines. Immunoprecipitated epitope-tagged SAC3 hydrolyzed the D5 phosphate from PtdIns(4,5)P2, PtdIns(3,5)P2, and PtdIns(3,4,5)P3, but it did not use PtdIns(5)P or other PtdIns substrates. Mutation analysis showed that asp488 was required for SAC3 phosphatase activity. Overexpression of SAC3 in HEK293 cells did not produce an obvious morphologic phenotype, but it rendered cells prone to developing dilated intracellular membranes, consistent with perturbation of membrane PtdIns(3,5)P2 levels. In contrast, depletion of SAC3 via small interfering RNA enhanced endosome carrier vesicles/multivesicular body formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17556371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="Lenk, G. M., Meisler, M. H. <strong>Chloroquine corrects enlarged lysosomes in FIG4 null cells and reduces neurodegeneration in Fig4 null mice.</strong> Molec. Genet. Metab. 137: 382-387, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36434903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36434903</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36434903[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.ymgme.2022.11.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36434903">Lenk and Meisler (2022)</a> used CRISPR editing to generate FIG4 -/- 3D4 cells and treated the cells with chloroquine, a drug that is known to reduce lysosomal acidity. Treatment with chloroquine corrected the abnormal appearance of abnormal lysosomes that were seen in the untreated mutant cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36434903" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Charcot-Marie-Tooth Disease 4J, Autosomal Recessive</em></strong></p><p>
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In 4 unrelated patients with autosomal recessive Charcot-Marie-Tooth disease type 4J (CMT4J; <a href="/entry/611228">611228</a>), <a href="#4" class="mim-tip-reference" title="Chow, C. Y., Zhang, Y., Dowling, J. J., Jin, N., Adamska, M., Shiga, K., Szigeti, K., Shy, M. E., Li, J., Zhang, X., Lupski, J. R., Weisman, L. S., Meisler, M. H. <strong>Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J.</strong> Nature 448: 68-72, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17572665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17572665</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17572665[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/nature05876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17572665">Chow et al. (2007)</a> identified compound heterozygous mutations in the FIG4 gene (<a href="#0001">609390.0001</a>-<a href="#0005">609390.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17572665" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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 3 unrelated patients of Australian descent with CMT4J, <a href="#14" class="mim-tip-reference" title="Nicholson, G., Lenk, G. M., Reddel, S. W., Grant, A. E., Towne, C. F., Ferguson, C. J., Simpson, E., Scheuerle, A., Yasick, M., Hoffman, S., Blouin, R., Brandt, C., Coppola, G., Biesecker, L. G., Batish, S. D., Meisler, M. H. <strong>Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P2 phosphatase FIG4.</strong> Brain 134: 1959-1971, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21705420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21705420</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21705420[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/brain/awr148" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21705420">Nicholson et al. (2011)</a> identified compound heterozygosity for the ancestral I41T FIG4 mutation and 1 of 3 different truncating mutations. Direct screening of the FIG4 gene was performed in these patients based on the early-onset severe phenotype. The mutations segregated with the disorder in all families. Sequencing the FIG4 gene in 4,000 DNA samples submitted for a CMT gene panel identified 8 (0.2%) patients carrying compound heterozygous mutations (see, e.g., <a href="#0013">609390.0013</a> and <a href="#0014">609390.0014</a>). Seven of these patients carried the I41T allele in combination with a null allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21705420" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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>Amyotrophic Lateral Sclerosis 11</em></strong></p><p>
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In 5 unrelated patients with amyotrophic lateral sclerosis (ALS11; <a href="/entry/612577">612577</a>), <a href="#3" class="mim-tip-reference" title="Chow, C. Y., Landers, J. E., Bergren, S. K., Sapp, P. C., Grant, A. E., Jones, J. M., Everett, L., Lenk, G. M., McKenna-Yasek, D. M., Weisman, L. S., Figlewicz, D., Brown, R. H., Meisler, M. H. <strong>Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS.</strong> Am. J. Hum. Genet. 84: 85-88, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19118816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19118816</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.12.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19118816">Chow et al. (2009)</a> identified heterozygosity for a missense, 2 splice site, and 2 truncating mutations in the FIG4 gene (see, e.g., <a href="#0006">609390.0006</a>-<a href="#0008">609390.0008</a>). The mutations were shown to result in complete or significant loss of protein function. Five different missense FIG4 mutations were identified in 5 patients with a diagnosis of ALS or adult-onset primary lateral sclerosis (PLSA1; <a href="/entry/611637">611637</a>), but these mutations were not clearly shown to be pathogenic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19118816" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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>Yunis-Varon Syndrome</em></strong></p><p>
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In 5 patients from 3 unrelated families with Yunis-Varon syndrome (YVS; <a href="/entry/216340">216340</a>), <a href="#2" class="mim-tip-reference" title="Campeau, P. M., Lenk, G. M., Lu, J. T., Bae, Y., Burrage, L., Turnpenny, P., Corona-Rivera J. R., Morandi, L., Mora, M., Reutter, H., Vulto-van Silfhout, A. T., Faivre, L., Haan, E., Gibbs, R. A., Meisler, M. H., Lee, B. H. <strong>Yunis-Varon syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase.</strong> Am. J. Hum. Genet. 92: 781-791, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23623387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23623387</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23623387[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.2013.03.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23623387">Campeau et al. (2013)</a> identified homozygous or compound heterozygous mutations in the FIG4 gene (<a href="#0009">609390.0009</a>-<a href="#0012">609390.0012</a>). The phenotype was severe, characterized by cleidocranial dysplasia, digital anomalies, hypotonia, dysmorphic facial features, and severe neurologic involvement, all apparent from birth. Most patients died in infancy. Tissue samples showed enlarged cytoplasmic vacuoles. All the mutations, which were found by exome sequencing, resulted in complete loss of protein function, which <a href="#2" class="mim-tip-reference" title="Campeau, P. M., Lenk, G. M., Lu, J. T., Bae, Y., Burrage, L., Turnpenny, P., Corona-Rivera J. R., Morandi, L., Mora, M., Reutter, H., Vulto-van Silfhout, A. T., Faivre, L., Haan, E., Gibbs, R. A., Meisler, M. H., Lee, B. H. <strong>Yunis-Varon syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase.</strong> Am. J. Hum. Genet. 92: 781-791, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23623387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23623387</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23623387[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.2013.03.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23623387">Campeau et al. (2013)</a> suggested resulted in a more severe phenotype than that observed in CMT4J; the latter disorder is associated with at least 1 missense hypomorphic mutation in the FIG4 gene. The report demonstrated that absence of FIG4 activity leads to central nervous system dysfunction and extensive skeletal anomalies, which suggested a role for PI(3,5)P2 signaling in skeletal development and maintenance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23623387" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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>Bilateral Temporooccipital Polymicrogyria</em></strong></p><p>
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In affected members of a consanguineous Moroccan family with bilateral temporooccipital polymicrogyria (BTOP; <a href="/entry/612691">612691</a>), <a href="#1" class="mim-tip-reference" title="Baulac, S., Lenk, G. M., Dufresnois, B., Ouled Amar Bencheikh, B., Couarch, P., Renard, J., Larson, P. A., Ferguson, C. J., Noe, E., Poirier, K., Hubans, C., Ferreira, S., Guerrini, R., Ouazzani, R., El Hachimi, K. H., Meisler, M. H., Leguern, E. <strong>Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria.</strong> Neurology 82: 1068-1075, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24598713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24598713</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24598713[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/10.1212/WNL.0000000000000241" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24598713">Baulac et al. (2014)</a> identified a homozygous missense mutation in the FIG4 gene (D783V; <a href="#0016">609390.0016</a>). The mutation was found by whole-exome sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24598713" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>The phenotype of the 'pale tremor' (plt) mouse, identified by <a href="#4" class="mim-tip-reference" title="Chow, C. Y., Zhang, Y., Dowling, J. J., Jin, N., Adamska, M., Shiga, K., Szigeti, K., Shy, M. E., Li, J., Zhang, X., Lupski, J. R., Weisman, L. S., Meisler, M. H. <strong>Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J.</strong> Nature 448: 68-72, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17572665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17572665</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17572665[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/nature05876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17572665">Chow et al. (2007)</a>, is characterized by a multi-organ disorder with neuronal degeneration in the central nervous system, peripheral neuronopathy, and diluted pigmentation. Positional cloning identified insertion of ETn2-beta (early transposon 2-beta) into intron 18 of the mouse Fig4 gene, the homolog of a yeast suppressor of actin (SAC) domain phosphatidylinositol(3,5)P(2)5-phosphatase located in the vacuolar membrane. The abnormal concentration of phosphatidylinositol-3,5-bisphosphate in cultured fibroblasts from pale tremor mice demonstrated the conserved biochemical function of mammalian Fig4. The cytoplasm of fibroblasts from pale tremor mice was filled with large vacuoles that were immunoreactive for Lamp2 (<a href="/entry/309060">309060</a>), consistent with dysfunction of the late endosome-lysosome axis. Neonatal neurodegeneration in sensory and autonomic ganglia was followed by loss of neurons from layers 4 and 5 of the cortex, deep cerebellar nuclei, and other localized brain regions. The sciatic nerve exhibited reduced numbers of large-diameter myelinated axons, slowed nerve conduction velocity, and reduced amplitude of compound muscle action potentials. <a href="#18" class="mim-tip-reference" title="Zhang, X., Chow, C. Y., Sahenk, Z., Shy, M. E., Meisler, M. H., Li, J. <strong>Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration.</strong> Brain 131: 1990-2001, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18556664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18556664</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18556664[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/brain/awn114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18556664">Zhang et al. (2008)</a> found a profound loss of large motor neurons in the anterior horns of the spinal cord of plt mice. Remaining neurons contained large vacuoles that did not stain for ubiquitin or neurofilaments. There was no evidence of apoptosis of neurons or Schwann cells in plt mice, but there was a loss of large-diameter motor axons as well as evidence of segmental demyelination. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18556664+17572665" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Mutations affecting the conversion of PI3P to the signaling lipid PI(3,5)P2 result in spongiform degeneration of mouse brain and are associated with the human disorders Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis (ALS). <a href="#7" class="mim-tip-reference" title="Ferguson, C. J., Lenk, G. M., Meisler, M. H. <strong>Defective autophagy in neurons and astrocytes from mice deficient in PI(3,5)P2.</strong> Hum. Molec. Genet. 18: 4868-4878, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19793721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19793721</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19793721[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/ddp460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19793721">Ferguson et al. (2009)</a> reported accumulation of the proteins Lc3II (MAP1LC3A; <a href="/entry/601242">601242</a>), p62 (SQSTM1; <a href="/entry/601530">601530</a>), and Lamp2 in neurons and astrocytes of mice with mutations in 2 components of the PI(3,5)P2 regulatory complex, Fig4 and Vac14 (<a href="/entry/604632">604632</a>). Cytoplasmic inclusion bodies containing p62 and ubiquitinated proteins were present in regions of the mutant brain that underwent degeneration. Colocalization of p62 and LAMP2 in affected cells indicated that formation or recycling of the autolysosome may be impaired. The authors proposed a role for PI(3,5)P2 in autophagy in the mammalian central nervous system and demonstrated that mutations affecting PI(3,5)P2 may contribute to inclusion body disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19793721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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 patient fibroblasts, cell culture, and transgenic mice, <a href="#9" class="mim-tip-reference" title="Lenk, G. M., Ferguson, C. J., Chow, C. Y., Jin, N., Jones, J. M., Grant, A. E., Zolov, S. N., Winters, J. J., Giger, R. J., Dowling, J. J., Weisman, L. S., Meisler, M. H. <strong>Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-Tooth disease CMT4J.</strong> PLoS Genet. 7: e1002104, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21655088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21655088</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21655088[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/10.1371/journal.pgen.1002104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21655088">Lenk et al. (2011)</a> demonstrated that the I41T mutant protein (<a href="#0001">609390.0001</a>) is unstable, resulting in low levels of FIG4. Low levels of the protein resulted from impaired interaction with VAC14, which stabilizes FIG4. Overexpression of mutant I41T in Fig4-null mice to 10% of wildtype levels rescued the severe neurodegenerative phenotype, whereas lesser overexpression (2-fold) resulted in partial rescue and a CMT-like phenotype. The abundance of the I41T protein in cultured cells could be increased by treatment with a proteasome inhibitor. The findings indicated that I41T is a hypomorphic allele and suggested that increasing expression of the I41T mutant allele in CMT4J patients with the mutation may be therapeutic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21655088" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Winters, J. J., Ferguson, C. J., Lenk, G. M., Giger-Mateeva, V. I., Shrager, P., Meisler, M. H., Giger, R. J. <strong>Congenital CNS hypomyelination in the Fig4 null mouse is rescued by neuronal expression of the PI(3,5)P2 phosphatase Fig4.</strong> J. Neurosci. 31: 17736-17751, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22131434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22131434</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22131434[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/10.1523/JNEUROSCI.1482-11.2011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22131434">Winters et al. (2011)</a> found that Fig4 -/- mice had a pronounced reduction of myelin in central nerve system (CNS). Examination of Fig4 -/- optic nerve revealed that, in spite of a normal number of axons, loss of Fig4 caused severe dysmyelination due to developmental failure to myelinate small and intermediate size axons. Fig4 -/- optic nerve also had disorganized nodes of Ranvier and paranodes, with an increased number of slow conducting axons. Loss of Fig4 resulted in a decreased number of myelinating oligodendrocytes throughout the CNS due to arrest of oligodendrocyte precursor cell maturation. Neuron-specific expression of wildtype mouse Fig4 rescued the optic nerve dysmyelination phenotype of Fig4 -/- mice, demonstrating that oligodendrocyte precursor cell maturation and myelin development in Fig4 -/- mice were secondary to neuronal defects and that Fig4 had a non-cell-autonomous function in oligodendrocyte development. Global overexpression of the human FIG4 I41T variant, which retains low-level function, rescued Fig4 -/- mice from the myelination defect and early lethality. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22131434" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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 tissue, <a href="#2" class="mim-tip-reference" title="Campeau, P. M., Lenk, G. M., Lu, J. T., Bae, Y., Burrage, L., Turnpenny, P., Corona-Rivera J. R., Morandi, L., Mora, M., Reutter, H., Vulto-van Silfhout, A. T., Faivre, L., Haan, E., Gibbs, R. A., Meisler, M. H., Lee, B. H. <strong>Yunis-Varon syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase.</strong> Am. J. Hum. Genet. 92: 781-791, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23623387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23623387</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23623387[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.2013.03.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23623387">Campeau et al. (2013)</a> found that Fig4 expression in calvaria, osteoblasts, and bone marrow cells was comparable to its expression in brain. Fig4-null mice showed a smaller skeleton than wildtype mice at day P21, with smaller long bones, clavicles, and pelvic bones. Although the shapes of the bones were similar to wildtype, Fig4-null mouse bones had significantly lower (50%) trabecular and cortical density, bone volume fraction, bone surface, trabecular number, and connectivity density, consistent with abnormal ossification. Cultures of isolated osteoblasts from calvarial tissue showed extensive vacuolization. Fig4-null mice did not exhibit aplasia or hypoplasia of digits on the front or rear limbs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23623387" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="Baulac, S., Lenk, G. M., Dufresnois, B., Ouled Amar Bencheikh, B., Couarch, P., Renard, J., Larson, P. A., Ferguson, C. J., Noe, E., Poirier, K., Hubans, C., Ferreira, S., Guerrini, R., Ouazzani, R., El Hachimi, K. H., Meisler, M. H., Leguern, E. <strong>Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria.</strong> Neurology 82: 1068-1075, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24598713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24598713</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24598713[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/10.1212/WNL.0000000000000241" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24598713">Baulac et al. (2014)</a> found that the brains of postnatal Fig4-null mice were macroscopically normal, but there was a transient increase in neuronal density associated with apoptosis. There was also delayed maturation of interneurons and dentate granule cells and their processes in various brain regions. The findings indicated postmigration abnormalities in the brains of Fig4-null mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24598713" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Mironova, Y. A., Lin, J.-P., Kalinski, A. L., Huffman, L. D., Lenk, G. M., Havton, L. A., Meisler, M. H., Giger, R. J. <strong>Protective role of the lipid phosphatase Fig4 in the adult nervous system.</strong> Hum. Molec. Genet. 27: 2443-2453, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29688489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29688489</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29688489[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/ddy145" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29688489">Mironova et al. (2018)</a> found that neonatal knockout of Fig4 in mice recapitulated the neurologic defects of constitutive Fig4 -/- mice, including regional spongiform degeneration, CNS hypomyelination, and accumulation of vacuoles in oligodendrocytes. Induced deletion of Fig4 in adult mice recapitulated the lethal disorder of constitutive Fig4 -/- mice with a similar time course. However, adult mice with induced Fig4 deletion displayed normal abundance of CNS myelin proteins, normal structural integrity of myelin sheaths in optic nerve cross sections, and normal electrophysiologic properties. Adult mice with induced Fig4 deletion were defective in axon remyelination and timely repair of damaged white matter. Histologic examination revealed severe Wallerian degeneration of sciatic nerve, but not C-fiber axons in Remak bundles, in mice with induced Fig4 deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29688489" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="Lenk, G. M., Meisler, M. H. <strong>Chloroquine corrects enlarged lysosomes in FIG4 null cells and reduces neurodegeneration in Fig4 null mice.</strong> Molec. Genet. Metab. 137: 382-387, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36434903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36434903</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36434903[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.ymgme.2022.11.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36434903">Lenk and Meisler (2022)</a> treated Fig4 -/- mice with chloroquine, a drug that is known to reduce lysosomal acidity. The treated Fig4 -/- mice were larger compared to untreated Fig4 -/- mice, and at 30 days of age, the treated mutant mice had improved mobility and other behaviors (running, rearing, grooming) compared to untreated mutant mice. The treated mutant mice survived about 4 weeks longer than the untreated mutant mice. Brain tissue from treated mutant mice had decreased vacuolization compared to untreated mutant mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36434903" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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=609390[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908287 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908287;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908287?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908287" 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=rs121908287" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 4 unrelated patients with severe early-onset autosomal recessive Charcot-Marie-Tooth disease (CMT4J; <a href="/entry/611228">611228</a>), <a href="#4" class="mim-tip-reference" title="Chow, C. Y., Zhang, Y., Dowling, J. J., Jin, N., Adamska, M., Shiga, K., Szigeti, K., Shy, M. E., Li, J., Zhang, X., Lupski, J. R., Weisman, L. S., Meisler, M. H. <strong>Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J.</strong> Nature 448: 68-72, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17572665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17572665</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17572665[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/nature05876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17572665">Chow et al. (2007)</a> found the same mutation in the FIG4 gene, a T-to-C transition at nucleotide 122 resulting in an ile-to-thr substitution at codon 41 (I41T). The mutation occurred in compound heterozygosity in each patient with 1 of 4 other FIG4 mutations (<a href="#0002">609390.0002</a>-<a href="#0005">609390.0005</a>). The 4 patients carried I41T on the same 15-kb haplotype, defined by 3 single-nucleotide polymorphisms (SNPs), consistent with inheritance of a common ancestral mutant allele. The isoleucine at codon 41 is invariant from human to yeast. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17572665" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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 patient fibroblasts, cell culture, and transgenic mice, <a href="#9" class="mim-tip-reference" title="Lenk, G. M., Ferguson, C. J., Chow, C. Y., Jin, N., Jones, J. M., Grant, A. E., Zolov, S. N., Winters, J. J., Giger, R. J., Dowling, J. J., Weisman, L. S., Meisler, M. H. <strong>Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-Tooth disease CMT4J.</strong> PLoS Genet. 7: e1002104, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21655088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21655088</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21655088[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/10.1371/journal.pgen.1002104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21655088">Lenk et al. (2011)</a> demonstrated that the I41T mutant protein is unstable, resulting in low levels of FIG4. Low levels of the protein resulted from impaired interaction with VAC14 (<a href="/entry/604362">604362</a>), which stabilizes FIG4. Overexpression of mutant I41T in Fig4-null mice to 10% of wildtype levels rescued the neurodegenerative phenotype. The abundance of the I41T protein in cultured cells could be increased by treatment with a proteasome inhibitor. The findings indicated that I41T is a hypomorphic allele and suggested that increasing expression of the I41T mutant allele in patients with the mutation may be therapeutic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21655088" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Nicholson, G., Lenk, G. M., Reddel, S. W., Grant, A. E., Towne, C. F., Ferguson, C. J., Simpson, E., Scheuerle, A., Yasick, M., Hoffman, S., Blouin, R., Brandt, C., Coppola, G., Biesecker, L. G., Batish, S. D., Meisler, M. H. <strong>Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P2 phosphatase FIG4.</strong> Brain 134: 1959-1971, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21705420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21705420</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21705420[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/brain/awr148" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21705420">Nicholson et al. (2011)</a> found that the allele frequency of I41T is 0.001 (13 heterozygotes among 5,769 Northern European controls). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21705420" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs1562648373 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1562648373;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=rs1562648373" 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=rs1562648373" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient with Charcot-Marie-Tooth disease type 4J (CMT4J; <a href="/entry/611228">611228</a>), <a href="#4" class="mim-tip-reference" title="Chow, C. Y., Zhang, Y., Dowling, J. J., Jin, N., Adamska, M., Shiga, K., Szigeti, K., Shy, M. E., Li, J., Zhang, X., Lupski, J. R., Weisman, L. S., Meisler, M. H. <strong>Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J.</strong> Nature 448: 68-72, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17572665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17572665</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17572665[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/nature05876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17572665">Chow et al. (2007)</a> identified a single-basepair deletion, of thymidine, at nucleotide 294 of the FIG4 gene, resulting in frameshift and premature termination of the protein (Phe98fsTer102). The patient was compound heterozygous for the I41T allele (<a href="#0001">609390.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17572665" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0003 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 4J</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908288 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908288;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908288?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908288" 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=rs121908288" 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=RCV000001793 OR RCV000001796 OR RCV000235305 OR RCV001046714 OR RCV001095516 OR RCV003944790" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001793, RCV000001796, RCV000235305, RCV001046714, RCV001095516, RCV003944790" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001793...</a>
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<p>In a patient and her sib with Charcot-Marie-Tooth disease type 4J (CMT4J; <a href="/entry/611228">611228</a>), <a href="#4" class="mim-tip-reference" title="Chow, C. Y., Zhang, Y., Dowling, J. J., Jin, N., Adamska, M., Shiga, K., Szigeti, K., Shy, M. E., Li, J., Zhang, X., Lupski, J. R., Weisman, L. S., Meisler, M. H. <strong>Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J.</strong> Nature 448: 68-72, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17572665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17572665</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17572665[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/nature05876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17572665">Chow et al. (2007)</a> found compound heterozygosity for a C-to-T transition at nucleotide 718 of the FIG4 gene, resulting in an arg-to-ter substitution at codon 183 (R183X), and the I41T mutation (<a href="#0001">609390.0001</a>). Both sibs had severe disease. The proband was a functional quadriplegic, and her sib was wheelchair-bound with normal use of his arms. Both had slow nerve conduction velocities. A sural nerve biopsy from the proband demonstrated profound axonal loss, thinly myelinated nerve fibers, and evidence of de- and remyelination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17572665" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0004 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 4J</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">rs1368013631 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1368013631;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=rs1368013631" 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=rs1368013631" 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=RCV000001794 OR RCV000789115 OR RCV001851563" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001794, RCV000789115, RCV001851563" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001794...</a>
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<p>In a patient with Charcot-Marie-Tooth disease type 4J (CMT4J; <a href="/entry/611228">611228</a>), <a href="#4" class="mim-tip-reference" title="Chow, C. Y., Zhang, Y., Dowling, J. J., Jin, N., Adamska, M., Shiga, K., Szigeti, K., Shy, M. E., Li, J., Zhang, X., Lupski, J. R., Weisman, L. S., Meisler, M. H. <strong>Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J.</strong> Nature 448: 68-72, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17572665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17572665</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17572665[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/nature05876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17572665">Chow et al. (2007)</a> found compound heterozygosity for the I41T mutation in FIG4 (<a href="#0001">609390.0001</a>) and an 8-basepair deletion, of ATCAGGCA, starting at nucleotide position 1043 (Asp348fsTer359). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17572665" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 4J</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs764717219 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs764717219;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs764717219?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs764717219" 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=rs764717219" 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=RCV000001795 OR RCV000416492 OR RCV000517693 OR RCV000533386 OR RCV000789114" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001795, RCV000416492, RCV000517693, RCV000533386, RCV000789114" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001795...</a>
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<p>In a patient with Charcot-Marie-Tooth disease type 4J (CMT4J; <a href="/entry/611228">611228</a>), <a href="#4" class="mim-tip-reference" title="Chow, C. Y., Zhang, Y., Dowling, J. J., Jin, N., Adamska, M., Shiga, K., Szigeti, K., Shy, M. E., Li, J., Zhang, X., Lupski, J. R., Weisman, L. S., Meisler, M. H. <strong>Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J.</strong> Nature 448: 68-72, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17572665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17572665</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17572665[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/nature05876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17572665">Chow et al. (2007)</a> found a single-basepair deletion of a guanine at position 759 of the FIG4 gene, resulting in a frameshift and early termination (Gly253fsTer261). The patient carried this mutation in compound heterozygosity with the I41T mutation (<a href="#0001">609390.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17572665" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908288 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908288;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908288?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908288" 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=rs121908288" 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=RCV000001793 OR RCV000001796 OR RCV000235305 OR RCV001046714 OR RCV001095516 OR RCV003944790" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001793, RCV000001796, RCV000235305, RCV001046714, RCV001095516, RCV003944790" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001793...</a>
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<p>In a man with probable amyotrophic lateral sclerosis (ALS11; <a href="/entry/612577">612577</a>), <a href="#3" class="mim-tip-reference" title="Chow, C. Y., Landers, J. E., Bergren, S. K., Sapp, P. C., Grant, A. E., Jones, J. M., Everett, L., Lenk, G. M., McKenna-Yasek, D. M., Weisman, L. S., Figlewicz, D., Brown, R. H., Meisler, M. H. <strong>Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS.</strong> Am. J. Hum. Genet. 84: 85-88, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19118816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19118816</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.12.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19118816">Chow et al. (2009)</a> identified a heterozygous 547C-T transition in exon 6 of the FIG4 gene, resulting in an arg183-to-ter (R183X) substitution, predicted to result in loss of phosphatase activity. He had onset at age 62 and presented with bulbar signs. He had prominent cortical spinal tract findings and moderate lower motor neuron findings. EMG showed mild denervation of 3 extremities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19118816" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs200730266 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs200730266;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs200730266?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs200730266" 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=rs200730266" 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=RCV000235449 OR RCV001323814 OR RCV001839451 OR RCV003447130" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000235449, RCV001323814, RCV001839451, RCV003447130" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000235449...</a>
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<p>In a woman with amyotrophic lateral sclerosis (ALS11; <a href="/entry/612577">612577</a>), <a href="#3" class="mim-tip-reference" title="Chow, C. Y., Landers, J. E., Bergren, S. K., Sapp, P. C., Grant, A. E., Jones, J. M., Everett, L., Lenk, G. M., McKenna-Yasek, D. M., Weisman, L. S., Figlewicz, D., Brown, R. H., Meisler, M. H. <strong>Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS.</strong> Am. J. Hum. Genet. 84: 85-88, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19118816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19118816</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.12.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19118816">Chow et al. (2009)</a> identified a heterozygous G-to-T transversion in intron 11 (1386+5G-T) of the FIG4 gene, predicted to result in the skipping of exon 12 or premature termination. She had onset at age 57 and presented with involvement of the upper extremity. She had both upper and lower motor neuron signs and acute and chronic denervation on EMG. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19118816" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs121908290 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908290;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=rs121908290" 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=rs121908290" 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=RCV000001798 OR RCV003447064" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001798, RCV003447064" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001798...</a>
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<p>In a woman with amyotrophic lateral sclerosis (ALS11; <a href="/entry/612577">612577</a>), <a href="#3" class="mim-tip-reference" title="Chow, C. Y., Landers, J. E., Bergren, S. K., Sapp, P. C., Grant, A. E., Jones, J. M., Everett, L., Lenk, G. M., McKenna-Yasek, D. M., Weisman, L. S., Figlewicz, D., Brown, R. H., Meisler, M. H. <strong>Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS.</strong> Am. J. Hum. Genet. 84: 85-88, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19118816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19118816</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.12.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19118816">Chow et al. (2009)</a> identified a heterozygous 157G-T transversion in exon 2 of the FIG4 gene, resulting in an asp53-to-tyr (D53Y) substitution. In vitro functional expression studies in yeast showed that the mutant protein had significantly less activity compared to wildtype. The patient presented at age 56 with bulbar signs. She had moderate corticospinal findings, and autopsy showed lower motor neuron loss. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19118816" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 YUNIS-VARON 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">rs397509394 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397509394;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=rs397509394" 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=rs397509394" 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=RCV000043689" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000043689" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000043689</a>
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<p>In 2 sibs, born of consanguineous Mexican parents, with Yunis-Varon syndrome (YVS; <a href="/entry/216340">216340</a>), who had been reported by <a href="#5" class="mim-tip-reference" title="Corona-Rivera, J. R., Romo-Huerta, C. O., Lopez-Marure, E., Ramos, F. J., Estrada-Padilla, S. A., Zepeda-Romero, L. C. <strong>New ocular findings in two sisters with Yunis-Varon syndrome and literature review.</strong> Europ. J. Med. Genet. 54: 76-81, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20932945/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20932945</a>] [<a href="https://doi.org/10.1016/j.ejmg.2010.09.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20932945">Corona-Rivera et al. (2011)</a>, <a href="#2" class="mim-tip-reference" title="Campeau, P. M., Lenk, G. M., Lu, J. T., Bae, Y., Burrage, L., Turnpenny, P., Corona-Rivera J. R., Morandi, L., Mora, M., Reutter, H., Vulto-van Silfhout, A. T., Faivre, L., Haan, E., Gibbs, R. A., Meisler, M. H., Lee, B. H. <strong>Yunis-Varon syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase.</strong> Am. J. Hum. Genet. 92: 781-791, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23623387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23623387</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23623387[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.2013.03.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23623387">Campeau et al. (2013)</a> identified a homozygous 2-bp deletion (c.1260_1261delGT) in exon 11 of the FIG4 gene, resulting in a frameshift and premature termination (Thr422GlnfsTer6) predicted to cause protein truncation upstream of the phosphatase catalytic motif and complete loss of function. Each unaffected parent was heterozygous for the mutation, which was found by exome sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20932945+23623387" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0010 YUNIS-VARON 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">rs397509395 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397509395;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=rs397509395" 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=rs397509395" 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=RCV000043690 OR RCV003447105" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000043690, RCV003447105" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000043690...</a>
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<p>In 2 sibs, born of unrelated English parents, with Yunis-Varon syndrome (YVS; <a href="/entry/216340">216340</a>), who had been reported by <a href="#8" class="mim-tip-reference" title="Garrett, C., Berry, A. C., Simpson, R. H., Hall, C. M. <strong>Yunis-Varon syndrome with severe osteodysplasty.</strong> J. Med. Genet. 27: 114-121, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2319578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2319578</a>] [<a href="https://doi.org/10.1136/jmg.27.2.114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2319578">Garrett et al. (1990)</a>, <a href="#2" class="mim-tip-reference" title="Campeau, P. M., Lenk, G. M., Lu, J. T., Bae, Y., Burrage, L., Turnpenny, P., Corona-Rivera J. R., Morandi, L., Mora, M., Reutter, H., Vulto-van Silfhout, A. T., Faivre, L., Haan, E., Gibbs, R. A., Meisler, M. H., Lee, B. H. <strong>Yunis-Varon syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase.</strong> Am. J. Hum. Genet. 92: 781-791, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23623387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23623387</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23623387[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.2013.03.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23623387">Campeau et al. (2013)</a> identified compound heterozygous mutations in the FIG4 gene: a c.311G-A transition in exon 4, resulting in a gly104-to-asp (G104D) substitution at a highly conserved residue located at the beginning of beta-sheet 7 in the noncatalytic, protein-binding domain of FIG4, and an 8-bp deletion (c.831_838delTAAATTTG; <a href="#0011">609390.0011</a>) in exon 8, resulting in a frameshift and premature termination (Lys278TrpfsTer6). Each unaffected parent carried 1 of the mutations, which were found by exome sequencing. Transfection of the G104D mutation in cultured fibroblasts from the Fig4-null mouse failed to correct cytoplasmic vacuolization, consistent with complete loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2319578+23623387" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs786200937 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786200937;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=rs786200937" 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=rs786200937" 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=RCV000043691 OR RCV000236453 OR RCV001248346 OR RCV001255783 OR RCV002426591 OR RCV003447106" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000043691, RCV000236453, RCV001248346, RCV001255783, RCV002426591, RCV003447106" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000043691...</a>
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<p>For discussion of the 8-bp deletion in the FIG4 gene (c.831_838delTAAATTTG) that was found in compound heterozygous state in patients with Yunis-Varon syndrome (YVS; <a href="/entry/216340">216340</a>) by <a href="#2" class="mim-tip-reference" title="Campeau, P. M., Lenk, G. M., Lu, J. T., Bae, Y., Burrage, L., Turnpenny, P., Corona-Rivera J. R., Morandi, L., Mora, M., Reutter, H., Vulto-van Silfhout, A. T., Faivre, L., Haan, E., Gibbs, R. A., Meisler, M. H., Lee, B. H. <strong>Yunis-Varon syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase.</strong> Am. J. Hum. Genet. 92: 781-791, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23623387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23623387</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23623387[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.2013.03.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23623387">Campeau et al. (2013)</a>, see <a href="#0010">609390.0010</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23623387" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0012 YUNIS-VARON 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">rs397514707 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514707;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=rs397514707" 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=rs397514707" 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=RCV000043692 OR RCV003447107" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000043692, RCV003447107" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000043692...</a>
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<p>In an Italian girl, born of unrelated parents, with Yunis-Varon syndrome (YVS; <a href="/entry/216340">216340</a>), who had been described by <a href="#6" class="mim-tip-reference" title="Dworzak, F., Mora, M., Borroni, C., Cornelio, F., Blasevich, F., Cappellini, A., Tagliavini, F., Bertagnolio, B. <strong>Generalized lysosomal storage in Yunis Varon syndrome.</strong> Neuromusc. Disord. 5: 423-428, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7496176/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7496176</a>] [<a href="https://doi.org/10.1016/0960-8966(94)00089-r" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7496176">Dworzak et al. (1995)</a>, <a href="#2" class="mim-tip-reference" title="Campeau, P. M., Lenk, G. M., Lu, J. T., Bae, Y., Burrage, L., Turnpenny, P., Corona-Rivera J. R., Morandi, L., Mora, M., Reutter, H., Vulto-van Silfhout, A. T., Faivre, L., Haan, E., Gibbs, R. A., Meisler, M. H., Lee, B. H. <strong>Yunis-Varon syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase.</strong> Am. J. Hum. Genet. 92: 781-791, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23623387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23623387</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23623387[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.2013.03.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23623387">Campeau et al. (2013)</a> identified a homozygous c.524T-C transition in exon 6 of the FIG4 gene, resulting in a leu175-to-pro (L175P) substitution at a highly conserved residue in alpha-helix 2 of a noncatalytic, protein-binding domain of FIG4. Each unaffected parent was heterozygous for the mutation, which was found by exome sequencing. Transfection of the mutation in cultured fibroblasts from the Fig4-null mouse failed to correct cytoplasmic vacuolization, consistent with complete loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7496176+23623387" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0013 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 4J</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs587777713 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777713;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs587777713?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587777713" 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=rs587777713" 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=RCV000144071 OR RCV000697297 OR RCV003447113" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144071, RCV000697297, RCV003447113" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144071...</a>
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<p>In a patient with Charcot-Marie-Tooth disease type 4J (CMT4J; <a href="/entry/611228">611228</a>), <a href="#14" class="mim-tip-reference" title="Nicholson, G., Lenk, G. M., Reddel, S. W., Grant, A. E., Towne, C. F., Ferguson, C. J., Simpson, E., Scheuerle, A., Yasick, M., Hoffman, S., Blouin, R., Brandt, C., Coppola, G., Biesecker, L. G., Batish, S. D., Meisler, M. H. <strong>Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P2 phosphatase FIG4.</strong> Brain 134: 1959-1971, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21705420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21705420</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21705420[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/brain/awr148" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21705420">Nicholson et al. (2011)</a> identified compound heterozygous mutations in the FIG4 gene: leu17-to-pro (L17P) and a null allele (Phe254SerfsTer7). The L17P substitution occurs at a conserved residue and was predicted to alter the conformation of the protein and affect interaction with other proteins, similar to I41T (<a href="#0001">609390.0001</a>). The patient was ascertained from a large cohort of 4,000 CMT patients who were screened for FIG4 mutations; clinical information on this patient was not available. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21705420" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs587777714 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777714;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs587777714?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587777714" 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=rs587777714" 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=RCV000144072 OR RCV001857490 OR RCV003447114" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144072, RCV001857490, RCV003447114" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144072...</a>
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<p>In a woman with adult-onset Charcot-Marie-Tooth disease type 4J (CMT4J; <a href="/entry/611228">611228</a>), <a href="#14" class="mim-tip-reference" title="Nicholson, G., Lenk, G. M., Reddel, S. W., Grant, A. E., Towne, C. F., Ferguson, C. J., Simpson, E., Scheuerle, A., Yasick, M., Hoffman, S., Blouin, R., Brandt, C., Coppola, G., Biesecker, L. G., Batish, S. D., Meisler, M. H. <strong>Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P2 phosphatase FIG4.</strong> Brain 134: 1959-1971, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21705420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21705420</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21705420[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/brain/awr148" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21705420">Nicholson et al. (2011)</a> identified compound heterozygous mutations in the FIG4 gene: a glu302-to-lys (E302K) substitution at a highly conserved residue at the interface between the catalytic domain and the N-terminal protein interaction domain, and the common ancestral allele (I41T; <a href="#0001">609390.0001</a>). Residue E302 is important for protein stabilization. The E302K mutant was unable to rescue vacuole enlargement in Fig4-null yeast, indicating that it is a functionally null allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21705420" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs587777715 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777715;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs587777715?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587777715" 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=rs587777715" 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=RCV000144073 OR RCV000789118" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144073, RCV000789118" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144073...</a>
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<p>In a 13-year-old girl, born of unrelated Caucasian parents, with Charcot-Marie-Tooth disease type 4J (CMT4J; <a href="/entry/611228">611228</a>), <a href="#11" class="mim-tip-reference" title="Menezes, M. P., Waddell, L., Lenk, G. M., Kaur, S., MacArthur, D. G., Meisler, M. H., Clarke, N. F. <strong>Whole exome sequencing identifies three recessive FIG4 mutations in an apparently dominant pedigree with Charcot-Marie-Tooth disease.</strong> Neuromusc. Disord. 24: 666-670, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24878229/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24878229</a>] [<a href="https://doi.org/10.1016/j.nmd.2014.04.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24878229">Menezes et al. (2014)</a> identified compound heterozygous mutations in the FIG4 gene: an A-to-T transversion (c.290-2A-T) in a spite site consensus sequence that was predicted to prevent normal splicing of exon 4 (Phe98fsTer38), and the recurrent I41T mutation (<a href="#0001">609390.0001</a>). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were filtered against the 1000 Genomes Project and Exome Sequencing Project databases and an in-house database of 25,991 reference exomes. Each parent was heterozygous for 1 of the mutations. In addition, the mildly affected mother carried an exonic deletion in the FIG4 gene on the other other allele. The proband, who was severely affected, was found to carry a de novo heterozygous nonsense mutation (R1844X) in the DMD gene (<a href="/entry/300377">300377</a>), which may have contributed to the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24878229" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs587777716 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777716;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=rs587777716" 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=rs587777716" 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=RCV000144074 OR RCV003447115" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144074, RCV003447115" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144074...</a>
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<p>In affected members of a consanguineous Moroccan family with bilateral temporooccipital polymicrogyria (BTOP; <a href="/entry/612691">612691</a>) previously reported by <a href="#15" class="mim-tip-reference" title="Ouled Amar Ben Cheikh, B., Baulac, S., Lahjouji, F., Bouhouche, A., Couarch, P., Khalili, N., Regragui, W., Lehericy, S., Ruberg, M., Benomar, A., Heath, S., Chkili, T., Yahyaoui, M., Jiddane, M., Ouazzani, R., LeGuern, E. <strong>A locus for bilateral occipital polymicrogyria maps to chromosome 6q16-q22.</strong> Neurogenetics 10: 35-42, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18758830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18758830</a>] [<a href="https://doi.org/10.1007/s10048-008-0143-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18758830">Ouled Amar Ben Cheikh et al. (2009)</a>, <a href="#1" class="mim-tip-reference" title="Baulac, S., Lenk, G. M., Dufresnois, B., Ouled Amar Bencheikh, B., Couarch, P., Renard, J., Larson, P. A., Ferguson, C. J., Noe, E., Poirier, K., Hubans, C., Ferreira, S., Guerrini, R., Ouazzani, R., El Hachimi, K. H., Meisler, M. H., Leguern, E. <strong>Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria.</strong> Neurology 82: 1068-1075, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24598713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24598713</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24598713[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/10.1212/WNL.0000000000000241" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24598713">Baulac et al. (2014)</a> identified a homozygous c.2348A-T transversion in the FIG4 gene, resulting in an asp784-to-val (D783V) substitution at a highly conserved residue in the C terminus. The mutation, which was found using a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family and was not present in the dbSNP (build 135), 1000 Genomes Project, or Exome Variant Server databases or in 750 in-house controls. The patients had onset of seizures mainly in childhood and most had psychiatric disturbances. Expression of the D783V mutation in Fig4-null cells was unable to rescue the abnormal vacuolization phenotype as well as wildtype FIG4, suggesting that the mutation caused a partial loss of function. Examination of Fig4-null mice showed postmigration abnormalities in several brain regions, consistent with mechanisms underlying polymicrogyria in humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18758830+24598713" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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[<a href="https://doi.org/10.1212/WNL.0000000000000241" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2013.03.020" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature05876" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1371/journal.pgen.1002104" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2022.11.004" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24878229/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24878229</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24878229" 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.nmd.2014.04.010" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddy145" target="_blank">Full Text</a>]
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Nagase, T., Seki, N., Ishikawa, K., Ohira, M., Kawarabayasi, Y., Ohara, O., Tanaka, A., Kotani, H., Miyajima, N., Nomura, N.
|
|
<strong>Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain.</strong>
|
|
DNA Res. 3: 321-329, 1996.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9039502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9039502</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9039502" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/dnares/3.5.321" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Nicholson2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Nicholson, G., Lenk, G. M., Reddel, S. W., Grant, A. E., Towne, C. F., Ferguson, C. J., Simpson, E., Scheuerle, A., Yasick, M., Hoffman, S., Blouin, R., Brandt, C., Coppola, G., Biesecker, L. G., Batish, S. D., Meisler, M. H.
|
|
<strong>Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P2 phosphatase FIG4.</strong>
|
|
Brain 134: 1959-1971, 2011.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21705420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21705420</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21705420[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=21705420" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/awr148" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Ouled Amar Ben Cheikh2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ouled Amar Ben Cheikh, B., Baulac, S., Lahjouji, F., Bouhouche, A., Couarch, P., Khalili, N., Regragui, W., Lehericy, S., Ruberg, M., Benomar, A., Heath, S., Chkili, T., Yahyaoui, M., Jiddane, M., Ouazzani, R., LeGuern, E.
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|
<strong>A locus for bilateral occipital polymicrogyria maps to chromosome 6q16-q22.</strong>
|
|
Neurogenetics 10: 35-42, 2009.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18758830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18758830</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18758830" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s10048-008-0143-3" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Sbrissa2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sbrissa, D., Ikonomov, O. C., Fu, Z., Ijuin, T., Gruenberg, J., Takenawa, T., Shisheva, A.
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<strong>Core protein machinery for mammalian phosphatidylinositol 3,5-bisphosphate synthesis and turnover that regulates the progression of endosomal transport: novel Sac phosphatase joins the ArPIKfyve-PIKfyve complex.</strong>
|
|
J. Biol. Chem. 282: 23878-23891, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17556371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17556371</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17556371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M611678200" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Winters2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Winters, J. J., Ferguson, C. J., Lenk, G. M., Giger-Mateeva, V. I., Shrager, P., Meisler, M. H., Giger, R. J.
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|
<strong>Congenital CNS hypomyelination in the Fig4 null mouse is rescued by neuronal expression of the PI(3,5)P2 phosphatase Fig4.</strong>
|
|
J. Neurosci. 31: 17736-17751, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22131434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22131434</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22131434[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=22131434" 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/10.1523/JNEUROSCI.1482-11.2011" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Zhang2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, X., Chow, C. Y., Sahenk, Z., Shy, M. E., Meisler, M. H., Li, J.
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<strong>Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration.</strong>
|
|
Brain 131: 1990-2001, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18556664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18556664</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18556664[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=18556664" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/awn114" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</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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Hilary J. Vernon - updated : 02/09/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 09/06/2019<br>Cassandra L. Kniffin - updated : 9/15/2014<br>Cassandra L. Kniffin - updated !$ : 6/17/2013<br>Cassandra L. Kniffin - updated : 3/27/2012<br>George E. Tiller - updated : 11/1/2010<br>Patricia A. Hartz - updated : 2/23/2010<br>Cassandra L. Kniffin - updated : 2/3/2009<br>Patricia A. Hartz - updated : 8/20/2008<br>Ada Hamosh - updated : 7/19/2007
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz : 5/31/2005
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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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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carol : 09/10/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 02/09/2023<br>mgross : 09/09/2019<br>carol : 09/07/2019<br>mgross : 09/06/2019<br>alopez : 10/05/2016<br>ckniffin : 08/24/2015<br>carol : 6/8/2015<br>mcolton : 4/6/2015<br>carol : 9/18/2014<br>alopez : 9/17/2014<br>ckniffin : 9/15/2014<br>carol : 9/13/2013<br>carol : 6/21/2013<br>carol : 6/21/2013<br>ckniffin : 6/17/2013<br>carol : 4/4/2012<br>terry : 4/4/2012<br>ckniffin : 3/27/2012<br>alopez : 11/5/2010<br>terry : 11/1/2010<br>mgross : 2/26/2010<br>terry : 2/23/2010<br>wwang : 3/3/2009<br>ckniffin : 2/3/2009<br>mgross : 8/21/2008<br>terry : 8/20/2008<br>mgross : 4/23/2008<br>alopez : 7/20/2007<br>terry : 7/19/2007<br>carol : 5/31/2005
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div 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> 609390
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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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FIG4 PHOSPHOINOSITIDE 5-PHOSPHATASE; FIG4
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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">
|
|
FIG4, S. CEREVISIAE, HOMOLOG OF<br />
|
|
SAC DOMAIN-CONTAINING INOSITOL PHOSPHATASE 3; SAC3<br />
|
|
KIAA0274
|
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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-text-font">
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<strong><em>HGNC Approved Gene Symbol: FIG4</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> 720638000;
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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>
|
|
Cytogenetic location: 6q21
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 6:109,691,296-109,825,426 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</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">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
|
</thead>
|
|
<tbody>
|
|
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<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
6q21
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
?Polymicrogyria, bilateral temporooccipital
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
612691
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Amyotrophic lateral sclerosis 11
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
612577
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
|
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</tr>
|
|
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|
|
|
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Charcot-Marie-Tooth disease, type 4J
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
611228
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Yunis-Varon syndrome
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
216340
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</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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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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<p>The content of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) in endosomal membranes changes dynamically with fission and fusion events that generate or absorb intracellular transport vesicles. FIG4 is a PtdIns(3,5)P2 5-phosphatase that functions in a trimolecular complex that tightly regulates the level of PtdIns(3,5)P2. Other components of this complex are the PtdIns(3,5)P2-synthesizing enzyme PIKFYVE (609414) and its activator, VAC14 (604632) (Sbrissa et al., 2007). </p>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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<p>By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1996) cloned full-length FIG4, which they called KIAA0274. The deduced protein contains 907 amino acids. Northern blot analysis detected expression in all tissues examined, with highest expression in testis. </p><p>Sbrissa et al. (2007) stated that the full-length 907-amino acid SAC3 protein contains an N-terminal SAC phosphatase domain of about 400 amino acids. SAC3 also has multiple sites for serine/threonine and tyrosine phosphorylation and numerous motifs for interaction with intracellular transport and sorting molecules. Western blot analysis of HEK293 human embryonic kidney cells and other mammalian cell lines detected SAC3 at an apparent molecular mass of 97 kD. The presence of a broad band suggested posttranslational modification of the protein. Fractionation of HEK293 cells showed that SAC3 associated with both cytosol and membranes. </p>
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<strong>Gene Structure</strong>
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<span class="mim-text-font">
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<p>Chow et al. (2007) determined that the human FIG4 gene comprises 23 coding exons. </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p>By radiation hybrid analysis, Nagase et al. (1996) mapped the KIAA0274 gene to chromosome 6. Chow et al. (2007) localized the gene to chromosome 6q21. </p>
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<h4>
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<strong>Gene Function</strong>
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<p>Using coimmunoprecipitation analysis, Sbrissa et al. (2007) showed that endogenous SAC3, PIKFYVE, and ARPIKFYVE (VAC14) formed a stable ternary complex in HEK293 cells and other mammalian cell lines. Immunoprecipitated epitope-tagged SAC3 hydrolyzed the D5 phosphate from PtdIns(4,5)P2, PtdIns(3,5)P2, and PtdIns(3,4,5)P3, but it did not use PtdIns(5)P or other PtdIns substrates. Mutation analysis showed that asp488 was required for SAC3 phosphatase activity. Overexpression of SAC3 in HEK293 cells did not produce an obvious morphologic phenotype, but it rendered cells prone to developing dilated intracellular membranes, consistent with perturbation of membrane PtdIns(3,5)P2 levels. In contrast, depletion of SAC3 via small interfering RNA enhanced endosome carrier vesicles/multivesicular body formation. </p><p>Lenk and Meisler (2022) used CRISPR editing to generate FIG4 -/- 3D4 cells and treated the cells with chloroquine, a drug that is known to reduce lysosomal acidity. Treatment with chloroquine corrected the abnormal appearance of abnormal lysosomes that were seen in the untreated mutant cells. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p><strong><em>Charcot-Marie-Tooth Disease 4J, Autosomal Recessive</em></strong></p><p>
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In 4 unrelated patients with autosomal recessive Charcot-Marie-Tooth disease type 4J (CMT4J; 611228), Chow et al. (2007) identified compound heterozygous mutations in the FIG4 gene (609390.0001-609390.0005). </p><p>In 3 unrelated patients of Australian descent with CMT4J, Nicholson et al. (2011) identified compound heterozygosity for the ancestral I41T FIG4 mutation and 1 of 3 different truncating mutations. Direct screening of the FIG4 gene was performed in these patients based on the early-onset severe phenotype. The mutations segregated with the disorder in all families. Sequencing the FIG4 gene in 4,000 DNA samples submitted for a CMT gene panel identified 8 (0.2%) patients carrying compound heterozygous mutations (see, e.g., 609390.0013 and 609390.0014). Seven of these patients carried the I41T allele in combination with a null allele. </p><p><strong><em>Amyotrophic Lateral Sclerosis 11</em></strong></p><p>
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In 5 unrelated patients with amyotrophic lateral sclerosis (ALS11; 612577), Chow et al. (2009) identified heterozygosity for a missense, 2 splice site, and 2 truncating mutations in the FIG4 gene (see, e.g., 609390.0006-609390.0008). The mutations were shown to result in complete or significant loss of protein function. Five different missense FIG4 mutations were identified in 5 patients with a diagnosis of ALS or adult-onset primary lateral sclerosis (PLSA1; 611637), but these mutations were not clearly shown to be pathogenic. </p><p><strong><em>Yunis-Varon Syndrome</em></strong></p><p>
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In 5 patients from 3 unrelated families with Yunis-Varon syndrome (YVS; 216340), Campeau et al. (2013) identified homozygous or compound heterozygous mutations in the FIG4 gene (609390.0009-609390.0012). The phenotype was severe, characterized by cleidocranial dysplasia, digital anomalies, hypotonia, dysmorphic facial features, and severe neurologic involvement, all apparent from birth. Most patients died in infancy. Tissue samples showed enlarged cytoplasmic vacuoles. All the mutations, which were found by exome sequencing, resulted in complete loss of protein function, which Campeau et al. (2013) suggested resulted in a more severe phenotype than that observed in CMT4J; the latter disorder is associated with at least 1 missense hypomorphic mutation in the FIG4 gene. The report demonstrated that absence of FIG4 activity leads to central nervous system dysfunction and extensive skeletal anomalies, which suggested a role for PI(3,5)P2 signaling in skeletal development and maintenance. </p><p><strong><em>Bilateral Temporooccipital Polymicrogyria</em></strong></p><p>
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In affected members of a consanguineous Moroccan family with bilateral temporooccipital polymicrogyria (BTOP; 612691), Baulac et al. (2014) identified a homozygous missense mutation in the FIG4 gene (D783V; 609390.0016). The mutation was found by whole-exome sequencing. </p>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</h4>
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<p>The phenotype of the 'pale tremor' (plt) mouse, identified by Chow et al. (2007), is characterized by a multi-organ disorder with neuronal degeneration in the central nervous system, peripheral neuronopathy, and diluted pigmentation. Positional cloning identified insertion of ETn2-beta (early transposon 2-beta) into intron 18 of the mouse Fig4 gene, the homolog of a yeast suppressor of actin (SAC) domain phosphatidylinositol(3,5)P(2)5-phosphatase located in the vacuolar membrane. The abnormal concentration of phosphatidylinositol-3,5-bisphosphate in cultured fibroblasts from pale tremor mice demonstrated the conserved biochemical function of mammalian Fig4. The cytoplasm of fibroblasts from pale tremor mice was filled with large vacuoles that were immunoreactive for Lamp2 (309060), consistent with dysfunction of the late endosome-lysosome axis. Neonatal neurodegeneration in sensory and autonomic ganglia was followed by loss of neurons from layers 4 and 5 of the cortex, deep cerebellar nuclei, and other localized brain regions. The sciatic nerve exhibited reduced numbers of large-diameter myelinated axons, slowed nerve conduction velocity, and reduced amplitude of compound muscle action potentials. Zhang et al. (2008) found a profound loss of large motor neurons in the anterior horns of the spinal cord of plt mice. Remaining neurons contained large vacuoles that did not stain for ubiquitin or neurofilaments. There was no evidence of apoptosis of neurons or Schwann cells in plt mice, but there was a loss of large-diameter motor axons as well as evidence of segmental demyelination. </p><p>Mutations affecting the conversion of PI3P to the signaling lipid PI(3,5)P2 result in spongiform degeneration of mouse brain and are associated with the human disorders Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis (ALS). Ferguson et al. (2009) reported accumulation of the proteins Lc3II (MAP1LC3A; 601242), p62 (SQSTM1; 601530), and Lamp2 in neurons and astrocytes of mice with mutations in 2 components of the PI(3,5)P2 regulatory complex, Fig4 and Vac14 (604632). Cytoplasmic inclusion bodies containing p62 and ubiquitinated proteins were present in regions of the mutant brain that underwent degeneration. Colocalization of p62 and LAMP2 in affected cells indicated that formation or recycling of the autolysosome may be impaired. The authors proposed a role for PI(3,5)P2 in autophagy in the mammalian central nervous system and demonstrated that mutations affecting PI(3,5)P2 may contribute to inclusion body disease. </p><p>In patient fibroblasts, cell culture, and transgenic mice, Lenk et al. (2011) demonstrated that the I41T mutant protein (609390.0001) is unstable, resulting in low levels of FIG4. Low levels of the protein resulted from impaired interaction with VAC14, which stabilizes FIG4. Overexpression of mutant I41T in Fig4-null mice to 10% of wildtype levels rescued the severe neurodegenerative phenotype, whereas lesser overexpression (2-fold) resulted in partial rescue and a CMT-like phenotype. The abundance of the I41T protein in cultured cells could be increased by treatment with a proteasome inhibitor. The findings indicated that I41T is a hypomorphic allele and suggested that increasing expression of the I41T mutant allele in CMT4J patients with the mutation may be therapeutic. </p><p>Winters et al. (2011) found that Fig4 -/- mice had a pronounced reduction of myelin in central nerve system (CNS). Examination of Fig4 -/- optic nerve revealed that, in spite of a normal number of axons, loss of Fig4 caused severe dysmyelination due to developmental failure to myelinate small and intermediate size axons. Fig4 -/- optic nerve also had disorganized nodes of Ranvier and paranodes, with an increased number of slow conducting axons. Loss of Fig4 resulted in a decreased number of myelinating oligodendrocytes throughout the CNS due to arrest of oligodendrocyte precursor cell maturation. Neuron-specific expression of wildtype mouse Fig4 rescued the optic nerve dysmyelination phenotype of Fig4 -/- mice, demonstrating that oligodendrocyte precursor cell maturation and myelin development in Fig4 -/- mice were secondary to neuronal defects and that Fig4 had a non-cell-autonomous function in oligodendrocyte development. Global overexpression of the human FIG4 I41T variant, which retains low-level function, rescued Fig4 -/- mice from the myelination defect and early lethality. </p><p>In mouse tissue, Campeau et al. (2013) found that Fig4 expression in calvaria, osteoblasts, and bone marrow cells was comparable to its expression in brain. Fig4-null mice showed a smaller skeleton than wildtype mice at day P21, with smaller long bones, clavicles, and pelvic bones. Although the shapes of the bones were similar to wildtype, Fig4-null mouse bones had significantly lower (50%) trabecular and cortical density, bone volume fraction, bone surface, trabecular number, and connectivity density, consistent with abnormal ossification. Cultures of isolated osteoblasts from calvarial tissue showed extensive vacuolization. Fig4-null mice did not exhibit aplasia or hypoplasia of digits on the front or rear limbs. </p><p>Baulac et al. (2014) found that the brains of postnatal Fig4-null mice were macroscopically normal, but there was a transient increase in neuronal density associated with apoptosis. There was also delayed maturation of interneurons and dentate granule cells and their processes in various brain regions. The findings indicated postmigration abnormalities in the brains of Fig4-null mice. </p><p>Mironova et al. (2018) found that neonatal knockout of Fig4 in mice recapitulated the neurologic defects of constitutive Fig4 -/- mice, including regional spongiform degeneration, CNS hypomyelination, and accumulation of vacuoles in oligodendrocytes. Induced deletion of Fig4 in adult mice recapitulated the lethal disorder of constitutive Fig4 -/- mice with a similar time course. However, adult mice with induced Fig4 deletion displayed normal abundance of CNS myelin proteins, normal structural integrity of myelin sheaths in optic nerve cross sections, and normal electrophysiologic properties. Adult mice with induced Fig4 deletion were defective in axon remyelination and timely repair of damaged white matter. Histologic examination revealed severe Wallerian degeneration of sciatic nerve, but not C-fiber axons in Remak bundles, in mice with induced Fig4 deletion. </p><p>Lenk and Meisler (2022) treated Fig4 -/- mice with chloroquine, a drug that is known to reduce lysosomal acidity. The treated Fig4 -/- mice were larger compared to untreated Fig4 -/- mice, and at 30 days of age, the treated mutant mice had improved mobility and other behaviors (running, rearing, grooming) compared to untreated mutant mice. The treated mutant mice survived about 4 weeks longer than the untreated mutant mice. Brain tissue from treated mutant mice had decreased vacuolization compared to untreated mutant mice. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>16 Selected Examples):</strong>
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</h4>
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<div>
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<p />
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<h4>
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<span class="mim-font">
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<strong>.0001 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 4J</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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FIG4, ILE41THR
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<br />
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SNP: rs121908287,
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gnomAD: rs121908287,
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ClinVar: RCV000001791, RCV000143812, RCV000416487, RCV000476702, RCV001095515, RCV001270162, RCV001330564, RCV001535566, RCV002362551, RCV003952336
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<span class="mim-text-font">
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<p>In 4 unrelated patients with severe early-onset autosomal recessive Charcot-Marie-Tooth disease (CMT4J; 611228), Chow et al. (2007) found the same mutation in the FIG4 gene, a T-to-C transition at nucleotide 122 resulting in an ile-to-thr substitution at codon 41 (I41T). The mutation occurred in compound heterozygosity in each patient with 1 of 4 other FIG4 mutations (609390.0002-609390.0005). The 4 patients carried I41T on the same 15-kb haplotype, defined by 3 single-nucleotide polymorphisms (SNPs), consistent with inheritance of a common ancestral mutant allele. The isoleucine at codon 41 is invariant from human to yeast. </p><p>In patient fibroblasts, cell culture, and transgenic mice, Lenk et al. (2011) demonstrated that the I41T mutant protein is unstable, resulting in low levels of FIG4. Low levels of the protein resulted from impaired interaction with VAC14 (604362), which stabilizes FIG4. Overexpression of mutant I41T in Fig4-null mice to 10% of wildtype levels rescued the neurodegenerative phenotype. The abundance of the I41T protein in cultured cells could be increased by treatment with a proteasome inhibitor. The findings indicated that I41T is a hypomorphic allele and suggested that increasing expression of the I41T mutant allele in patients with the mutation may be therapeutic. </p><p>Nicholson et al. (2011) found that the allele frequency of I41T is 0.001 (13 heterozygotes among 5,769 Northern European controls). </p>
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</span>
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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>.0002 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 4J</strong>
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</span>
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</h4>
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<div>
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<span class="mim-text-font">
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FIG4, 1-BP DEL, 294T
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<br />
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SNP: rs1562648373,
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ClinVar: RCV000001792, RCV000789113, RCV001195964
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with Charcot-Marie-Tooth disease type 4J (CMT4J; 611228), Chow et al. (2007) identified a single-basepair deletion, of thymidine, at nucleotide 294 of the FIG4 gene, resulting in frameshift and premature termination of the protein (Phe98fsTer102). The patient was compound heterozygous for the I41T allele (609390.0001). </p>
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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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<h4>
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<span class="mim-font">
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<strong>.0003 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 4J</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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FIG4, ARG183TER
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<br />
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SNP: rs121908288,
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gnomAD: rs121908288,
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ClinVar: RCV000001793, RCV000001796, RCV000235305, RCV001046714, RCV001095516, RCV003944790
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient and her sib with Charcot-Marie-Tooth disease type 4J (CMT4J; 611228), Chow et al. (2007) found compound heterozygosity for a C-to-T transition at nucleotide 718 of the FIG4 gene, resulting in an arg-to-ter substitution at codon 183 (R183X), and the I41T mutation (609390.0001). Both sibs had severe disease. The proband was a functional quadriplegic, and her sib was wheelchair-bound with normal use of his arms. Both had slow nerve conduction velocities. A sural nerve biopsy from the proband demonstrated profound axonal loss, thinly myelinated nerve fibers, and evidence of de- and remyelination. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 4J</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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FIG4, 8-BP DEL, NT1043
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<br />
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SNP: rs1368013631,
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ClinVar: RCV000001794, RCV000789115, RCV001851563
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with Charcot-Marie-Tooth disease type 4J (CMT4J; 611228), Chow et al. (2007) found compound heterozygosity for the I41T mutation in FIG4 (609390.0001) and an 8-basepair deletion, of ATCAGGCA, starting at nucleotide position 1043 (Asp348fsTer359). </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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<h4>
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<span class="mim-font">
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<strong>.0005 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 4J</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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FIG4, 1-BP DEL, 759G
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<br />
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SNP: rs764717219,
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gnomAD: rs764717219,
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ClinVar: RCV000001795, RCV000416492, RCV000517693, RCV000533386, RCV000789114
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with Charcot-Marie-Tooth disease type 4J (CMT4J; 611228), Chow et al. (2007) found a single-basepair deletion of a guanine at position 759 of the FIG4 gene, resulting in a frameshift and early termination (Gly253fsTer261). The patient carried this mutation in compound heterozygosity with the I41T mutation (609390.0001). </p>
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</span>
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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>.0006 AMYOTROPHIC LATERAL SCLEROSIS 11</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">
|
|
|
|
FIG4, ARG183TER
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|
<br />
|
|
|
|
SNP: rs121908288,
|
|
|
|
|
|
gnomAD: rs121908288,
|
|
|
|
|
|
ClinVar: RCV000001793, RCV000001796, RCV000235305, RCV001046714, RCV001095516, RCV003944790
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a man with probable amyotrophic lateral sclerosis (ALS11; 612577), Chow et al. (2009) identified a heterozygous 547C-T transition in exon 6 of the FIG4 gene, resulting in an arg183-to-ter (R183X) substitution, predicted to result in loss of phosphatase activity. He had onset at age 62 and presented with bulbar signs. He had prominent cortical spinal tract findings and moderate lower motor neuron findings. EMG showed mild denervation of 3 extremities. </p>
|
|
</span>
|
|
</div>
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|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
|
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|
<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 AMYOTROPHIC LATERAL SCLEROSIS 11</strong>
|
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</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
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|
FIG4, IVS11DS, G-T, +5
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<br />
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|
|
SNP: rs200730266,
|
|
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|
|
gnomAD: rs200730266,
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|
|
|
ClinVar: RCV000235449, RCV001323814, RCV001839451, RCV003447130
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a woman with amyotrophic lateral sclerosis (ALS11; 612577), Chow et al. (2009) identified a heterozygous G-to-T transversion in intron 11 (1386+5G-T) of the FIG4 gene, predicted to result in the skipping of exon 12 or premature termination. She had onset at age 57 and presented with involvement of the upper extremity. She had both upper and lower motor neuron signs and acute and chronic denervation on EMG. </p>
|
|
</span>
|
|
</div>
|
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<div>
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|
<br />
|
|
</div>
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|
|
</div>
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|
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|
<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 AMYOTROPHIC LATERAL SCLEROSIS 11</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FIG4, ASP53TYR
|
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|
<br />
|
|
|
|
SNP: rs121908290,
|
|
|
|
|
|
|
|
ClinVar: RCV000001798, RCV003447064
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a woman with amyotrophic lateral sclerosis (ALS11; 612577), Chow et al. (2009) identified a heterozygous 157G-T transversion in exon 2 of the FIG4 gene, resulting in an asp53-to-tyr (D53Y) substitution. In vitro functional expression studies in yeast showed that the mutant protein had significantly less activity compared to wildtype. The patient presented at age 56 with bulbar signs. She had moderate corticospinal findings, and autopsy showed lower motor neuron loss. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 YUNIS-VARON SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FIG4, 2-BP DEL, 1260GT
|
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|
|
<br />
|
|
|
|
SNP: rs397509394,
|
|
|
|
|
|
|
|
ClinVar: RCV000043689
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs, born of consanguineous Mexican parents, with Yunis-Varon syndrome (YVS; 216340), who had been reported by Corona-Rivera et al. (2011), Campeau et al. (2013) identified a homozygous 2-bp deletion (c.1260_1261delGT) in exon 11 of the FIG4 gene, resulting in a frameshift and premature termination (Thr422GlnfsTer6) predicted to cause protein truncation upstream of the phosphatase catalytic motif and complete loss of function. Each unaffected parent was heterozygous for the mutation, which was found by exome sequencing. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 YUNIS-VARON SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FIG4, GLY104ASP
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs397509395,
|
|
|
|
|
|
|
|
ClinVar: RCV000043690, RCV003447105
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs, born of unrelated English parents, with Yunis-Varon syndrome (YVS; 216340), who had been reported by Garrett et al. (1990), Campeau et al. (2013) identified compound heterozygous mutations in the FIG4 gene: a c.311G-A transition in exon 4, resulting in a gly104-to-asp (G104D) substitution at a highly conserved residue located at the beginning of beta-sheet 7 in the noncatalytic, protein-binding domain of FIG4, and an 8-bp deletion (c.831_838delTAAATTTG; 609390.0011) in exon 8, resulting in a frameshift and premature termination (Lys278TrpfsTer6). Each unaffected parent carried 1 of the mutations, which were found by exome sequencing. Transfection of the G104D mutation in cultured fibroblasts from the Fig4-null mouse failed to correct cytoplasmic vacuolization, consistent with complete loss of function. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 YUNIS-VARON SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FIG4, 8-BP DEL, NT831
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs786200937,
|
|
|
|
|
|
|
|
ClinVar: RCV000043691, RCV000236453, RCV001248346, RCV001255783, RCV002426591, RCV003447106
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 8-bp deletion in the FIG4 gene (c.831_838delTAAATTTG) that was found in compound heterozygous state in patients with Yunis-Varon syndrome (YVS; 216340) by Campeau et al. (2013), see 609390.0010. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 YUNIS-VARON SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FIG4, LEU175PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397514707,
|
|
|
|
|
|
|
|
ClinVar: RCV000043692, RCV003447107
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Italian girl, born of unrelated parents, with Yunis-Varon syndrome (YVS; 216340), who had been described by Dworzak et al. (1995), Campeau et al. (2013) identified a homozygous c.524T-C transition in exon 6 of the FIG4 gene, resulting in a leu175-to-pro (L175P) substitution at a highly conserved residue in alpha-helix 2 of a noncatalytic, protein-binding domain of FIG4. Each unaffected parent was heterozygous for the mutation, which was found by exome sequencing. Transfection of the mutation in cultured fibroblasts from the Fig4-null mouse failed to correct cytoplasmic vacuolization, consistent with complete loss of function. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 4J</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FIG4, LEU17PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587777713,
|
|
|
|
|
|
gnomAD: rs587777713,
|
|
|
|
|
|
ClinVar: RCV000144071, RCV000697297, RCV003447113
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Charcot-Marie-Tooth disease type 4J (CMT4J; 611228), Nicholson et al. (2011) identified compound heterozygous mutations in the FIG4 gene: leu17-to-pro (L17P) and a null allele (Phe254SerfsTer7). The L17P substitution occurs at a conserved residue and was predicted to alter the conformation of the protein and affect interaction with other proteins, similar to I41T (609390.0001). The patient was ascertained from a large cohort of 4,000 CMT patients who were screened for FIG4 mutations; clinical information on this patient was not available. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 4J</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FIG4, GLU302LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587777714,
|
|
|
|
|
|
gnomAD: rs587777714,
|
|
|
|
|
|
ClinVar: RCV000144072, RCV001857490, RCV003447114
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a woman with adult-onset Charcot-Marie-Tooth disease type 4J (CMT4J; 611228), Nicholson et al. (2011) identified compound heterozygous mutations in the FIG4 gene: a glu302-to-lys (E302K) substitution at a highly conserved residue at the interface between the catalytic domain and the N-terminal protein interaction domain, and the common ancestral allele (I41T; 609390.0001). Residue E302 is important for protein stabilization. The E302K mutant was unable to rescue vacuole enlargement in Fig4-null yeast, indicating that it is a functionally null allele. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 4J</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FIG4, IVS4AS, A-T, -2
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587777715,
|
|
|
|
|
|
gnomAD: rs587777715,
|
|
|
|
|
|
ClinVar: RCV000144073, RCV000789118
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 13-year-old girl, born of unrelated Caucasian parents, with Charcot-Marie-Tooth disease type 4J (CMT4J; 611228), Menezes et al. (2014) identified compound heterozygous mutations in the FIG4 gene: an A-to-T transversion (c.290-2A-T) in a spite site consensus sequence that was predicted to prevent normal splicing of exon 4 (Phe98fsTer38), and the recurrent I41T mutation (609390.0001). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were filtered against the 1000 Genomes Project and Exome Sequencing Project databases and an in-house database of 25,991 reference exomes. Each parent was heterozygous for 1 of the mutations. In addition, the mildly affected mother carried an exonic deletion in the FIG4 gene on the other other allele. The proband, who was severely affected, was found to carry a de novo heterozygous nonsense mutation (R1844X) in the DMD gene (300377), which may have contributed to the phenotype. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 POLYMICROGYRIA, BILATERAL TEMPOROOCCIPITAL (1 family)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FIG4, ASP783VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587777716,
|
|
|
|
|
|
|
|
ClinVar: RCV000144074, RCV003447115
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a consanguineous Moroccan family with bilateral temporooccipital polymicrogyria (BTOP; 612691) previously reported by Ouled Amar Ben Cheikh et al. (2009), Baulac et al. (2014) identified a homozygous c.2348A-T transversion in the FIG4 gene, resulting in an asp784-to-val (D783V) substitution at a highly conserved residue in the C terminus. The mutation, which was found using a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family and was not present in the dbSNP (build 135), 1000 Genomes Project, or Exome Variant Server databases or in 750 in-house controls. The patients had onset of seizures mainly in childhood and most had psychiatric disturbances. Expression of the D783V mutation in Fig4-null cells was unable to rescue the abnormal vacuolization phenotype as well as wildtype FIG4, suggesting that the mutation caused a partial loss of function. Examination of Fig4-null mice showed postmigration abnormalities in several brain regions, consistent with mechanisms underlying polymicrogyria in humans. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Baulac, S., Lenk, G. M., Dufresnois, B., Ouled Amar Bencheikh, B., Couarch, P., Renard, J., Larson, P. A., Ferguson, C. J., Noe, E., Poirier, K., Hubans, C., Ferreira, S., Guerrini, R., Ouazzani, R., El Hachimi, K. H., Meisler, M. H., Leguern, E.
|
|
<strong>Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria.</strong>
|
|
Neurology 82: 1068-1075, 2014.
|
|
|
|
|
|
[PubMed: 24598713]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1212/WNL.0000000000000241]
|
|
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|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Campeau, P. M., Lenk, G. M., Lu, J. T., Bae, Y., Burrage, L., Turnpenny, P., Corona-Rivera J. R., Morandi, L., Mora, M., Reutter, H., Vulto-van Silfhout, A. T., Faivre, L., Haan, E., Gibbs, R. A., Meisler, M. H., Lee, B. H.
|
|
<strong>Yunis-Varon syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase.</strong>
|
|
Am. J. Hum. Genet. 92: 781-791, 2013.
|
|
|
|
|
|
[PubMed: 23623387]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.ajhg.2013.03.020]
|
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Chow, C. Y., Landers, J. E., Bergren, S. K., Sapp, P. C., Grant, A. E., Jones, J. M., Everett, L., Lenk, G. M., McKenna-Yasek, D. M., Weisman, L. S., Figlewicz, D., Brown, R. H., Meisler, M. H.
|
|
<strong>Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS.</strong>
|
|
Am. J. Hum. Genet. 84: 85-88, 2009.
|
|
|
|
|
|
[PubMed: 19118816]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.ajhg.2008.12.010]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Chow, C. Y., Zhang, Y., Dowling, J. J., Jin, N., Adamska, M., Shiga, K., Szigeti, K., Shy, M. E., Li, J., Zhang, X., Lupski, J. R., Weisman, L. S., Meisler, M. H.
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