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Entry
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- *606158 - BSCL2 GENE; BSCL2
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*606158</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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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/606158">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 role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div 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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<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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<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=ENSG00000168000;t=ENST00000360796" 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=26580" 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=606158" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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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=ENSG00000168000;t=ENST00000360796" 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_001122955,NM_001130702,NM_001386027,NM_001386028,NM_032667" 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_001122955" 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=606158" 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=05858&isoform_id=05858_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/BSCL2" 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/13436206,14042263,15082445,22761328,27371186,40068505,45503826,62205286,62898944,63089558,119594476,119594477,119594478,119594479,119594480,119594481,119594482,119594483,119594484,119594486,119594487,169244942,171906569,269849705,325974509,957950991,957950994,1885010648,1885011230" 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/Q96G97" 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=26580" 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=ENSG00000168000;t=ENST00000360796" 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=BSCL2" 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=BSCL2" 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+26580" 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/BSCL2" 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:26580" 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/26580" 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=chr11&hgg_gene=ENST00000360796.10&hgg_start=62690262&hgg_end=62709537&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:15832" 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://medlineplus.gov/genetics/gene/bscl2" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=606158[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=606158[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://gnomad.broadinstitute.org/gene/ENSG00000168000" 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=BSCL2" 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=BSCL2" 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=BSCL2" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.molgen.ua.ac.be/CMTMutations/" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=BSCL2&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/PA25432" 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:15832" 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/FBgn0040336.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:1298392" 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/BSCL2#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:1298392" 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/26580/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=26580" 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=WBGene00019808;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-051113-140" 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">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=BSCL2&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> 230263009<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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606158
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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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BSCL2 GENE; BSCL2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
SEIPIN<br />
|
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GNG3LG, MOUSE, HOMOLOG OF
|
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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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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=BSCL2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">BSCL2</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/11/489?start=-3&limit=10&highlight=489">11q12.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr11:62690262-62709537&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'})">11:62,690,262-62,709,537</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;">
|
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<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
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</div>
|
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<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>
|
|
Phenotype
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=615924,269700,619112,270685" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
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</span>
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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|
Inheritance
|
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</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
|
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|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/11/489?start=-3&limit=10&highlight=489">
|
|
11q12.3
|
|
</a>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Encephalopathy, progressive, with or without lipodystrophy
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/615924"> 615924 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
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|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
|
|
Lipodystrophy, congenital generalized, type 2
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|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/269700"> 269700 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
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</span>
|
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</td>
|
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</tr>
|
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<tr>
|
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<td>
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<p>BSCL2, or seipin, is an endoplasmic reticulum (ER)-resident protein that is induced in late stages of preadipocyte differentiation and is predicted to function in lipid droplet formation and/or metabolism (summary by <a href="#8" class="mim-tip-reference" title="Cui, X., Wang, Y., Tang, Y., Liu, Y., Zhao, L., Deng, J., Xu, G., Peng, X., Ju, S., Liu, G., Yang, H. <strong>Seipin ablation in mice results in severe generalized lipodystrophy.</strong> Hum. Molec. Genet. 20: 3022-3030, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21551454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21551454</a>] [<a href="https://doi.org/10.1093/hmg/ddr205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21551454">Cui et al., 2011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21551454" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Within a 2.5-Mb critical region for Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2; <a href="/entry/269700">269700</a>), <a href="#21" class="mim-tip-reference" title="Magre, J., Delepine, M., Khallouf, E., Gedde-Dahl, T., Jr., Van Maldergem, L., Sobel, E., Papp, J., Meier, M., Megarbane, A., BSCL Working Group, Lathrop, M., Capeau, J. <strong>Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.</strong> Nature Genet. 28: 365-370, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479539</a>] [<a href="https://doi.org/10.1038/ng585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479539">Magre et al. (2001)</a> identified a gene that is homologous to the mouse 'gamma-3-linked gene' (Gng3lg). <a href="#21" class="mim-tip-reference" title="Magre, J., Delepine, M., Khallouf, E., Gedde-Dahl, T., Jr., Van Maldergem, L., Sobel, E., Papp, J., Meier, M., Megarbane, A., BSCL Working Group, Lathrop, M., Capeau, J. <strong>Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.</strong> Nature Genet. 28: 365-370, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479539</a>] [<a href="https://doi.org/10.1038/ng585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479539">Magre et al. (2001)</a> found that the BSCL2 open reading frame encodes a deduced 398-amino acid protein, seipin, with at least 2 hydrophobic amino acid stretches, indicating that it could be a transmembrane protein. It has 87% identity to the mouse Gng3lg product, and partial homology to Drosophila CG9904 protein. Using Northern blot analysis, <a href="#21" class="mim-tip-reference" title="Magre, J., Delepine, M., Khallouf, E., Gedde-Dahl, T., Jr., Van Maldergem, L., Sobel, E., Papp, J., Meier, M., Megarbane, A., BSCL Working Group, Lathrop, M., Capeau, J. <strong>Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.</strong> Nature Genet. 28: 365-370, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479539</a>] [<a href="https://doi.org/10.1038/ng585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479539">Magre et al. (2001)</a> observed highest expression in brain and testis. Dot-blot analysis indicated that the BSCL2 gene is highly expressed in most regions of the central nervous system. <a href="#21" class="mim-tip-reference" title="Magre, J., Delepine, M., Khallouf, E., Gedde-Dahl, T., Jr., Van Maldergem, L., Sobel, E., Papp, J., Meier, M., Megarbane, A., BSCL Working Group, Lathrop, M., Capeau, J. <strong>Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.</strong> Nature Genet. 28: 365-370, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479539</a>] [<a href="https://doi.org/10.1038/ng585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479539">Magre et al. (2001)</a> identified a putative initiation codon located in the second exon. <a href="#1" class="mim-tip-reference" title="Agarwal, A. K., Garg, A. <strong>Seipin: a mysterious protein.</strong> Trends Molec. Med. 10: 440-444, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15350896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15350896</a>] [<a href="https://doi.org/10.1016/j.molmed.2004.07.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15350896">Agarwal and Garg (2004)</a> noted that an alternative upstream initiation codon could extend the seipin protein by 64 amino acids at the putative N terminus. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11479539+15350896" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By Northern blot analysis, <a href="#25" class="mim-tip-reference" title="Windpassinger, C., Auer-Grumbach, M., Irobi, J., Patel, H., Petek, E., Horl, G., Malli, R., Reed, J. A., Dierick, I., Verpoorten, N., Warner, T. T., Proukakis, C., Van den Bergh, P., Verellen, C., Van Maldergem, L., Merlini, L., De Jonghe, P., Timmerman, V., Crosby, A. H., Wagner, K. <strong>Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome.</strong> Nature Genet. 36: 271-276, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14981520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14981520</a>] [<a href="https://doi.org/10.1038/ng1313" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14981520">Windpassinger et al. (2004)</a> detected a 1.8-kb brain-specific transcript in all brain regions examined and a 2.2-kb transcript in placenta, lung, liver, skeletal muscle, kidney, and pancreas. Fluorescence microscopy showed seipin and calreticulin (<a href="/entry/109091">109091</a>) colocalized in the endoplasmic reticulum (ER) of transfected human umbilical vein endothelial cells. They identified a conserved N-glycosylation site at residues 88 to 90. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14981520" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Lundin, C., Nordstrom, R., Wagner, K., Windpassinger, C., Andersson, H., von Heijne, G., Nilsson, I. <strong>Membrane topology of the human seipin protein.</strong> FEBS Lett. 580: 2281-2284, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16574104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16574104</a>] [<a href="https://doi.org/10.1016/j.febslet.2006.03.040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16574104">Lundin et al. (2006)</a> found that the predominant form of seipin is 462 residues in length, and is generated by an initiation site upstream of the site found originally. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16574104" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By immunoblot analysis of mouse and human cells transfected with full-length BSCL2, <a href="#15" class="mim-tip-reference" title="Ito, D., Suzuki, N. <strong>Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases.</strong> Ann. Neurol. 61: 237-250, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17387721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17387721</a>] [<a href="https://doi.org/10.1002/ana.21070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17387721">Ito and Suzuki (2007)</a> detected full-length seipin as a 74-kD band and N- and C-terminal fragments of seipin between 35 and 48 kD, suggesting that seipin is highly modified after translation. Seipin immunoreactivity was present in anterior horns of mouse spinal cord and clearly localized to the endoplasmic reticulum. Transiently expressed human seipin appeared to be proteolytically cleaved into an N-terminal fragment, and full-length seipin was polyubiquitinated in cultured neuronal and nonneuronal cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17387721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#14" class="mim-tip-reference" title="Ito, D., Fujisawa, T., Iida, H., Suzuki, N. <strong>Characterization of seipin/BSCL2, a protein associated with spastic paraplegia 17.</strong> Neurobiol. Dis. 31: 266-277, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18585921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18585921</a>] [<a href="https://doi.org/10.1016/j.nbd.2008.05.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18585921">Ito et al. (2008)</a> found expression of seipin in cortical neurons of human frontal lobe and motor neurons of human spinal cord. Seipin immunostaining was also observed specifically in mouse spermatids and cells of the anterior lobe of the mouse pituitary gland. Cellular studies in HeLa cells and mouse neuroblastoma cells indicated that seipin has a glycosylated loop facing the ER lumen with both N and C termini facing the cytosol. The first transmembrane domain is necessary for ER retention. Neuronal and nonneuronal cells expressing the N88S (<a href="#0013">606158.0013</a>) and S90L (<a href="#0014">606158.0014</a>) mutant proteins showed that both mutant proteins localized correctly. Mutant cells also contained inclusion bodies that were found to be distinct from aggresomes. The second transmembrane domain was found to be critical for inclusion formation, and both transmembrane domains were critical for activation of the unfolded protein response (UPR). In a review of the function of seipin and its role in disease, <a href="#16" class="mim-tip-reference" title="Ito, D., Suzuki, N. <strong>Seipinopathy: a novel endoplasmic reticulum stress-associated disease.</strong> Brain 132: 8-15, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18790819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18790819</a>] [<a href="https://doi.org/10.1093/brain/awn216" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18790819">Ito and Suzuki (2009)</a> noted that seipin is an N-glycosylated protein that is proteolytically cleaved into N- and C-terminal fragments and is polyubiquitinated. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18790819+18585921" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Yang, W., Thein, S., Wang, X., Bi, X., Ericksen, R. E., Xu, F., Han, W. <strong>BSCL2/seipin regulates adipogenesis through actin cytoskeleton remodelling.</strong> Hum. Molec. Genet. 23: 502-513, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24026679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24026679</a>] [<a href="https://doi.org/10.1093/hmg/ddt444" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24026679">Yang et al. (2014)</a> had previously found that mouse seipin promotes adipogenesis to accommodate storage of excess nutrients in the form of lipids, whereas it inhibits lipid droplet production and accumulation in preadipocytes and other nonadipocyte lineages. Using mass spectrometry to identify proteins that interacted with seipin in adipose tissue lysates, <a href="#27" class="mim-tip-reference" title="Yang, W., Thein, S., Wang, X., Bi, X., Ericksen, R. E., Xu, F., Han, W. <strong>BSCL2/seipin regulates adipogenesis through actin cytoskeleton remodelling.</strong> Hum. Molec. Genet. 23: 502-513, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24026679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24026679</a>] [<a href="https://doi.org/10.1093/hmg/ddt444" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24026679">Yang et al. (2014)</a> identified the scaffold protein 14-3-3-beta (YWHAB; <a href="/entry/601289">601289</a>). Interaction of seipin with 14-3-3-beta did not depend on insulin stimulation. In insulin (INS; <a href="/entry/176730">176730</a>)-stimulated 3T3-L1 mouse adipocytes, 14-3-3-beta interacted with the actin-severing protein cofilin-1 (CFL1; <a href="/entry/601442">601442</a>), and this interaction required serine phosphorylation of cofilin-1. Adipogenesis in 3T3-L1 cells was accompanied by remodeling of the actin cytoskeleton from central stress fibers to the cell cortex, concomitant with lipid droplet accumulation. Knockdown of seipin, 14-3-3-beta, or cofilin-1 in 3T3-L1 cells impaired adipocyte development and inhibited lipid drop accumulation, but stress fibers remained intact. Impaired adipogenesis was also present in 3T3-L1 cells expressing a severing-resistant actin mutant. <a href="#27" class="mim-tip-reference" title="Yang, W., Thein, S., Wang, X., Bi, X., Ericksen, R. E., Xu, F., Han, W. <strong>BSCL2/seipin regulates adipogenesis through actin cytoskeleton remodelling.</strong> Hum. Molec. Genet. 23: 502-513, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24026679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24026679</a>] [<a href="https://doi.org/10.1093/hmg/ddt444" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24026679">Yang et al. (2014)</a> concluded that the interaction of seipin with 14-3-3-beta recruits cofilin-1 to remodel the actin cytoskeleton for adipocyte differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24026679" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#21" class="mim-tip-reference" title="Magre, J., Delepine, M., Khallouf, E., Gedde-Dahl, T., Jr., Van Maldergem, L., Sobel, E., Papp, J., Meier, M., Megarbane, A., BSCL Working Group, Lathrop, M., Capeau, J. <strong>Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.</strong> Nature Genet. 28: 365-370, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479539</a>] [<a href="https://doi.org/10.1038/ng585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479539">Magre et al. (2001)</a> determined that the BSCL2 gene contains 11 exons spanning at least 14 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11479539" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#21" class="mim-tip-reference" title="Magre, J., Delepine, M., Khallouf, E., Gedde-Dahl, T., Jr., Van Maldergem, L., Sobel, E., Papp, J., Meier, M., Megarbane, A., BSCL Working Group, Lathrop, M., Capeau, J. <strong>Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.</strong> Nature Genet. 28: 365-370, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479539</a>] [<a href="https://doi.org/10.1038/ng585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479539">Magre et al. (2001)</a> reported that the BSCL2 gene is homologous to the mouse 'gamma-3-linked gene' (Gng3lg), which is localized in the region of mouse chromosome 19 orthologous to human 11q. By positional cloning, they located the BSCL2 gene within a 2.5-Mb critical region for a form of Berardinelli-Seip congenital lipodystrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11479539" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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In chromosome 11q13-linked families with congenital generalized lipodystrophy type 2, and in 3 isolated patients, <a href="#21" class="mim-tip-reference" title="Magre, J., Delepine, M., Khallouf, E., Gedde-Dahl, T., Jr., Van Maldergem, L., Sobel, E., Papp, J., Meier, M., Megarbane, A., BSCL Working Group, Lathrop, M., Capeau, J. <strong>Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.</strong> Nature Genet. 28: 365-370, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479539</a>] [<a href="https://doi.org/10.1038/ng585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479539">Magre et al. (2001)</a> identified mutations in the BSCL2 gene (<a href="#0001">606158.0001</a>-<a href="#0012">606158.0012</a>). Most of the variants were null mutations predicted to result in the severe disruption of the protein. Affected individuals were either homozygous for a specific mutation or compound heterozygous; all parents of unaffected sibs carried only 1 mutation. <a href="#21" class="mim-tip-reference" title="Magre, J., Delepine, M., Khallouf, E., Gedde-Dahl, T., Jr., Van Maldergem, L., Sobel, E., Papp, J., Meier, M., Megarbane, A., BSCL Working Group, Lathrop, M., Capeau, J. <strong>Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.</strong> Nature Genet. 28: 365-370, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479539</a>] [<a href="https://doi.org/10.1038/ng585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479539">Magre et al. (2001)</a> did not find any mutation in affected individuals of the 9 families in which BSCL is not linked to 11q13 or in 13 additional patients who had been diagnosed with Lawrence syndrome (<a href="#18" class="mim-tip-reference" title="Lawrence, R. D. <strong>Lipodystrophy and hepatomegaly with diabetes, lipaemia, and other metabolic disturbances: a case throwing new light on the action of insulin.</strong> Lancet 247: 724-731 and 773-775, 1946. Note: Originally Volume I.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20982387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20982387</a>]" pmid="20982387">Lawrence, 1946</a>), in which lipoatrophy is not present at birth but develops at a later age. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11479539+20982387" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Fu, M., Kazlauskaite, R., de Fatima Paiva Baracho, M., Do Nascimento Santos, M. G., Brandao-Neto, J., Villares, S., Celi, F. S., Wajchenberg, B. L., Shuldiner, A. R. <strong>Mutations in Gng31g and AGPAT2 in Berardinelli-Seip congenital lipodystrophy and Brunzell syndrome: phenotype variability suggests important modifier effects.</strong> J. Clin. Endocr. Metab. 89: 2916-2922, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15181077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15181077</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15181077[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/10.1210/jc.2003-030485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15181077">Fu et al. (2004)</a> screened for mutations in AGPAT2 (<a href="/entry/603100">603100</a>) and BSCL2 in 27 families with congenital generalized lipodystrophy. They found mutations in either AGPAT2 or BSCL2 in all but 4 probands. Eighteen patients with congenital generalized lipodystrophy from 15 families from the same region of northeastern Brazil were homozygous for a frameshift mutation in BSCL2 (669insA; <a href="#0006">606158.0006</a>). Despite having the same mutation, the subjects had widely divergent clinical manifestations. <a href="#11" class="mim-tip-reference" title="Fu, M., Kazlauskaite, R., de Fatima Paiva Baracho, M., Do Nascimento Santos, M. G., Brandao-Neto, J., Villares, S., Celi, F. S., Wajchenberg, B. L., Shuldiner, A. R. <strong>Mutations in Gng31g and AGPAT2 in Berardinelli-Seip congenital lipodystrophy and Brunzell syndrome: phenotype variability suggests important modifier effects.</strong> J. Clin. Endocr. Metab. 89: 2916-2922, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15181077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15181077</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15181077[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/10.1210/jc.2003-030485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15181077">Fu et al. (2004)</a> concluded that there did not appear to be any distinguishing clinical characteristics between subjects with congenital generalized lipodystrophy with AGPAT2 or BSCL2 mutations, with the exception of mental retardation in carriers of BSCL2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15181077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Szymanski, K. M., Binns, D., Bartz, R., Grishin, N. V., Li, W.-P., Agarwal, A. K., Garg, A., Anderson, R. G. W., Goodman, J. M. <strong>The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology.</strong> Proc. Nat. Acad. Sci. 104: 20890-20895, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18093937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18093937</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18093937[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0704154104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18093937">Szymanski et al. (2007)</a> screened a yeast deletion library for aberrant lipid droplets and found that absence of yeast seipin resulted in irregular lipid droplets often clustered alongside proliferated ER; giant lipid droplets were also seen. Electron microscopy showed abnormal small irregular lipid droplets in fibroblasts from a BSCL2 patient with a 5-bp deletion (<a href="#0005">606158.0005</a>). In yeast, almost all lipid droplets appeared to be on the ER, and seipin was found at these junctions. Human seipin could functionally replace yeast seipin, but A212P (<a href="#0009">606158.0009</a>)-mutant human seipin that causes lipodystrophy could not. <a href="#23" class="mim-tip-reference" title="Szymanski, K. M., Binns, D., Bartz, R., Grishin, N. V., Li, W.-P., Agarwal, A. K., Garg, A., Anderson, R. G. W., Goodman, J. M. <strong>The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology.</strong> Proc. Nat. Acad. Sci. 104: 20890-20895, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18093937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18093937</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18093937[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0704154104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18093937">Szymanski et al. (2007)</a> hypothesized that seipin is important for lipid droplet maintenance and perhaps assembly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18093937" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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>Autosomal Dominant Distal Hereditary Motor Neuropathy 13 and Silver Syndrome</em></strong></p><p>
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In a large Austrian family with autosomal dominant distal hereditary motor neuropathy-13 (HMND13; <a href="/entry/619112">619112</a>) reported by <a href="#2" class="mim-tip-reference" title="Auer-Grumbach, M., Loscher, W. N., Wagner, K., Petek, E., Korner, E., Offenbacher, H., Hartung, H.-P. <strong>Phenotypic and genotypic heterogeneity in hereditary motor neuronopathy type V: a clinical, electrophysiological and genetic study.</strong> Brain 123: 1612-1623, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10908191/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10908191</a>] [<a href="https://doi.org/10.1093/brain/123.8.1612" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10908191">Auer-Grumbach et al. (2000)</a>, <a href="#26" class="mim-tip-reference" title="Windpassinger, C., Wagner, K., Petek, E., Fischer, R., Auer-Grumbach, M. <strong>Refinement of the 'Silver syndrome locus' on chromosome 11q12-q14 in four families and exclusion of eight candidate genes.</strong> Hum. Genet. 114: 99-109, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13680364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13680364</a>] [<a href="https://doi.org/10.1007/s00439-003-1021-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13680364">Windpassinger et al. (2003)</a> established linkage of the disorder to 11q12-q14, a chromosomal region overlapping that of Silver spastic paraplegia syndrome (SPG17; <a href="/entry/270685">270685</a>). <a href="#25" class="mim-tip-reference" title="Windpassinger, C., Auer-Grumbach, M., Irobi, J., Patel, H., Petek, E., Horl, G., Malli, R., Reed, J. A., Dierick, I., Verpoorten, N., Warner, T. T., Proukakis, C., Van den Bergh, P., Verellen, C., Van Maldergem, L., Merlini, L., De Jonghe, P., Timmerman, V., Crosby, A. H., Wagner, K. <strong>Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome.</strong> Nature Genet. 36: 271-276, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14981520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14981520</a>] [<a href="https://doi.org/10.1038/ng1313" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14981520">Windpassinger et al. (2004)</a> confirmed linkage to the SPG17 locus in 16 additional families with a phenotype characteristic of Silver syndrome. After refining the critical region to 1 Mb, <a href="#25" class="mim-tip-reference" title="Windpassinger, C., Auer-Grumbach, M., Irobi, J., Patel, H., Petek, E., Horl, G., Malli, R., Reed, J. A., Dierick, I., Verpoorten, N., Warner, T. T., Proukakis, C., Van den Bergh, P., Verellen, C., Van Maldergem, L., Merlini, L., De Jonghe, P., Timmerman, V., Crosby, A. H., Wagner, K. <strong>Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome.</strong> Nature Genet. 36: 271-276, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14981520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14981520</a>] [<a href="https://doi.org/10.1038/ng1313" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14981520">Windpassinger et al. (2004)</a> sequenced the BSCL2 gene, which lies within that region, and identified heterozygous missense mutations in the family with DSMAV and those with SPG17. The mutations N88S (<a href="#0013">606158.0013</a>) and S90L (<a href="#0014">606158.0014</a>) affected glycosylation of seipin and resulted in aggregate formation, predicted to cause neurodegeneration. Their findings indicated that Silver syndrome and some forms of dHMN are, in fact, extreme phenotypes resulting from mutations in the same gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14981520+10908191+13680364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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 affected members of a multigenerational Korean family with autosomal dominant distal hereditary motor neuronopathy-13 (HMND13; <a href="/entry/619112">619112</a>) and features of axonal Charcot-Marie-Tooth disease type 2 (CMT2), <a href="#7" class="mim-tip-reference" title="Choi, B.-O., Park, M.-H., Chung, K. W., Woo, H.-M., Koo, H., Chung, H.-K., Choi, K.-G., Park, K. D., Lee, H. J., Hyun, Y. S., Koo, S. K. <strong>Clinical and histopathological study of Charcot-Marie-Tooth neuropathy with a novel S90W mutation in BSCL2.</strong> Neurogenetics 14: 35-42, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23142943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23142943</a>] [<a href="https://doi.org/10.1007/s10048-012-0346-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23142943">Choi et al. (2013)</a> identified a heterozygous S90W mutation in the BSCL2 gene (<a href="#0020">606158.0020</a>). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the affected residue is the same as the previously identified S90L mutation (<a href="#0014">606158.0014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23142943" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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>Progressive Encephalopathy with or without Lipodystrophy</em></strong></p><p>
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In 6 children from 4 unrelated families from Murcia in southeastern Spain with autosomal recessive progressive encephalopathy with or without lipodystrophy (PELD; <a href="/entry/615924">615924</a>), <a href="#12" class="mim-tip-reference" title="Guillen-Navarro, E., Sanchez-Iglesias, S., Domingo-Jimenez, R., Victoria, B., Ruiz-Riquelme, A., Rabano, A., Loidi, L., Beiras, A., Gonzalez-Mendez, B., Ramos, A., Lopez-Gonzalez, V., Ballesta-Martinez, M. J., Garrido-Pumar, M., Aguiar, P., Ruibal, A., Requena, J. R., Araujo-Vilar, D. <strong>A new seipin-associated neurodegenerative syndrome.</strong> J. Med. Genet. 50: 401-409, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23564749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23564749</a>] [<a href="https://doi.org/10.1136/jmedgenet-2013-101525" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23564749">Guillen-Navarro et al. (2013)</a> identified homozygous or compound heterozygous truncating mutations in the BSCL2 gene (<a href="#0017">606158.0017</a>-<a href="#0019">606158.0019</a>). All patients carried the same mutation (c.985C-T; <a href="#0017">606158.0017</a>) on at least 1 allele, consistent with a founder effect. The phenotype was severe, resulting in death of 5 children between ages 6 and 8 years. Most, but not all, patients had some evidence of lipodystrophy, but all 5 patients who died developed a progressive encephalopathy with psychomotor regression, loss of speech, cognitive decline, spasticity, and seizures between ages 2 and 3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23564749" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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>Variant Function</em></strong></p><p>
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By in vitro functional expression analysis, <a href="#15" class="mim-tip-reference" title="Ito, D., Suzuki, N. <strong>Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases.</strong> Ann. Neurol. 61: 237-250, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17387721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17387721</a>] [<a href="https://doi.org/10.1002/ana.21070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17387721">Ito and Suzuki (2007)</a> demonstrated that the N88S and S90L mutations in the BSCL2 gene disrupt glycosylation of the seipin protein. Overexpressed mutant seipin was highly ubiquitinated and degraded by the proteasome, and improper glycosylation exacerbated endoplasmic reticulum retention. Mutant proteins activated the unfolded protein response, resulting in apoptotic cell death through ER stress. <a href="#15" class="mim-tip-reference" title="Ito, D., Suzuki, N. <strong>Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases.</strong> Ann. Neurol. 61: 237-250, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17387721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17387721</a>] [<a href="https://doi.org/10.1002/ana.21070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17387721">Ito and Suzuki (2007)</a> concluded that the N88S and S90L mutations, which result in motor neuron disease, have a gain-of-function effect, resulting in conformational protein changes, activation of the unfolded protein response, cell death, and neurodegeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17387721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#8" class="mim-tip-reference" title="Cui, X., Wang, Y., Tang, Y., Liu, Y., Zhao, L., Deng, J., Xu, G., Peng, X., Ju, S., Liu, G., Yang, H. <strong>Seipin ablation in mice results in severe generalized lipodystrophy.</strong> Hum. Molec. Genet. 20: 3022-3030, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21551454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21551454</a>] [<a href="https://doi.org/10.1093/hmg/ddr205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21551454">Cui et al. (2011)</a> obtained seipin -/- mice at the expected mendelian ratio. Seipin -/- mice were growth delayed, but they eventually achieved normal weight. They showed significantly reduced adipose tissue mass, including about 60% reduction in brown adipose tissue, glucose intolerance, hyperinsulinemia, and hepatic steatosis, with elevated expression of select lipogenic genes. Levels of leptin (LEP; <a href="/entry/164160">164160</a>) and adiponectin (ADIPOQ; <a href="/entry/605441">605441</a>) were significantly decreased in seipin -/- mice, as were nonesterified fatty acids upon fasting. Hypertriglyceridemia, which is common in human BSCL, was not observed in seipin -/- mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21551454" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Zhou, L., Yin, J., Wang, C., Liao, J., Liu, G., Chen, L. <strong>Lack of seipin in neurons results in anxiety- and depression-like behaviors via down regulation of PPAR-gamma.</strong> Hum. Molec. Genet. 23: 4094-4102, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24651066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24651066</a>] [<a href="https://doi.org/10.1093/hmg/ddu126" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24651066">Zhou et al. (2014)</a> found that male, but not female, neuron-specific seipin-knockout mice displayed anxiety- and depression-like behaviors. Male, but not female, neuron-specific seipin-knockout mice also showed reduced mRNA and protein levels of Pparg (<a href="/entry/601487">601487</a>) in hippocampus and cortex. Treatment of male neuron-specific seipin-knockout mice with 17-beta-estradiol or a Pparg agonist alleviated affective disorders. Ovariectomy resulted in anxiety- and depression-like behaviors and reduced Pparg levels in female neuron-specific seipin-knockout mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24651066" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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=606158[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">rs786205068 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205068;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=rs786205068" 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=rs786205068" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 families with Berardinelli-Seip congenital lipodystrophy (CGL2; <a href="/entry/269700">269700</a>), 1 from eastern Norway and 1 from Italy, <a href="#21" class="mim-tip-reference" title="Magre, J., Delepine, M., Khallouf, E., Gedde-Dahl, T., Jr., Van Maldergem, L., Sobel, E., Papp, J., Meier, M., Megarbane, A., BSCL Working Group, Lathrop, M., Capeau, J. <strong>Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.</strong> Nature Genet. 28: 365-370, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479539</a>] [<a href="https://doi.org/10.1038/ng585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479539">Magre et al. (2001)</a> found homozygosity for a mutation in exon 2 of the BSCL2 gene, the replacement of 2 CC nucleotides at position 536 with 3 nucleotides (GGA), resulting in a frameshift following phenylalanine-63 with a termination codon at amino acid 75. They also found the mutation in heterozygous state in 2 affected families from southwestern Norway and the United Kingdom, respectively. The phenotype presented at birth in the Norwegian and U.K. families and before 9 months of age in the Italian family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11479539" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs786205069 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205069;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=rs786205069" 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=rs786205069" 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 consanguineous Brazilian family with Berardinelli-Seip congenital lipodystrophy (CGL2; <a href="/entry/269700">269700</a>), <a href="#21" class="mim-tip-reference" title="Magre, J., Delepine, M., Khallouf, E., Gedde-Dahl, T., Jr., Van Maldergem, L., Sobel, E., Papp, J., Meier, M., Megarbane, A., BSCL Working Group, Lathrop, M., Capeau, J. <strong>Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.</strong> Nature Genet. 28: 365-370, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479539</a>] [<a href="https://doi.org/10.1038/ng585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479539">Magre et al. (2001)</a> found homozygosity for an insertion of 2 adenines at nucleotide 645 of the BSCL2 gene, resulting in a frameshift and premature termination at codon 111. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11479539" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs786205070 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205070;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/rs786205070?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=rs786205070" 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=rs786205070" 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=RCV000004791 OR RCV003311637" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004791, RCV003311637" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004791...</a>
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<p>In a French family segregating Berardinelli-Seip congenital lipodystrophy (CGL2; <a href="/entry/269700">269700</a>), <a href="#21" class="mim-tip-reference" title="Magre, J., Delepine, M., Khallouf, E., Gedde-Dahl, T., Jr., Van Maldergem, L., Sobel, E., Papp, J., Meier, M., Megarbane, A., BSCL Working Group, Lathrop, M., Capeau, J. <strong>Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.</strong> Nature Genet. 28: 365-370, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479539</a>] [<a href="https://doi.org/10.1038/ng585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479539">Magre et al. (2001)</a> identified compound heterozygosity for mutations in the BSCL2 gene: deletion of 2 basepairs (GT) at nucleotide 659, resulting in a frameshift and premature termination at codon 112; and a 258-bp deletion/12-bp insertion in exons 5-6 (<a href="#0004">606158.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11479539" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 2</strong>
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<p>For discussion of the 258-bp deletion/12-bp insertion in exons 5-6 of the BSCL2 gene that was found in compound heterozygous state in a family segregating Berardinelli-Seip congenital lipodystrophy (CGL2; <a href="/entry/269700">269700</a>) by <a href="#21" class="mim-tip-reference" title="Magre, J., Delepine, M., Khallouf, E., Gedde-Dahl, T., Jr., Van Maldergem, L., Sobel, E., Papp, J., Meier, M., Megarbane, A., BSCL Working Group, Lathrop, M., Capeau, J. <strong>Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.</strong> Nature Genet. 28: 365-370, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479539</a>] [<a href="https://doi.org/10.1038/ng585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479539">Magre et al. (2001)</a>, see <a href="#0003">606158.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11479539" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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=RCV000004793 OR RCV000133399 OR RCV001091624 OR RCV003311638 OR RCV005089168" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004793, RCV000133399, RCV001091624, RCV003311638, RCV005089168" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004793...</a>
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<p><a href="#21" class="mim-tip-reference" title="Magre, J., Delepine, M., Khallouf, E., Gedde-Dahl, T., Jr., Van Maldergem, L., Sobel, E., Papp, J., Meier, M., Megarbane, A., BSCL Working Group, Lathrop, M., Capeau, J. <strong>Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.</strong> Nature Genet. 28: 365-370, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479539</a>] [<a href="https://doi.org/10.1038/ng585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479539">Magre et al. (2001)</a> found that all Lebanese patients with Berardinelli-Seip congenital lipodystrophy (CGL2; <a href="/entry/269700">269700</a>) whom they studied were homozygous for a frameshift mutation resulting from the deletion of GTATC at nucleotide 659 of the BSCL2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11479539" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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 fibroblasts from a BSCL2 patient with the 5-bp deletion, <a href="#23" class="mim-tip-reference" title="Szymanski, K. M., Binns, D., Bartz, R., Grishin, N. V., Li, W.-P., Agarwal, A. K., Garg, A., Anderson, R. G. W., Goodman, J. M. <strong>The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology.</strong> Proc. Nat. Acad. Sci. 104: 20890-20895, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18093937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18093937</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18093937[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0704154104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18093937">Szymanski et al. (2007)</a> found abnormal cytoplasmic lipid droplets. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18093937" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs786205071 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205071;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/rs786205071?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=rs786205071" 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=rs786205071" 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=RCV000004794 OR RCV002496260 OR RCV002512772 OR RCV003311639" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004794, RCV002496260, RCV002512772, RCV003311639" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004794...</a>
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<p>In 2 South African Portuguese families with Berardinelli-Seip congenital lipodystrophy (CGL2; <a href="/entry/269700">269700</a>), <a href="#21" class="mim-tip-reference" title="Magre, J., Delepine, M., Khallouf, E., Gedde-Dahl, T., Jr., Van Maldergem, L., Sobel, E., Papp, J., Meier, M., Megarbane, A., BSCL Working Group, Lathrop, M., Capeau, J. <strong>Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.</strong> Nature Genet. 28: 365-370, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479539</a>] [<a href="https://doi.org/10.1038/ng585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479539">Magre et al. (2001)</a> found homozygosity for a frameshift resulting from insertion of an adenine at nucleotide 669 of the BSCL2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11479539" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Bhayana, S., Siu, V. M., Joubert, G. I., Clarson, C. L., Cao, H., Hegele, R. A. <strong>Cardiomyopathy in congenital complete lipodystrophy.</strong> Clin. Genet. 61: 283-287, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12030893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12030893</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2002.610407.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12030893">Bhayana et al. (2002)</a> described the same mutation in a 10-year-old girl from Canada whose parents were not known to be consanguineous, although they came from the same region of Portugal. The family history was positive for BSCL on both sides of the family. Her father had 2 affected male cousins who were born to consanguineous parents and died in childhood. Another affected female first cousin of the father died at 30 years of age with renal failure. An affected male, the second cousin of the patient's mother, died at 28 years of age. In addition to having the typical attributes of complete lipodystrophy, the patient had been diagnosed with hypertrophic cardiomyopathy in the first year of life. A relationship between congenital lipodystrophy syndromes and cardiac disorders is suggested by the fact that mutations in lamin A/C (LMNA; <a href="/entry/150330">150330</a>) cause either lipodystrophy or cardiomyopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12030893" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Fu, M., Kazlauskaite, R., de Fatima Paiva Baracho, M., Do Nascimento Santos, M. G., Brandao-Neto, J., Villares, S., Celi, F. S., Wajchenberg, B. L., Shuldiner, A. R. <strong>Mutations in Gng31g and AGPAT2 in Berardinelli-Seip congenital lipodystrophy and Brunzell syndrome: phenotype variability suggests important modifier effects.</strong> J. Clin. Endocr. Metab. 89: 2916-2922, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15181077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15181077</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15181077[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/10.1210/jc.2003-030485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15181077">Fu et al. (2004)</a> found this mutation in 18 patients from 15 Caucasian families from the same region of Serido county of Rio Grande do Norte State in northeastern Brazil. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15181077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 2</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> rs137852970 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852970;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/rs137852970?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=rs137852970" 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=rs137852970" 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=RCV000004795 OR RCV002298433 OR RCV002326662 OR RCV003311640" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004795, RCV002298433, RCV002326662, RCV003311640" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004795...</a>
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<p>In a French Portuguese family and 2 additional Portuguese families with Berardinelli-Seip congenital lipodystrophy (CGL2; <a href="/entry/269700">269700</a>), <a href="#21" class="mim-tip-reference" title="Magre, J., Delepine, M., Khallouf, E., Gedde-Dahl, T., Jr., Van Maldergem, L., Sobel, E., Papp, J., Meier, M., Megarbane, A., BSCL Working Group, Lathrop, M., Capeau, J. <strong>Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.</strong> Nature Genet. 28: 365-370, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479539</a>] [<a href="https://doi.org/10.1038/ng585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479539">Magre et al. (2001)</a> identified homozygosity for an arg138-to-stop mutation that resulted from a C-to-T transition at nucleotide 756 of the BSCL2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11479539" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs1945400235 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1945400235;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=rs1945400235" 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=rs1945400235" 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=RCV000004796 OR RCV003311641" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004796, RCV003311641" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004796...</a>
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<p>In a consanguineous Turkish family segregating Berardinelli-Seip congenital lipodystrophy (CGL2; <a href="/entry/269700">269700</a>), <a href="#21" class="mim-tip-reference" title="Magre, J., Delepine, M., Khallouf, E., Gedde-Dahl, T., Jr., Van Maldergem, L., Sobel, E., Papp, J., Meier, M., Megarbane, A., BSCL Working Group, Lathrop, M., Capeau, J. <strong>Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.</strong> Nature Genet. 28: 365-370, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479539</a>] [<a href="https://doi.org/10.1038/ng585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479539">Magre et al. (2001)</a> identified a G-to-A transition at the +1 position of intron 4, resulting in skipping of exon 4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11479539" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs137852971 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852971;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/rs137852971?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=rs137852971" 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=rs137852971" 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=RCV000004797 OR RCV003311642 OR RCV003581554 OR RCV005049316" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004797, RCV003311642, RCV003581554, RCV005049316" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004797...</a>
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<p>In 4 southwestern Norwegian families segregating Berardinelli-Seip congenital lipodystrophy (CGL2; <a href="/entry/269700">269700</a>), <a href="#21" class="mim-tip-reference" title="Magre, J., Delepine, M., Khallouf, E., Gedde-Dahl, T., Jr., Van Maldergem, L., Sobel, E., Papp, J., Meier, M., Megarbane, A., BSCL Working Group, Lathrop, M., Capeau, J. <strong>Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.</strong> Nature Genet. 28: 365-370, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479539</a>] [<a href="https://doi.org/10.1038/ng585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479539">Magre et al. (2001)</a> identified a G-to-C transversion at nucleotide 978 of the BSCL2 gene, resulting in an alanine-to-proline substitution at codon 212. This mutation was found in homozygosity in 3 of the families and in compound heterozygosity in 1. The condition manifested at birth in these families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11479539" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 2</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> rs758843908 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs758843908;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/rs758843908?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=rs758843908" 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=rs758843908" 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=RCV000004798 OR RCV001851654 OR RCV003311643" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004798, RCV001851654, RCV003311643" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004798...</a>
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<p>In a consanguineous Indian family segregating Berardinelli-Seip congenital lipodystrophy (CGL2; <a href="/entry/269700">269700</a>), <a href="#21" class="mim-tip-reference" title="Magre, J., Delepine, M., Khallouf, E., Gedde-Dahl, T., Jr., Van Maldergem, L., Sobel, E., Papp, J., Meier, M., Megarbane, A., BSCL Working Group, Lathrop, M., Capeau, J. <strong>Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.</strong> Nature Genet. 28: 365-370, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479539</a>] [<a href="https://doi.org/10.1038/ng585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479539">Magre et al. (2001)</a> identified homozygosity for a mutation in the BSCL2 gene, the deletion of a C at nucleotide 980 resulting in a frameshift at codon 213 and premature termination at codon 232. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11479539" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0011 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 2</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">rs786205072 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205072;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=rs786205072" 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=rs786205072" 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=RCV000004799 OR RCV001847581 OR RCV003311644 OR RCV005049317" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004799, RCV001847581, RCV003311644, RCV005049317" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004799...</a>
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<p>In a British family segregating Berardinelli-Seip congenital lipodystrophy (CGL2; <a href="/entry/269700">269700</a>), <a href="#21" class="mim-tip-reference" title="Magre, J., Delepine, M., Khallouf, E., Gedde-Dahl, T., Jr., Van Maldergem, L., Sobel, E., Papp, J., Meier, M., Megarbane, A., BSCL Working Group, Lathrop, M., Capeau, J. <strong>Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.</strong> Nature Genet. 28: 365-370, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479539</a>] [<a href="https://doi.org/10.1038/ng585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479539">Magre et al. (2001)</a> identified a G-to-A transition at the +5 position of intron 6 of the BSCL2 gene, which resulted in activation of a cryptic splice site leading to premature termination at codon 225. The patient was compound heterozygous for this mutation, and the condition manifested at birth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11479539" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 2</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">rs786205073 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205073;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=rs786205073" 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=rs786205073" 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=RCV000004800 OR RCV003311645" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004800, RCV003311645" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004800...</a>
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<p>In a Turkish French family segregating Berardinelli-Seip congenital lipodystrophy (CGL2; <a href="/entry/269700">269700</a>), <a href="#21" class="mim-tip-reference" title="Magre, J., Delepine, M., Khallouf, E., Gedde-Dahl, T., Jr., Van Maldergem, L., Sobel, E., Papp, J., Meier, M., Megarbane, A., BSCL Working Group, Lathrop, M., Capeau, J. <strong>Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.</strong> Nature Genet. 28: 365-370, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479539</a>] [<a href="https://doi.org/10.1038/ng585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479539">Magre et al. (2001)</a> identified homozygosity for a C-to-G transversion at the -3 position of intron 6. This mutation resulted in skipping of exon 7. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11479539" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 SILVER SPASTIC PARAPLEGIA SYNDROME</strong>
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NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 13, INCLUDED
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BSCL2, ASN88SER
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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> rs137852972 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852972;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/rs137852972?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=rs137852972" 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=rs137852972" 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=RCV000004801 OR RCV000004802 OR RCV000168078 OR RCV000340485 OR RCV000507071 OR RCV001270680 OR RCV001813949 OR RCV001847582 OR RCV002426488 OR RCV003311646 OR RCV004795375" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004801, RCV000004802, RCV000168078, RCV000340485, RCV000507071, RCV001270680, RCV001813949, RCV001847582, RCV002426488, RCV003311646, RCV004795375" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004801...</a>
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<p>In affected members of 1 English and 4 Austrian families with Silver spastic paraplegia syndrome (SPG17; <a href="/entry/270685">270685</a>), <a href="#25" class="mim-tip-reference" title="Windpassinger, C., Auer-Grumbach, M., Irobi, J., Patel, H., Petek, E., Horl, G., Malli, R., Reed, J. A., Dierick, I., Verpoorten, N., Warner, T. T., Proukakis, C., Van den Bergh, P., Verellen, C., Van Maldergem, L., Merlini, L., De Jonghe, P., Timmerman, V., Crosby, A. H., Wagner, K. <strong>Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome.</strong> Nature Genet. 36: 271-276, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14981520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14981520</a>] [<a href="https://doi.org/10.1038/ng1313" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14981520">Windpassinger et al. (2004)</a> identified heterozygosity for a 263A-G transition (c.263A-G, NM_032667) in the BSCL2 gene, resulting in an asn88-to-ser (N88S) mutation. The English family was the original one reported by <a href="#22" class="mim-tip-reference" title="Silver, J. R. <strong>Familial spastic paraplegia with amyotrophy of the hands.</strong> Ann. Hum. Genet. 30: 69-75, 1966.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5964029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5964029</a>] [<a href="https://doi.org/10.1111/j.1469-1809.1966.tb00007.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5964029">Silver (1966)</a>. In affected members of 1 Italian, 1 English, and 8 Austrian families with autosomal dominant distal hereditary motor neuronopathy-13 (HMND13; <a href="/entry/619112">619112</a>), they identified the N88S mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14981520+5964029" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Auer-Grumbach, M., Schlotter-Weigel, B., Lochmuller, H., Strobl-Wildemann, G., Auer-Grumbach, P., Fischer, R., Offenbacher, H., Zwick, E. B., Robl, T., Hartl, G., Hartung, H.-P., Wagner, K., Windpassinger, C., Austrian Peripheral Neuropathy Study Group. <strong>Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation.</strong> Ann. Neurol. 57: 415-424, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15732094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15732094</a>] [<a href="https://doi.org/10.1002/ana.20410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15732094">Auer-Grumbach et al. (2005)</a> reported the phenotypic findings in 90 patients from 1 large Austrian family and 2 unrelated German families with the N88S mutation. There was considerable phenotypic variability, including asymptomatic nonpenetrance (4.4%), subclinical involvement (20%), distal spinal muscular atrophy characterized by prominent hand muscle involvement (31.1%), Silver syndrome (14.5%) with hand muscle involvement and spasticity, a Charcot-Marie-Tooth-like phenotype with distal muscle weakness and wasting of the lower limbs and sensory abnormalities (20%), and spastic paraparesis without hand involvement (10%). <a href="#3" class="mim-tip-reference" title="Auer-Grumbach, M., Schlotter-Weigel, B., Lochmuller, H., Strobl-Wildemann, G., Auer-Grumbach, P., Fischer, R., Offenbacher, H., Zwick, E. B., Robl, T., Hartl, G., Hartung, H.-P., Wagner, K., Windpassinger, C., Austrian Peripheral Neuropathy Study Group. <strong>Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation.</strong> Ann. Neurol. 57: 415-424, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15732094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15732094</a>] [<a href="https://doi.org/10.1002/ana.20410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15732094">Auer-Grumbach et al. (2005)</a> concluded that the N88S mutation causes a motor neuron disease affecting the upper motor neurons, lower motor neurons, or both. Hand muscle involvement was a frequent, although not regular, feature, and sensory involvement was usually not present. Genealogic studies of the Austrian kindred traced the disease to a common parent pair born in 1682. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15732094" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Van de Warrenburg, B. P. C., Scheffer, H., van Eijk, J. J. J., Versteeg, M. H. A., Kremer, H., Zwarts, M. J., Schelhaas, H. J., van Engelen, B. G. M. <strong>BSCL2 mutations in two Dutch families with overlapping Silver syndrome-distal hereditary motor neuropathy.</strong> Neuromusc. Disord. 16: 122-125, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16427281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16427281</a>] [<a href="https://doi.org/10.1016/j.nmd.2005.11.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16427281">Van de Warrenburg et al. (2006)</a> reported 2 Dutch families with multiple affected individuals carrying a heterozygous N88S mutation. The phenotype in both families overlapped between Silver syndrome and HMND13. Affected members in both families had foot and lower limb atrophy with slowly progressive hyperreflexia and extensor plantar responses without prominent spasticity. Hand involvement occurred in most patients and was restricted to interosseus muscles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16427281" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="#5" class="mim-tip-reference" title="Brusse, E., Majoor-Krakauer, D., de Graaf, B. M., Visser, G. H., Swagemakers, S., Boon, A. J. W., Oostra, B. A., Bertoli-Avella, A. M. <strong>A novel 16p locus associated with BSCL2 hereditary motor neuronopathy: a genetic modifier?</strong> Neurogenetics 10: 289-297, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19396477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19396477</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19396477[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/10.1007/s10048-009-0193-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19396477">Brusse et al. (2009)</a> reported 12 members of a large 3-generation Dutch family with phenotypic overlap between Silver syndrome and distal HMND13 who carried a heterozygous N88S mutation. The phenotype was variable, and the distribution of muscle weakness and atrophy included predominantly the feet (in 4), the hands (in 1), or both upper and lower extremities (in 4). Three individuals showed evidence of pyramidal features, including spasticity, hyperreflexia, and extensor plantar responses. Severity of the disease ranged from adolescent patients with disabling muscle weakness to an elderly patient with only mild weakness of the ankle dorsiflexors and bilateral pes cavus. <a href="#5" class="mim-tip-reference" title="Brusse, E., Majoor-Krakauer, D., de Graaf, B. M., Visser, G. H., Swagemakers, S., Boon, A. J. W., Oostra, B. A., Bertoli-Avella, A. M. <strong>A novel 16p locus associated with BSCL2 hereditary motor neuronopathy: a genetic modifier?</strong> Neurogenetics 10: 289-297, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19396477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19396477</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19396477[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/10.1007/s10048-009-0193-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19396477">Brusse et al. (2009)</a> noted the extreme phenotypic variability associated with the N88S mutation in their family and in those reported by <a href="#3" class="mim-tip-reference" title="Auer-Grumbach, M., Schlotter-Weigel, B., Lochmuller, H., Strobl-Wildemann, G., Auer-Grumbach, P., Fischer, R., Offenbacher, H., Zwick, E. B., Robl, T., Hartl, G., Hartung, H.-P., Wagner, K., Windpassinger, C., Austrian Peripheral Neuropathy Study Group. <strong>Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation.</strong> Ann. Neurol. 57: 415-424, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15732094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15732094</a>] [<a href="https://doi.org/10.1002/ana.20410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15732094">Auer-Grumbach et al. (2005)</a> and <a href="#24" class="mim-tip-reference" title="Van de Warrenburg, B. P. C., Scheffer, H., van Eijk, J. J. J., Versteeg, M. H. A., Kremer, H., Zwarts, M. J., Schelhaas, H. J., van Engelen, B. G. M. <strong>BSCL2 mutations in two Dutch families with overlapping Silver syndrome-distal hereditary motor neuropathy.</strong> Neuromusc. Disord. 16: 122-125, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16427281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16427281</a>] [<a href="https://doi.org/10.1016/j.nmd.2005.11.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16427281">van de Warrenburg et al. (2006)</a>, and suggested the presence of other genetic or environmental factors. In their family, <a href="#5" class="mim-tip-reference" title="Brusse, E., Majoor-Krakauer, D., de Graaf, B. M., Visser, G. H., Swagemakers, S., Boon, A. J. W., Oostra, B. A., Bertoli-Avella, A. M. <strong>A novel 16p locus associated with BSCL2 hereditary motor neuronopathy: a genetic modifier?</strong> Neurogenetics 10: 289-297, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19396477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19396477</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19396477[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/10.1007/s10048-009-0193-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19396477">Brusse et al. (2009)</a> used genomewide linkage analysis to identify a candidate disease modifier on chromosome 16p13.3-p13.12 between SNPs <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs6500882;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs6500882</a> and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs7192086;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs7192086</a> that was shared by all 12 affected individuals (maximum lod score of 3.28). One family member without the N88S mutation but with the chromosome 16p haplotype showed mild electrophysiologic abnormalities. <a href="#5" class="mim-tip-reference" title="Brusse, E., Majoor-Krakauer, D., de Graaf, B. M., Visser, G. H., Swagemakers, S., Boon, A. J. W., Oostra, B. A., Bertoli-Avella, A. M. <strong>A novel 16p locus associated with BSCL2 hereditary motor neuronopathy: a genetic modifier?</strong> Neurogenetics 10: 289-297, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19396477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19396477</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19396477[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/10.1007/s10048-009-0193-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19396477">Brusse et al. (2009)</a> postulated that a locus on chromosome 16p may contain a disease modifier in their family. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19396477+16427281+15732094" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Chaudhry, R., Kidambi, A., Brewer, M. H., Antonellis, A., Mathews, K., Nicholson, G., Kennerson, M. <strong>Re-analysis of an original CMTX3 family using exome sequencing identifies a known BSCL2 mutation.</strong> Muscle Nerve 47: 922-924, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23553728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23553728</a>] [<a href="https://doi.org/10.1002/mus.23743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23553728">Chaudhry et al. (2013)</a> identified a heterozygous N88S mutation in a man with SPG17. He had onset of weakness of the hands and feet at around 12 years of age. Examination at age 14 showed distal weakness and wasting with clawed hands and flat feet, extensor plantar responses, mild tremor, and distal sensory impairment. The disorder was slowly progressive, and he remained ambulatory with orthotics at age 36. His affected uncle also carried the mutation, as did his unaffected mother, suggesting incomplete penetrance. The mutation was identified by exome sequencing of the proband. The family was originally reported by <a href="#13" class="mim-tip-reference" title="Ionasescu, V. V., Trofatter, J., Haines, J. L., Summers, A. M., Ionasescu, R., Searby, C. <strong>Heterogeneity in X-linked recessive Charcot-Marie-Tooth neuropathy.</strong> Am. J. Hum. Genet. 48: 1075-1083, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1674639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1674639</a>]" pmid="1674639">Ionasescu et al. (1991)</a> as having an X-linked form of CMT (<a href="/entry/302802">302802</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1674639+23553728" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0014 SILVER SPASTIC PARAPLEGIA 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">rs137852973 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852973;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=rs137852973" 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=rs137852973" 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=RCV000004803 OR RCV000235980 OR RCV000547334 OR RCV000755016 OR RCV001270681 OR RCV001813950 OR RCV003311647 OR RCV004766979" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004803, RCV000235980, RCV000547334, RCV000755016, RCV001270681, RCV001813950, RCV003311647, RCV004766979" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004803...</a>
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<p>In affected members of a Belgian family and a Brazilian family with Silver spastic paraplegia syndrome (SPG17; <a href="/entry/270685">270685</a>), <a href="#25" class="mim-tip-reference" title="Windpassinger, C., Auer-Grumbach, M., Irobi, J., Patel, H., Petek, E., Horl, G., Malli, R., Reed, J. A., Dierick, I., Verpoorten, N., Warner, T. T., Proukakis, C., Van den Bergh, P., Verellen, C., Van Maldergem, L., Merlini, L., De Jonghe, P., Timmerman, V., Crosby, A. H., Wagner, K. <strong>Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome.</strong> Nature Genet. 36: 271-276, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14981520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14981520</a>] [<a href="https://doi.org/10.1038/ng1313" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14981520">Windpassinger et al. (2004)</a> identified heterozygosity for a c.269C-T transition (c.269C-T, NM_032667) in the BSCL2 gene, resulting in a ser90-to-leu (S90L) mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14981520" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an Italian mother and her 2 affected daughters with variable manifestations of autosomal dominant distal hereditary motor neuronopathy-13 (HMND13; <a href="/entry/619112">619112</a>), <a href="#19" class="mim-tip-reference" title="Luigetti, M., Fabrizi, G. M., Madia, F., Ferrarini, M., Conte, A., Delgrande, A., Tonali, P. A., Sabatelli, M. <strong>Seipin S90L mutation in an Italian family with CMT2/dHMN and pyramidal signs.</strong> Muscle Nerve 42: 448-451, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20806400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20806400</a>] [<a href="https://doi.org/10.1002/mus.21734" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20806400">Luigetti et al. (2010)</a> identified a heterozygous S90L mutation in the BSCL2 gene. The mutation was found by sequence analysis of candidate genes. Functional studies of the variant and studies of patient cells were not performed. The patients had predominant motor impairment with distal muscle weakness and atrophy of the upper and lower limbs, as well as features of spasticity. One had subclinical sensory impairment, thus expanding the phenotypic spectrum associated with this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20806400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0015 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 2</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> rs137852974 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852974;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/rs137852974?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=rs137852974" 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=rs137852974" 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=RCV000004804 OR RCV003311648" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004804, RCV003311648" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004804...</a>
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<p>In 3 Japanese patients with Berardinelli-Seip congenital generalized lipodystrophy (CGL2; <a href="/entry/269700">269700</a>) from independent families, <a href="#9" class="mim-tip-reference" title="Ebihara, K., Kusakabe, T., Masuzaki, H., Kobayashi, N., Tanaka, T., Chusho, H., Miyanaga, F., Miyazawa, T., Hayashi, T., Hosoda, K., Ogawa, Y., Nakao, K. <strong>Gene and phenotype analysis of congenital generalized lipodystrophy in Japanese: a novel homozygous nonsense mutation in seipin gene.</strong> J. Clin. Endocr. Metab. 89: 2360-2364, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15126564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15126564</a>] [<a href="https://doi.org/10.1210/jc.2003-031211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15126564">Ebihara et al. (2004)</a> identified a homozygous C-to-T transition in exon 8 of the BSCL2 gene that resulted in premature termination of seipin at codon 275 (R275X). Analysis of microsatellite markers and SNPs demonstrated common ancestry. The authors stated that their study was the first report on gene and phenotype analysis of congenital generalized lipodystrophy in Japanese. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15126564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0016" class="mim-anchor"></a>
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<strong>.0016 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 2</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> rs137852975 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852975;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/rs137852975?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=rs137852975" 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=rs137852975" 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=RCV000004805 OR RCV000196081 OR RCV003311649" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004805, RCV000196081, RCV003311649" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004805...</a>
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<p>In a Chinese infant with Berardinelli-Seip congenital generalized lipodystrophy (CGL2; <a href="/entry/269700">269700</a>), <a href="#10" class="mim-tip-reference" title="Friguls, B., Coroleu, W., del Alcazar, R., Hilbert, P., Van Maldergem, L., Pintos-Morell, G. <strong>Severe cardiac phenotype of Berardinelli-Seip congenital lipodystrophy in an infant with homozygous E189X BSCL2 mutation.</strong> Europ. J. Med. Genet. 52: 14-16, 2009. Note: Erratum: Europ. J. Med. Genet. 52: 278-279, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19041432/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19041432</a>] [<a href="https://doi.org/10.1016/j.ejmg.2008.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19041432">Friguls et al. (2009)</a> identified a homozygous 565G-T transversion in exon 5 of the BSCL2 gene, resulting in a glu189-to-ter (E189X) substitution. In addition to classic features of the disorder, the patient had hypertension, an apical murmur, and severe obstructive and asymmetric septal hypertrophic cardiomyopathy. The authors emphasized the early onset of severe cardiac disease in this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19041432" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="Jin, J., Cao, L., Zhao, Z., Shen, S., Kiess, W., Zhi, D., Ye, R., Cheng, R., Chen, L., Yang, Y., Luo, F. <strong>Novel BSCL2 gene mutation E189X in Chinese congenital generalized lipodystrophy child with early onset diabetes mellitus.</strong> Europ. J. Endocr. 157: 783-787, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18057387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18057387</a>] [<a href="https://doi.org/10.1530/EJE-07-0393" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18057387">Jin et al. (2007)</a> had identified the E189X mutation in another Chinese boy with congenital generalized lipodystrophy with early-onset diabetes mellitus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18057387" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0017" class="mim-anchor"></a>
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<strong>.0017 ENCEPHALOPATHY, PROGRESSIVE, WITH OR WITHOUT LIPODYSTROPHY</strong>
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</h4>
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BSCL2, 985C-T
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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> rs587777606 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777606;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/rs587777606?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=rs587777606" 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=rs587777606" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000133397 OR RCV000412493 OR RCV000800475 OR RCV003311693" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000133397, RCV000412493, RCV000800475, RCV003311693" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000133397...</a>
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<p>In 2 unrelated children from Murcia in southeastern Spain with autosomal recessive progressive encephalopathy, with and without lipodystrophy, respectively (PELD; <a href="/entry/615924">615924</a>), <a href="#12" class="mim-tip-reference" title="Guillen-Navarro, E., Sanchez-Iglesias, S., Domingo-Jimenez, R., Victoria, B., Ruiz-Riquelme, A., Rabano, A., Loidi, L., Beiras, A., Gonzalez-Mendez, B., Ramos, A., Lopez-Gonzalez, V., Ballesta-Martinez, M. J., Garrido-Pumar, M., Aguiar, P., Ruibal, A., Requena, J. R., Araujo-Vilar, D. <strong>A new seipin-associated neurodegenerative syndrome.</strong> J. Med. Genet. 50: 401-409, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23564749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23564749</a>] [<a href="https://doi.org/10.1136/jmedgenet-2013-101525" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23564749">Guillen-Navarro et al. (2013)</a> identified a homozygous c.985C-T transition in the BSCL2 gene, predicted to result in an arg329-to-ter (R329X) substitution. The c.985C-T transition also causes an aberrant splicing site, resulting in the skipping of exon 7 and premature termination (Tyr289LeufsTer64). Each unaffected parent was heterozygous for the mutation, which was also found in 8 ethnically matched controls (allele frequency of 0.012). Patient cells showed increased expression of the exon 7-skipping transcript. Expression of the mutation in HeLa cells showed that the mutant protein localized to the nucleus. The c.985C-T mutation was also found in compound heterozygosity with another pathogenic truncating BSCL2 mutation (<a href="#0018">606158.0018</a> and <a href="#0019">606158.0019</a>) in 4 additional children with a similar phenotype from 2 families from the Murcia region. Haplotype analysis suggested a founder effect for the c.985C-T transition in the Murcia population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23564749" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0018" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0018 ENCEPHALOPATHY, PROGRESSIVE, WITH LIPODYSTROPHY</strong>
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</h4>
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BSCL2, GLU180TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587777607 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777607;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=rs587777607" 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=rs587777607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000133398 OR RCV003311694" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000133398, RCV003311694" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000133398...</a>
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</span>
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<span class="mim-text-font">
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<p>In the unaffected parents of a boy from Murcia, Spain, with autosomal recessive progressive encephalopathy with lipodystrophy (PELD; <a href="/entry/615924">615924</a>), <a href="#12" class="mim-tip-reference" title="Guillen-Navarro, E., Sanchez-Iglesias, S., Domingo-Jimenez, R., Victoria, B., Ruiz-Riquelme, A., Rabano, A., Loidi, L., Beiras, A., Gonzalez-Mendez, B., Ramos, A., Lopez-Gonzalez, V., Ballesta-Martinez, M. J., Garrido-Pumar, M., Aguiar, P., Ruibal, A., Requena, J. R., Araujo-Vilar, D. <strong>A new seipin-associated neurodegenerative syndrome.</strong> J. Med. Genet. 50: 401-409, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23564749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23564749</a>] [<a href="https://doi.org/10.1136/jmedgenet-2013-101525" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23564749">Guillen-Navarro et al. (2013)</a> identified heterozygous mutations in the BSCL2 gene: 1 parent carried a c.538G-T transversion, resulting in a glu180-to-ter (E180X) substitution, and the other carried a c.985C-T transition (<a href="#0017">606158.0017</a>) resulting in premature termination. The patient, who died at 8 years of age, was presumed to be compound heterozygous for the mutations, but DNA was not available. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23564749" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0019" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0019 ENCEPHALOPATHY, PROGRESSIVE, WITH LIPODYSTROPHY</strong>
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</span>
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</h4>
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<div>
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BSCL2, 5-BP DEL, NT507
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000004793 OR RCV000133399 OR RCV001091624 OR RCV003311638 OR RCV005089168" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004793, RCV000133399, RCV001091624, RCV003311638, RCV005089168" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004793...</a>
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<span class="mim-text-font">
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<p>In a 3-year-old girl from Murcia, Spain, with autosomal recessive progressive encephalopathy with lipodystrophy (PELD; <a href="/entry/615924">615924</a>), <a href="#12" class="mim-tip-reference" title="Guillen-Navarro, E., Sanchez-Iglesias, S., Domingo-Jimenez, R., Victoria, B., Ruiz-Riquelme, A., Rabano, A., Loidi, L., Beiras, A., Gonzalez-Mendez, B., Ramos, A., Lopez-Gonzalez, V., Ballesta-Martinez, M. J., Garrido-Pumar, M., Aguiar, P., Ruibal, A., Requena, J. R., Araujo-Vilar, D. <strong>A new seipin-associated neurodegenerative syndrome.</strong> J. Med. Genet. 50: 401-409, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23564749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23564749</a>] [<a href="https://doi.org/10.1136/jmedgenet-2013-101525" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23564749">Guillen-Navarro et al. (2013)</a> identified compound heterozygous mutations in the BSCL2 gene: a 5-bp deletion (c.507_511del), resulting in a frameshift and premature termination (Tyr170CysfsTer6), and a c.985C-T transition (<a href="#0017">606158.0017</a>), resulting in premature termination. Each unaffected parent was heterozygous for 1 of the mutations. The patient had 2 uncles with a similar disorder, who both died in childhood; DNA was not available from these patients, but analysis of their unaffected parents showed that each was heterozygous for 1 of the mutations found in the girl, suggesting that the uncles were compound heterozygous for the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23564749" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0020" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0020 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 13</strong>
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</span>
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BSCL2, SER90TRP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852973 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852973;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=rs137852973" 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=rs137852973" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000536990 OR RCV000789082 OR RCV001270682 OR RCV002284966 OR RCV003311850" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000536990, RCV000789082, RCV001270682, RCV002284966, RCV003311850" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000536990...</a>
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<span class="mim-text-font">
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<p>In affected members of a multigenerational Korean family with autosomal dominant distal hereditary motor neuronopathy-13 (HMND13; <a href="/entry/619112">619112</a>) and features of axonal Charcot-Marie-Tooth disease type 2 (CMT2), <a href="#7" class="mim-tip-reference" title="Choi, B.-O., Park, M.-H., Chung, K. W., Woo, H.-M., Koo, H., Chung, H.-K., Choi, K.-G., Park, K. D., Lee, H. J., Hyun, Y. S., Koo, S. K. <strong>Clinical and histopathological study of Charcot-Marie-Tooth neuropathy with a novel S90W mutation in BSCL2.</strong> Neurogenetics 14: 35-42, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23142943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23142943</a>] [<a href="https://doi.org/10.1007/s10048-012-0346-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23142943">Choi et al. (2013)</a> identified a heterozygous c.269C-G transversion (c.269C-G, NM_032667.6) in exon 3 of the BSCL2 gene, resulting in a ser90-to-trp (S90W) substitution. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the affected residue is the same as the previously identified S90L mutation (<a href="#0014">606158.0014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23142943" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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Choi, B.-O., Park, M.-H., Chung, K. W., Woo, H.-M., Koo, H., Chung, H.-K., Choi, K.-G., Park, K. D., Lee, H. J., Hyun, Y. S., Koo, S. K.
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<strong>Clinical and histopathological study of Charcot-Marie-Tooth neuropathy with a novel S90W mutation in BSCL2.</strong>
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Neurogenetics 14: 35-42, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23142943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23142943</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23142943" 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/10.1210/jc.2003-030485" target="_blank">Full Text</a>]
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Guillen-Navarro, E., Sanchez-Iglesias, S., Domingo-Jimenez, R., Victoria, B., Ruiz-Riquelme, A., Rabano, A., Loidi, L., Beiras, A., Gonzalez-Mendez, B., Ramos, A., Lopez-Gonzalez, V., Ballesta-Martinez, M. J., Garrido-Pumar, M., Aguiar, P., Ruibal, A., Requena, J. R., Araujo-Vilar, D.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18585921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18585921</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18585921" 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.nbd.2008.05.004" target="_blank">Full Text</a>]
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Ito, D., Suzuki, N.
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<strong>Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases.</strong>
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[<a href="https://doi.org/10.1002/ana.21070" target="_blank">Full Text</a>]
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Ito, D., Suzuki, N.
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<strong>Seipinopathy: a novel endoplasmic reticulum stress-associated disease.</strong>
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Brain 132: 8-15, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18790819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18790819</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18790819" 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/awn216" target="_blank">Full Text</a>]
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Jin, J., Cao, L., Zhao, Z., Shen, S., Kiess, W., Zhi, D., Ye, R., Cheng, R., Chen, L., Yang, Y., Luo, F.
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<strong>Novel BSCL2 gene mutation E189X in Chinese congenital generalized lipodystrophy child with early onset diabetes mellitus.</strong>
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Europ. J. Endocr. 157: 783-787, 2007.
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[<a href="https://doi.org/10.1530/EJE-07-0393" target="_blank">Full Text</a>]
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Lawrence, R. D.
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<strong>Lipodystrophy and hepatomegaly with diabetes, lipaemia, and other metabolic disturbances: a case throwing new light on the action of insulin.</strong>
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Luigetti, M., Fabrizi, G. M., Madia, F., Ferrarini, M., Conte, A., Delgrande, A., Tonali, P. A., Sabatelli, M.
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<strong>Seipin S90L mutation in an Italian family with CMT2/dHMN and pyramidal signs.</strong>
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Muscle Nerve 42: 448-451, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20806400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20806400</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20806400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/mus.21734" target="_blank">Full Text</a>]
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Lundin, C., Nordstrom, R., Wagner, K., Windpassinger, C., Andersson, H., von Heijne, G., Nilsson, I.
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<strong>Membrane topology of the human seipin protein.</strong>
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FEBS Lett. 580: 2281-2284, 2006.
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[<a href="https://doi.org/10.1016/j.febslet.2006.03.040" target="_blank">Full Text</a>]
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Magre, J., Delepine, M., Khallouf, E., Gedde-Dahl, T., Jr., Van Maldergem, L., Sobel, E., Papp, J., Meier, M., Megarbane, A., BSCL Working Group, Lathrop, M., Capeau, J.
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<strong>Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.</strong>
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Nature Genet. 28: 365-370, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479539</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11479539" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng585" target="_blank">Full Text</a>]
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Silver, J. R.
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<strong>Familial spastic paraplegia with amyotrophy of the hands.</strong>
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Ann. Hum. Genet. 30: 69-75, 1966.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5964029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5964029</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5964029" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1469-1809.1966.tb00007.x" target="_blank">Full Text</a>]
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Szymanski, K. M., Binns, D., Bartz, R., Grishin, N. V., Li, W.-P., Agarwal, A. K., Garg, A., Anderson, R. G. W., Goodman, J. M.
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<strong>The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology.</strong>
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Proc. Nat. Acad. Sci. 104: 20890-20895, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18093937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18093937</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18093937[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=18093937" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0704154104" target="_blank">Full Text</a>]
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Van de Warrenburg, B. P. C., Scheffer, H., van Eijk, J. J. J., Versteeg, M. H. A., Kremer, H., Zwarts, M. J., Schelhaas, H. J., van Engelen, B. G. M.
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<strong>BSCL2 mutations in two Dutch families with overlapping Silver syndrome-distal hereditary motor neuropathy.</strong>
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Neuromusc. Disord. 16: 122-125, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16427281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16427281</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16427281" 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.2005.11.003" target="_blank">Full Text</a>]
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Windpassinger, C., Auer-Grumbach, M., Irobi, J., Patel, H., Petek, E., Horl, G., Malli, R., Reed, J. A., Dierick, I., Verpoorten, N., Warner, T. T., Proukakis, C., Van den Bergh, P., Verellen, C., Van Maldergem, L., Merlini, L., De Jonghe, P., Timmerman, V., Crosby, A. H., Wagner, K.
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<strong>Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome.</strong>
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Nature Genet. 36: 271-276, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14981520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14981520</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14981520" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1313" target="_blank">Full Text</a>]
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Windpassinger, C., Wagner, K., Petek, E., Fischer, R., Auer-Grumbach, M.
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<strong>Refinement of the 'Silver syndrome locus' on chromosome 11q12-q14 in four families and exclusion of eight candidate genes.</strong>
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Hum. Genet. 114: 99-109, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13680364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13680364</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13680364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00439-003-1021-6" target="_blank">Full Text</a>]
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Yang, W., Thein, S., Wang, X., Bi, X., Ericksen, R. E., Xu, F., Han, W.
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<strong>BSCL2/seipin regulates adipogenesis through actin cytoskeleton remodelling.</strong>
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Hum. Molec. Genet. 23: 502-513, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24026679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24026679</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24026679" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddt444" target="_blank">Full Text</a>]
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Zhou, L., Yin, J., Wang, C., Liao, J., Liu, G., Chen, L.
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<strong>Lack of seipin in neurons results in anxiety- and depression-like behaviors via down regulation of PPAR-gamma.</strong>
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Hum. Molec. Genet. 23: 4094-4102, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24651066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24651066</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24651066" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddu126" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 12/01/2020
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Patricia A. Hartz - updated : 10/10/2014<br>Patricia A. Hartz - updated : 9/2/2014<br>Cassandra L. Kniffin - updated : 8/11/2014<br>Cassandra L. Kniffin - updated : 4/29/2013<br>Patricia A. Hartz - updated : 4/10/2013<br>Cassandra L. Kniffin - updated : 3/18/2010<br>Cassandra L. Kniffin - updated : 12/10/2009<br>Cassandra L. Kniffin - updated : 6/9/2009<br>Cassandra L. Kniffin - updated : 4/4/2008<br>Patricia A. Hartz - updated : 2/28/2008<br>Cassandra L. Kniffin - updated : 10/11/2007<br>John A. Phillips, III - updated : 4/5/2006<br>John A. Phillips, III - updated : 7/21/2005<br>Cassandra L. Kniffin - updated : 5/18/2005<br>Victor A. McKusick - updated : 2/23/2004<br>Victor A. McKusick - updated : 8/12/2002
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Ada Hamosh : 7/30/2001
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alopez : 12/17/2020<br>alopez : 12/17/2020<br>ckniffin : 12/01/2020<br>carol : 08/09/2018<br>carol : 10/23/2015<br>alopez : 5/1/2015<br>mcolton : 4/17/2015<br>mgross : 10/13/2014<br>mcolton : 10/10/2014<br>mgross : 9/3/2014<br>mcolton : 9/2/2014<br>carol : 8/12/2014<br>mcolton : 8/12/2014<br>ckniffin : 8/11/2014<br>carol : 7/8/2013<br>carol : 4/29/2013<br>carol : 4/29/2013<br>ckniffin : 4/29/2013<br>mgross : 4/10/2013<br>carol : 8/1/2012<br>carol : 9/10/2010<br>carol : 4/2/2010<br>wwang : 3/23/2010<br>ckniffin : 3/18/2010<br>wwang : 12/28/2009<br>ckniffin : 12/10/2009<br>terry : 7/22/2009<br>wwang : 6/25/2009<br>ckniffin : 6/9/2009<br>terry : 4/3/2009<br>wwang : 4/14/2008<br>ckniffin : 4/4/2008<br>wwang : 2/28/2008<br>terry : 11/15/2007<br>wwang : 10/22/2007<br>ckniffin : 10/11/2007<br>alopez : 4/5/2006<br>alopez : 7/21/2005<br>tkritzer : 5/31/2005<br>ckniffin : 5/18/2005<br>terry : 6/18/2004<br>carol : 5/5/2004<br>carol : 5/5/2004<br>ckniffin : 4/28/2004<br>alopez : 4/1/2004<br>ckniffin : 3/31/2004<br>carol : 3/9/2004<br>joanna : 2/26/2004<br>tkritzer : 2/25/2004<br>terry : 2/23/2004<br>carol : 8/15/2002<br>tkritzer : 8/15/2002<br>tkritzer : 8/14/2002<br>terry : 8/12/2002<br>alopez : 7/30/2001
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<h3>
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<span class="mim-font">
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<strong>*</strong> 606158
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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BSCL2 GENE; BSCL2
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</span>
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</h3>
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</div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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SEIPIN<br />
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GNG3LG, MOUSE, HOMOLOG OF
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</h4>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: BSCL2</em></strong>
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</span>
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</p>
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</div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 230263009;
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<p>
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<strong>
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<em>
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Cytogenetic location: 11q12.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 11:62,690,262-62,709,537 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<td rowspan="4">
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<span class="mim-font">
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11q12.3
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<td>
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<span class="mim-font">
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Encephalopathy, progressive, with or without lipodystrophy
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</span>
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</td>
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<td>
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<span class="mim-font">
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615924
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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Lipodystrophy, congenital generalized, type 2
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</span>
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</td>
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<td>
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<span class="mim-font">
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269700
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</td>
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<td>
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<span class="mim-font">
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3
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<tr>
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<td>
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<span class="mim-font">
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Neuronopathy, distal hereditary motor, autosomal dominant 13
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</span>
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</td>
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<td>
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<span class="mim-font">
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619112
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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Silver spastic paraplegia syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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270685
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</tbody>
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</table>
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<br />
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>BSCL2, or seipin, is an endoplasmic reticulum (ER)-resident protein that is induced in late stages of preadipocyte differentiation and is predicted to function in lipid droplet formation and/or metabolism (summary by Cui et al., 2011). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Within a 2.5-Mb critical region for Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2; 269700), Magre et al. (2001) identified a gene that is homologous to the mouse 'gamma-3-linked gene' (Gng3lg). Magre et al. (2001) found that the BSCL2 open reading frame encodes a deduced 398-amino acid protein, seipin, with at least 2 hydrophobic amino acid stretches, indicating that it could be a transmembrane protein. It has 87% identity to the mouse Gng3lg product, and partial homology to Drosophila CG9904 protein. Using Northern blot analysis, Magre et al. (2001) observed highest expression in brain and testis. Dot-blot analysis indicated that the BSCL2 gene is highly expressed in most regions of the central nervous system. Magre et al. (2001) identified a putative initiation codon located in the second exon. Agarwal and Garg (2004) noted that an alternative upstream initiation codon could extend the seipin protein by 64 amino acids at the putative N terminus. </p><p>By Northern blot analysis, Windpassinger et al. (2004) detected a 1.8-kb brain-specific transcript in all brain regions examined and a 2.2-kb transcript in placenta, lung, liver, skeletal muscle, kidney, and pancreas. Fluorescence microscopy showed seipin and calreticulin (109091) colocalized in the endoplasmic reticulum (ER) of transfected human umbilical vein endothelial cells. They identified a conserved N-glycosylation site at residues 88 to 90. </p><p>Lundin et al. (2006) found that the predominant form of seipin is 462 residues in length, and is generated by an initiation site upstream of the site found originally. </p><p>By immunoblot analysis of mouse and human cells transfected with full-length BSCL2, Ito and Suzuki (2007) detected full-length seipin as a 74-kD band and N- and C-terminal fragments of seipin between 35 and 48 kD, suggesting that seipin is highly modified after translation. Seipin immunoreactivity was present in anterior horns of mouse spinal cord and clearly localized to the endoplasmic reticulum. Transiently expressed human seipin appeared to be proteolytically cleaved into an N-terminal fragment, and full-length seipin was polyubiquitinated in cultured neuronal and nonneuronal cells. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Ito et al. (2008) found expression of seipin in cortical neurons of human frontal lobe and motor neurons of human spinal cord. Seipin immunostaining was also observed specifically in mouse spermatids and cells of the anterior lobe of the mouse pituitary gland. Cellular studies in HeLa cells and mouse neuroblastoma cells indicated that seipin has a glycosylated loop facing the ER lumen with both N and C termini facing the cytosol. The first transmembrane domain is necessary for ER retention. Neuronal and nonneuronal cells expressing the N88S (606158.0013) and S90L (606158.0014) mutant proteins showed that both mutant proteins localized correctly. Mutant cells also contained inclusion bodies that were found to be distinct from aggresomes. The second transmembrane domain was found to be critical for inclusion formation, and both transmembrane domains were critical for activation of the unfolded protein response (UPR). In a review of the function of seipin and its role in disease, Ito and Suzuki (2009) noted that seipin is an N-glycosylated protein that is proteolytically cleaved into N- and C-terminal fragments and is polyubiquitinated. </p><p>Yang et al. (2014) had previously found that mouse seipin promotes adipogenesis to accommodate storage of excess nutrients in the form of lipids, whereas it inhibits lipid droplet production and accumulation in preadipocytes and other nonadipocyte lineages. Using mass spectrometry to identify proteins that interacted with seipin in adipose tissue lysates, Yang et al. (2014) identified the scaffold protein 14-3-3-beta (YWHAB; 601289). Interaction of seipin with 14-3-3-beta did not depend on insulin stimulation. In insulin (INS; 176730)-stimulated 3T3-L1 mouse adipocytes, 14-3-3-beta interacted with the actin-severing protein cofilin-1 (CFL1; 601442), and this interaction required serine phosphorylation of cofilin-1. Adipogenesis in 3T3-L1 cells was accompanied by remodeling of the actin cytoskeleton from central stress fibers to the cell cortex, concomitant with lipid droplet accumulation. Knockdown of seipin, 14-3-3-beta, or cofilin-1 in 3T3-L1 cells impaired adipocyte development and inhibited lipid drop accumulation, but stress fibers remained intact. Impaired adipogenesis was also present in 3T3-L1 cells expressing a severing-resistant actin mutant. Yang et al. (2014) concluded that the interaction of seipin with 14-3-3-beta recruits cofilin-1 to remodel the actin cytoskeleton for adipocyte differentiation. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Magre et al. (2001) determined that the BSCL2 gene contains 11 exons spanning at least 14 kb. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Magre et al. (2001) reported that the BSCL2 gene is homologous to the mouse 'gamma-3-linked gene' (Gng3lg), which is localized in the region of mouse chromosome 19 orthologous to human 11q. By positional cloning, they located the BSCL2 gene within a 2.5-Mb critical region for a form of Berardinelli-Seip congenital lipodystrophy. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Congenital Generalized Lipodystrophy Type 2</em></strong></p><p>
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In chromosome 11q13-linked families with congenital generalized lipodystrophy type 2, and in 3 isolated patients, Magre et al. (2001) identified mutations in the BSCL2 gene (606158.0001-606158.0012). Most of the variants were null mutations predicted to result in the severe disruption of the protein. Affected individuals were either homozygous for a specific mutation or compound heterozygous; all parents of unaffected sibs carried only 1 mutation. Magre et al. (2001) did not find any mutation in affected individuals of the 9 families in which BSCL is not linked to 11q13 or in 13 additional patients who had been diagnosed with Lawrence syndrome (Lawrence, 1946), in which lipoatrophy is not present at birth but develops at a later age. </p><p>Fu et al. (2004) screened for mutations in AGPAT2 (603100) and BSCL2 in 27 families with congenital generalized lipodystrophy. They found mutations in either AGPAT2 or BSCL2 in all but 4 probands. Eighteen patients with congenital generalized lipodystrophy from 15 families from the same region of northeastern Brazil were homozygous for a frameshift mutation in BSCL2 (669insA; 606158.0006). Despite having the same mutation, the subjects had widely divergent clinical manifestations. Fu et al. (2004) concluded that there did not appear to be any distinguishing clinical characteristics between subjects with congenital generalized lipodystrophy with AGPAT2 or BSCL2 mutations, with the exception of mental retardation in carriers of BSCL2. </p><p>Szymanski et al. (2007) screened a yeast deletion library for aberrant lipid droplets and found that absence of yeast seipin resulted in irregular lipid droplets often clustered alongside proliferated ER; giant lipid droplets were also seen. Electron microscopy showed abnormal small irregular lipid droplets in fibroblasts from a BSCL2 patient with a 5-bp deletion (606158.0005). In yeast, almost all lipid droplets appeared to be on the ER, and seipin was found at these junctions. Human seipin could functionally replace yeast seipin, but A212P (606158.0009)-mutant human seipin that causes lipodystrophy could not. Szymanski et al. (2007) hypothesized that seipin is important for lipid droplet maintenance and perhaps assembly. </p><p><strong><em>Autosomal Dominant Distal Hereditary Motor Neuropathy 13 and Silver Syndrome</em></strong></p><p>
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In a large Austrian family with autosomal dominant distal hereditary motor neuropathy-13 (HMND13; 619112) reported by Auer-Grumbach et al. (2000), Windpassinger et al. (2003) established linkage of the disorder to 11q12-q14, a chromosomal region overlapping that of Silver spastic paraplegia syndrome (SPG17; 270685). Windpassinger et al. (2004) confirmed linkage to the SPG17 locus in 16 additional families with a phenotype characteristic of Silver syndrome. After refining the critical region to 1 Mb, Windpassinger et al. (2004) sequenced the BSCL2 gene, which lies within that region, and identified heterozygous missense mutations in the family with DSMAV and those with SPG17. The mutations N88S (606158.0013) and S90L (606158.0014) affected glycosylation of seipin and resulted in aggregate formation, predicted to cause neurodegeneration. Their findings indicated that Silver syndrome and some forms of dHMN are, in fact, extreme phenotypes resulting from mutations in the same gene. </p><p>In affected members of a multigenerational Korean family with autosomal dominant distal hereditary motor neuronopathy-13 (HMND13; 619112) and features of axonal Charcot-Marie-Tooth disease type 2 (CMT2), Choi et al. (2013) identified a heterozygous S90W mutation in the BSCL2 gene (606158.0020). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the affected residue is the same as the previously identified S90L mutation (606158.0014). </p><p><strong><em>Progressive Encephalopathy with or without Lipodystrophy</em></strong></p><p>
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In 6 children from 4 unrelated families from Murcia in southeastern Spain with autosomal recessive progressive encephalopathy with or without lipodystrophy (PELD; 615924), Guillen-Navarro et al. (2013) identified homozygous or compound heterozygous truncating mutations in the BSCL2 gene (606158.0017-606158.0019). All patients carried the same mutation (c.985C-T; 606158.0017) on at least 1 allele, consistent with a founder effect. The phenotype was severe, resulting in death of 5 children between ages 6 and 8 years. Most, but not all, patients had some evidence of lipodystrophy, but all 5 patients who died developed a progressive encephalopathy with psychomotor regression, loss of speech, cognitive decline, spasticity, and seizures between ages 2 and 3. </p><p><strong><em>Variant Function</em></strong></p><p>
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By in vitro functional expression analysis, Ito and Suzuki (2007) demonstrated that the N88S and S90L mutations in the BSCL2 gene disrupt glycosylation of the seipin protein. Overexpressed mutant seipin was highly ubiquitinated and degraded by the proteasome, and improper glycosylation exacerbated endoplasmic reticulum retention. Mutant proteins activated the unfolded protein response, resulting in apoptotic cell death through ER stress. Ito and Suzuki (2007) concluded that the N88S and S90L mutations, which result in motor neuron disease, have a gain-of-function effect, resulting in conformational protein changes, activation of the unfolded protein response, cell death, and neurodegeneration. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Cui et al. (2011) obtained seipin -/- mice at the expected mendelian ratio. Seipin -/- mice were growth delayed, but they eventually achieved normal weight. They showed significantly reduced adipose tissue mass, including about 60% reduction in brown adipose tissue, glucose intolerance, hyperinsulinemia, and hepatic steatosis, with elevated expression of select lipogenic genes. Levels of leptin (LEP; 164160) and adiponectin (ADIPOQ; 605441) were significantly decreased in seipin -/- mice, as were nonesterified fatty acids upon fasting. Hypertriglyceridemia, which is common in human BSCL, was not observed in seipin -/- mice. </p><p>Zhou et al. (2014) found that male, but not female, neuron-specific seipin-knockout mice displayed anxiety- and depression-like behaviors. Male, but not female, neuron-specific seipin-knockout mice also showed reduced mRNA and protein levels of Pparg (601487) in hippocampus and cortex. Treatment of male neuron-specific seipin-knockout mice with 17-beta-estradiol or a Pparg agonist alleviated affective disorders. Ovariectomy resulted in anxiety- and depression-like behaviors and reduced Pparg levels in female neuron-specific seipin-knockout mice. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>20 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BSCL2, 2-BP DEL/3-BP INS, NT536
|
|
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|
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|
<br />
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|
|
|
SNP: rs786205068,
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|
|
|
|
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|
|
ClinVar: RCV000004789, RCV003311635
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 families with Berardinelli-Seip congenital lipodystrophy (CGL2; 269700), 1 from eastern Norway and 1 from Italy, Magre et al. (2001) found homozygosity for a mutation in exon 2 of the BSCL2 gene, the replacement of 2 CC nucleotides at position 536 with 3 nucleotides (GGA), resulting in a frameshift following phenylalanine-63 with a termination codon at amino acid 75. They also found the mutation in heterozygous state in 2 affected families from southwestern Norway and the United Kingdom, respectively. The phenotype presented at birth in the Norwegian and U.K. families and before 9 months of age in the Italian family. </p>
|
|
</span>
|
|
</div>
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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>.0002 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
BSCL2, 2-BP INS, 645AA
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|
<br />
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|
|
SNP: rs786205069,
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|
|
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|
|
ClinVar: RCV000004790, RCV003311636
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a consanguineous Brazilian family with Berardinelli-Seip congenital lipodystrophy (CGL2; 269700), Magre et al. (2001) found homozygosity for an insertion of 2 adenines at nucleotide 645 of the BSCL2 gene, resulting in a frameshift and premature termination at codon 111. </p>
|
|
</span>
|
|
</div>
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|
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|
|
|
<div>
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|
<br />
|
|
</div>
|
|
|
|
</div>
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|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BSCL2, 2-BP DEL, 659GT
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs786205070,
|
|
|
|
|
|
gnomAD: rs786205070,
|
|
|
|
|
|
ClinVar: RCV000004791, RCV003311637
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a French family segregating Berardinelli-Seip congenital lipodystrophy (CGL2; 269700), Magre et al. (2001) identified compound heterozygosity for mutations in the BSCL2 gene: deletion of 2 basepairs (GT) at nucleotide 659, resulting in a frameshift and premature termination at codon 112; and a 258-bp deletion/12-bp insertion in exons 5-6 (606158.0004). </p>
|
|
</span>
|
|
</div>
|
|
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|
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|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BSCL2, 258-BP DEL/12-BP INS
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000004792
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 258-bp deletion/12-bp insertion in exons 5-6 of the BSCL2 gene that was found in compound heterozygous state in a family segregating Berardinelli-Seip congenital lipodystrophy (CGL2; 269700) by Magre et al. (2001), see 606158.0003. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BSCL2, 5-BP DEL, NT659
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587777608,
|
|
|
|
|
|
|
|
ClinVar: RCV000004793, RCV000133399, RCV001091624, RCV003311638, RCV005089168
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Magre et al. (2001) found that all Lebanese patients with Berardinelli-Seip congenital lipodystrophy (CGL2; 269700) whom they studied were homozygous for a frameshift mutation resulting from the deletion of GTATC at nucleotide 659 of the BSCL2 gene. </p><p>In fibroblasts from a BSCL2 patient with the 5-bp deletion, Szymanski et al. (2007) found abnormal cytoplasmic lipid droplets. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BSCL2, 1-BP INS, 669A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs786205071,
|
|
|
|
|
|
gnomAD: rs786205071,
|
|
|
|
|
|
ClinVar: RCV000004794, RCV002496260, RCV002512772, RCV003311639
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 South African Portuguese families with Berardinelli-Seip congenital lipodystrophy (CGL2; 269700), Magre et al. (2001) found homozygosity for a frameshift resulting from insertion of an adenine at nucleotide 669 of the BSCL2 gene. </p><p>Bhayana et al. (2002) described the same mutation in a 10-year-old girl from Canada whose parents were not known to be consanguineous, although they came from the same region of Portugal. The family history was positive for BSCL on both sides of the family. Her father had 2 affected male cousins who were born to consanguineous parents and died in childhood. Another affected female first cousin of the father died at 30 years of age with renal failure. An affected male, the second cousin of the patient's mother, died at 28 years of age. In addition to having the typical attributes of complete lipodystrophy, the patient had been diagnosed with hypertrophic cardiomyopathy in the first year of life. A relationship between congenital lipodystrophy syndromes and cardiac disorders is suggested by the fact that mutations in lamin A/C (LMNA; 150330) cause either lipodystrophy or cardiomyopathy. </p><p>Fu et al. (2004) found this mutation in 18 patients from 15 Caucasian families from the same region of Serido county of Rio Grande do Norte State in northeastern Brazil. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BSCL2, ARG138TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852970,
|
|
|
|
|
|
gnomAD: rs137852970,
|
|
|
|
|
|
ClinVar: RCV000004795, RCV002298433, RCV002326662, RCV003311640
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a French Portuguese family and 2 additional Portuguese families with Berardinelli-Seip congenital lipodystrophy (CGL2; 269700), Magre et al. (2001) identified homozygosity for an arg138-to-stop mutation that resulted from a C-to-T transition at nucleotide 756 of the BSCL2 gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BSCL2, IVS4, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1945400235,
|
|
|
|
|
|
|
|
ClinVar: RCV000004796, RCV003311641
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a consanguineous Turkish family segregating Berardinelli-Seip congenital lipodystrophy (CGL2; 269700), Magre et al. (2001) identified a G-to-A transition at the +1 position of intron 4, resulting in skipping of exon 4. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BSCL2, ALA212PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852971,
|
|
|
|
|
|
gnomAD: rs137852971,
|
|
|
|
|
|
ClinVar: RCV000004797, RCV003311642, RCV003581554, RCV005049316
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 southwestern Norwegian families segregating Berardinelli-Seip congenital lipodystrophy (CGL2; 269700), Magre et al. (2001) identified a G-to-C transversion at nucleotide 978 of the BSCL2 gene, resulting in an alanine-to-proline substitution at codon 212. This mutation was found in homozygosity in 3 of the families and in compound heterozygosity in 1. The condition manifested at birth in these families. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BSCL2, 1-BP DEL, 980C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs758843908,
|
|
|
|
|
|
gnomAD: rs758843908,
|
|
|
|
|
|
ClinVar: RCV000004798, RCV001851654, RCV003311643
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a consanguineous Indian family segregating Berardinelli-Seip congenital lipodystrophy (CGL2; 269700), Magre et al. (2001) identified homozygosity for a mutation in the BSCL2 gene, the deletion of a C at nucleotide 980 resulting in a frameshift at codon 213 and premature termination at codon 232. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BSCL2, IVS6, G-A, +5
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs786205072,
|
|
|
|
|
|
|
|
ClinVar: RCV000004799, RCV001847581, RCV003311644, RCV005049317
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a British family segregating Berardinelli-Seip congenital lipodystrophy (CGL2; 269700), Magre et al. (2001) identified a G-to-A transition at the +5 position of intron 6 of the BSCL2 gene, which resulted in activation of a cryptic splice site leading to premature termination at codon 225. The patient was compound heterozygous for this mutation, and the condition manifested at birth. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BSCL2, IVS6, C-G, -3
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs786205073,
|
|
|
|
|
|
|
|
ClinVar: RCV000004800, RCV003311645
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Turkish French family segregating Berardinelli-Seip congenital lipodystrophy (CGL2; 269700), Magre et al. (2001) identified homozygosity for a C-to-G transversion at the -3 position of intron 6. This mutation resulted in skipping of exon 7. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 SILVER SPASTIC PARAPLEGIA SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 13, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BSCL2, ASN88SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852972,
|
|
|
|
|
|
gnomAD: rs137852972,
|
|
|
|
|
|
ClinVar: RCV000004801, RCV000004802, RCV000168078, RCV000340485, RCV000507071, RCV001270680, RCV001813949, RCV001847582, RCV002426488, RCV003311646, RCV004795375
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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 affected members of 1 English and 4 Austrian families with Silver spastic paraplegia syndrome (SPG17; 270685), Windpassinger et al. (2004) identified heterozygosity for a 263A-G transition (c.263A-G, NM_032667) in the BSCL2 gene, resulting in an asn88-to-ser (N88S) mutation. The English family was the original one reported by Silver (1966). In affected members of 1 Italian, 1 English, and 8 Austrian families with autosomal dominant distal hereditary motor neuronopathy-13 (HMND13; 619112), they identified the N88S mutation. </p><p>Auer-Grumbach et al. (2005) reported the phenotypic findings in 90 patients from 1 large Austrian family and 2 unrelated German families with the N88S mutation. There was considerable phenotypic variability, including asymptomatic nonpenetrance (4.4%), subclinical involvement (20%), distal spinal muscular atrophy characterized by prominent hand muscle involvement (31.1%), Silver syndrome (14.5%) with hand muscle involvement and spasticity, a Charcot-Marie-Tooth-like phenotype with distal muscle weakness and wasting of the lower limbs and sensory abnormalities (20%), and spastic paraparesis without hand involvement (10%). Auer-Grumbach et al. (2005) concluded that the N88S mutation causes a motor neuron disease affecting the upper motor neurons, lower motor neurons, or both. Hand muscle involvement was a frequent, although not regular, feature, and sensory involvement was usually not present. Genealogic studies of the Austrian kindred traced the disease to a common parent pair born in 1682. </p><p>Van de Warrenburg et al. (2006) reported 2 Dutch families with multiple affected individuals carrying a heterozygous N88S mutation. The phenotype in both families overlapped between Silver syndrome and HMND13. Affected members in both families had foot and lower limb atrophy with slowly progressive hyperreflexia and extensor plantar responses without prominent spasticity. Hand involvement occurred in most patients and was restricted to interosseus muscles. </p><p>Brusse et al. (2009) reported 12 members of a large 3-generation Dutch family with phenotypic overlap between Silver syndrome and distal HMND13 who carried a heterozygous N88S mutation. The phenotype was variable, and the distribution of muscle weakness and atrophy included predominantly the feet (in 4), the hands (in 1), or both upper and lower extremities (in 4). Three individuals showed evidence of pyramidal features, including spasticity, hyperreflexia, and extensor plantar responses. Severity of the disease ranged from adolescent patients with disabling muscle weakness to an elderly patient with only mild weakness of the ankle dorsiflexors and bilateral pes cavus. Brusse et al. (2009) noted the extreme phenotypic variability associated with the N88S mutation in their family and in those reported by Auer-Grumbach et al. (2005) and van de Warrenburg et al. (2006), and suggested the presence of other genetic or environmental factors. In their family, Brusse et al. (2009) used genomewide linkage analysis to identify a candidate disease modifier on chromosome 16p13.3-p13.12 between SNPs rs6500882 and rs7192086 that was shared by all 12 affected individuals (maximum lod score of 3.28). One family member without the N88S mutation but with the chromosome 16p haplotype showed mild electrophysiologic abnormalities. Brusse et al. (2009) postulated that a locus on chromosome 16p may contain a disease modifier in their family. </p><p>Chaudhry et al. (2013) identified a heterozygous N88S mutation in a man with SPG17. He had onset of weakness of the hands and feet at around 12 years of age. Examination at age 14 showed distal weakness and wasting with clawed hands and flat feet, extensor plantar responses, mild tremor, and distal sensory impairment. The disorder was slowly progressive, and he remained ambulatory with orthotics at age 36. His affected uncle also carried the mutation, as did his unaffected mother, suggesting incomplete penetrance. The mutation was identified by exome sequencing of the proband. The family was originally reported by Ionasescu et al. (1991) as having an X-linked form of CMT (302802). </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>.0014 SILVER SPASTIC PARAPLEGIA SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 13, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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BSCL2, SER90LEU
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<br />
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SNP: rs137852973,
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ClinVar: RCV000004803, RCV000235980, RCV000547334, RCV000755016, RCV001270681, RCV001813950, RCV003311647, RCV004766979
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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 affected members of a Belgian family and a Brazilian family with Silver spastic paraplegia syndrome (SPG17; 270685), Windpassinger et al. (2004) identified heterozygosity for a c.269C-T transition (c.269C-T, NM_032667) in the BSCL2 gene, resulting in a ser90-to-leu (S90L) mutation. </p><p>In an Italian mother and her 2 affected daughters with variable manifestations of autosomal dominant distal hereditary motor neuronopathy-13 (HMND13; 619112), Luigetti et al. (2010) identified a heterozygous S90L mutation in the BSCL2 gene. The mutation was found by sequence analysis of candidate genes. Functional studies of the variant and studies of patient cells were not performed. The patients had predominant motor impairment with distal muscle weakness and atrophy of the upper and lower limbs, as well as features of spasticity. One had subclinical sensory impairment, thus expanding the phenotypic spectrum associated with this mutation. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0015 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 2</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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BSCL2, ARG275TER
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<br />
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SNP: rs137852974,
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gnomAD: rs137852974,
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ClinVar: RCV000004804, RCV003311648
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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 3 Japanese patients with Berardinelli-Seip congenital generalized lipodystrophy (CGL2; 269700) from independent families, Ebihara et al. (2004) identified a homozygous C-to-T transition in exon 8 of the BSCL2 gene that resulted in premature termination of seipin at codon 275 (R275X). Analysis of microsatellite markers and SNPs demonstrated common ancestry. The authors stated that their study was the first report on gene and phenotype analysis of congenital generalized lipodystrophy in Japanese. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0016 LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 2</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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BSCL2, GLU189TER
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<br />
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SNP: rs137852975,
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gnomAD: rs137852975,
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ClinVar: RCV000004805, RCV000196081, RCV003311649
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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 Chinese infant with Berardinelli-Seip congenital generalized lipodystrophy (CGL2; 269700), Friguls et al. (2009) identified a homozygous 565G-T transversion in exon 5 of the BSCL2 gene, resulting in a glu189-to-ter (E189X) substitution. In addition to classic features of the disorder, the patient had hypertension, an apical murmur, and severe obstructive and asymmetric septal hypertrophic cardiomyopathy. The authors emphasized the early onset of severe cardiac disease in this patient. </p><p>Jin et al. (2007) had identified the E189X mutation in another Chinese boy with congenital generalized lipodystrophy with early-onset diabetes mellitus. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0017 ENCEPHALOPATHY, PROGRESSIVE, WITH OR WITHOUT LIPODYSTROPHY</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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BSCL2, 985C-T
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<br />
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SNP: rs587777606,
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gnomAD: rs587777606,
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ClinVar: RCV000133397, RCV000412493, RCV000800475, RCV003311693
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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 2 unrelated children from Murcia in southeastern Spain with autosomal recessive progressive encephalopathy, with and without lipodystrophy, respectively (PELD; 615924), Guillen-Navarro et al. (2013) identified a homozygous c.985C-T transition in the BSCL2 gene, predicted to result in an arg329-to-ter (R329X) substitution. The c.985C-T transition also causes an aberrant splicing site, resulting in the skipping of exon 7 and premature termination (Tyr289LeufsTer64). Each unaffected parent was heterozygous for the mutation, which was also found in 8 ethnically matched controls (allele frequency of 0.012). Patient cells showed increased expression of the exon 7-skipping transcript. Expression of the mutation in HeLa cells showed that the mutant protein localized to the nucleus. The c.985C-T mutation was also found in compound heterozygosity with another pathogenic truncating BSCL2 mutation (606158.0018 and 606158.0019) in 4 additional children with a similar phenotype from 2 families from the Murcia region. Haplotype analysis suggested a founder effect for the c.985C-T transition in the Murcia population. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0018 ENCEPHALOPATHY, PROGRESSIVE, WITH LIPODYSTROPHY</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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BSCL2, GLU180TER
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<br />
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SNP: rs587777607,
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|
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|
|
ClinVar: RCV000133398, RCV003311694
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In the unaffected parents of a boy from Murcia, Spain, with autosomal recessive progressive encephalopathy with lipodystrophy (PELD; 615924), Guillen-Navarro et al. (2013) identified heterozygous mutations in the BSCL2 gene: 1 parent carried a c.538G-T transversion, resulting in a glu180-to-ter (E180X) substitution, and the other carried a c.985C-T transition (606158.0017) resulting in premature termination. The patient, who died at 8 years of age, was presumed to be compound heterozygous for the mutations, but DNA was not available. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0019 ENCEPHALOPATHY, PROGRESSIVE, WITH LIPODYSTROPHY</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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BSCL2, 5-BP DEL, NT507
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<br />
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|
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ClinVar: RCV000004793, RCV000133399, RCV001091624, RCV003311638, RCV005089168
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</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 3-year-old girl from Murcia, Spain, with autosomal recessive progressive encephalopathy with lipodystrophy (PELD; 615924), Guillen-Navarro et al. (2013) identified compound heterozygous mutations in the BSCL2 gene: a 5-bp deletion (c.507_511del), resulting in a frameshift and premature termination (Tyr170CysfsTer6), and a c.985C-T transition (606158.0017), resulting in premature termination. Each unaffected parent was heterozygous for 1 of the mutations. The patient had 2 uncles with a similar disorder, who both died in childhood; DNA was not available from these patients, but analysis of their unaffected parents showed that each was heterozygous for 1 of the mutations found in the girl, suggesting that the uncles were compound heterozygous for the mutations. </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0020 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 13</strong>
|
|
</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BSCL2, SER90TRP
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<br />
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SNP: rs137852973,
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|
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ClinVar: RCV000536990, RCV000789082, RCV001270682, RCV002284966, RCV003311850
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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 affected members of a multigenerational Korean family with autosomal dominant distal hereditary motor neuronopathy-13 (HMND13; 619112) and features of axonal Charcot-Marie-Tooth disease type 2 (CMT2), Choi et al. (2013) identified a heterozygous c.269C-G transversion (c.269C-G, NM_032667.6) in exon 3 of the BSCL2 gene, resulting in a ser90-to-trp (S90W) substitution. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the affected residue is the same as the previously identified S90L mutation (606158.0014). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
|
|
</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Agarwal, A. K., Garg, A.
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<strong>Seipin: a mysterious protein.</strong>
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Trends Molec. Med. 10: 440-444, 2004.
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[PubMed: 15350896]
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[Full Text: https://doi.org/10.1016/j.molmed.2004.07.009]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Auer-Grumbach, M., Loscher, W. N., Wagner, K., Petek, E., Korner, E., Offenbacher, H., Hartung, H.-P.
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<strong>Phenotypic and genotypic heterogeneity in hereditary motor neuronopathy type V: a clinical, electrophysiological and genetic study.</strong>
|
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Brain 123: 1612-1623, 2000.
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[PubMed: 10908191]
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[Full Text: https://doi.org/10.1093/brain/123.8.1612]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Auer-Grumbach, M., Schlotter-Weigel, B., Lochmuller, H., Strobl-Wildemann, G., Auer-Grumbach, P., Fischer, R., Offenbacher, H., Zwick, E. B., Robl, T., Hartl, G., Hartung, H.-P., Wagner, K., Windpassinger, C., Austrian Peripheral Neuropathy Study Group.
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|
<strong>Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation.</strong>
|
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Ann. Neurol. 57: 415-424, 2005.
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[PubMed: 15732094]
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[Full Text: https://doi.org/10.1002/ana.20410]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Bhayana, S., Siu, V. M., Joubert, G. I., Clarson, C. L., Cao, H., Hegele, R. A.
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<strong>Cardiomyopathy in congenital complete lipodystrophy.</strong>
|
|
Clin. Genet. 61: 283-287, 2002.
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[PubMed: 12030893]
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[Full Text: https://doi.org/10.1034/j.1399-0004.2002.610407.x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Brusse, E., Majoor-Krakauer, D., de Graaf, B. M., Visser, G. H., Swagemakers, S., Boon, A. J. W., Oostra, B. A., Bertoli-Avella, A. M.
|
|
<strong>A novel 16p locus associated with BSCL2 hereditary motor neuronopathy: a genetic modifier?</strong>
|
|
Neurogenetics 10: 289-297, 2009.
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[PubMed: 19396477]
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[Full Text: https://doi.org/10.1007/s10048-009-0193-1]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Chaudhry, R., Kidambi, A., Brewer, M. H., Antonellis, A., Mathews, K., Nicholson, G., Kennerson, M.
|
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<strong>Re-analysis of an original CMTX3 family using exome sequencing identifies a known BSCL2 mutation.</strong>
|
|
Muscle Nerve 47: 922-924, 2013.
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[PubMed: 23553728]
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[Full Text: https://doi.org/10.1002/mus.23743]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Choi, B.-O., Park, M.-H., Chung, K. W., Woo, H.-M., Koo, H., Chung, H.-K., Choi, K.-G., Park, K. D., Lee, H. J., Hyun, Y. S., Koo, S. K.
|
|
<strong>Clinical and histopathological study of Charcot-Marie-Tooth neuropathy with a novel S90W mutation in BSCL2.</strong>
|
|
Neurogenetics 14: 35-42, 2013.
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[PubMed: 23142943]
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[Full Text: https://doi.org/10.1007/s10048-012-0346-5]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Cui, X., Wang, Y., Tang, Y., Liu, Y., Zhao, L., Deng, J., Xu, G., Peng, X., Ju, S., Liu, G., Yang, H.
|
|
<strong>Seipin ablation in mice results in severe generalized lipodystrophy.</strong>
|
|
Hum. Molec. Genet. 20: 3022-3030, 2011.
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|
[PubMed: 21551454]
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Thank you in advance for your generous support, <br />
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Ada Hamosh, MD, MPH <br />
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Scientific Director, OMIM <br />
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