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Entry
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- *603009 - DYSFERLIN; DYSF
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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">*603009</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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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>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/603009">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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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000135636;t=ENST00000410020" 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=8291" 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=603009" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000135636;t=ENST00000410020" 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_001130455,NM_001130976,NM_001130977,NM_001130978,NM_001130979,NM_001130980,NM_001130981,NM_001130982,NM_001130983,NM_001130984,NM_001130985,NM_001130986,NM_001130987,NM_003494" 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_001130987" 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=603009" 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=04307&isoform_id=04307_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/DYSF" 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/3600028,3646124,4503431,18676556,18677050,20137708,31620949,62822406,62988812,82734830,114479592,116734385,119620169,119620170,119620171,170293398,170293400,170293402,170293404,170293406,170293408,170293410,170293412,170293414,170293416,170293418,170293420,193786658,195976754,195976756,195976758,195976760,195976762,195976764,195976766,195976769,195976773,195976775,195976777,195976779,195976821,221040540,221044546,312274432" 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/O75923" 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=8291" 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=ENSG00000135636;t=ENST00000410020" 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=DYSF" 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=DYSF" 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+8291" 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/DYSF" 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:8291" 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/8291" 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=chr2&hgg_gene=ENST00000258104.8&hgg_start=71453561&hgg_end=71686763&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:3097" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=603009[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=603009[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/DYSF/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000135636" 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=DYSF" 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=DYSF" 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=DYSF" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.LOVD.nl/DYSF" 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=DYSF&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/PA27554" 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:3097" 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/FBgn0266757.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:1349385" 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/DYSF#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:1349385" 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/8291/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=8291" 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=WBGene00001414;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-070501-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
|
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
|
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<span class="small">
|
|
<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
|
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</div>
|
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</a>
|
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</span>
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</span>
|
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</div>
|
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=DYSF&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> 718179003, 782675008<br />
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<strong>ICD10CM:</strong> G71.033<br />
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">ICD+</a>
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</div>
|
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<div>
|
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<span class="h3">
|
|
<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
|
603009
|
|
</span>
|
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</span>
|
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</div>
|
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</div>
|
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<div>
|
|
<a id="preferredTitle" class="mim-anchor"></a>
|
|
<h3>
|
|
<span class="mim-font">
|
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DYSFERLIN; DYSF
|
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|
</span>
|
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</h3>
|
|
</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>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=DYSF" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">DYSF</a></em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/2/351?start=-3&limit=10&highlight=351">2p13.2</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:71453561-71686763&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'})">2:71,453,561-71,686,763</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
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</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=254130,253601,606768" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/2/351?start=-3&limit=10&highlight=351">
|
|
2p13.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Miyoshi muscular dystrophy 1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/254130"> 254130 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
|
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|
|
|
|
|
|
|
|
|
</tr>
|
|
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|
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|
|
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|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Muscular dystrophy, limb-girdle, autosomal recessive 2
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/253601"> 253601 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Myopathy, distal, with anterior tibial onset
|
|
|
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<p>Dysferlin belongs to a family of genes similar to Caenorhabditis elegans ferlin. Members of this family contain a type II transmembrane domain with the majority of the protein facing the cytoplasm, and they have multiple C2 domains, which are implicated in calcium-dependent membrane fusion events (<a href="#7" class="mim-tip-reference" title="Britton, S., Freeman, T., Vafiadaki, E., Keers, S., Harrison, R., Bushby, K., Bashir, R. <strong>The third human FER-1-like protein is highly similar to dysferlin.</strong> Genomics 68: 313-321, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10995573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10995573</a>] [<a href="https://doi.org/10.1006/geno.2000.6290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10995573">Britton et al., 2000</a>). Dysferlin plays an important role in muscle fiber repair (<a href="#4" class="mim-tip-reference" title="Bashir, R., Britton, S., Strachan, T., Keers, S., Vafiadaki, E., Lako, M., Richard, I., Marchand, S., Bourg, N., Argov, Z., Sadeh, M., Mahjneh, I., Marconi, G., Passos-Bueno, M. R., Moreira, E. S., Zatz, M., Beckmann, J. S., Bushby, K. <strong>A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B.</strong> Nature Genet. 20: 37-42, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9731527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9731527</a>] [<a href="https://doi.org/10.1038/1689" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9731527">Bashir et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9731527+10995573" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#20" class="mim-tip-reference" title="Liu, J., Wu, C., Bossie, K., Bejaoui, K., Hosler, B. A., Gingrich, J. C., Ben Hamida, M., Hentati, F., Schurr, E., de Jong, P. J., Brown, R. H., Jr. <strong>Generation of 3-Mb PAC contig spanning the Miyoshi myopathy/limb girdle muscular dystrophy (MM/LGMD2B) locus on chromosome 2p13.</strong> Genomics 49: 23-29, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9570945/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9570945</a>] [<a href="https://doi.org/10.1006/geno.1998.5204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9570945">Liu et al. (1998)</a> constructed a 3-Mb PAC contig spanning the Miyoshi myopathy (MMD1; <a href="/entry/254130">254130</a>) candidate region. This clarified the order of genetic markers across the area, provided 5 new polymorphic markers within it, and narrowed the locus to approximately 2 Mb. They found 5 skeletal muscle ESTs that mapped in this region. <a href="#19" class="mim-tip-reference" title="Liu, J., Aoki, M., Illa, I., Wu, C., Fardeau, M., Angelini, C., Serrano, C., Urtizberea, J. A., Hentati, F., Ben Hamida, M., Bohlega, S., Culper, E. J., Amato, A. A., Bossie, K., Oeltjen, J., Bejaoui, K., McKenna-Yasek, D., Hosler, B. A., Schurr, E., Arahata, K., de Jong, P. J., Brown, R. H., Jr. <strong>Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy.</strong> Nature Genet. 20: 31-36, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9731526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9731526</a>] [<a href="https://doi.org/10.1038/1682" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9731526">Liu et al. (1998)</a> reported that 1 of these ESTs is located in a novel, full-length 6.9-kb muscle cDNA; they designated the corresponding protein dysferlin. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9731526+9570945" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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 database analysis and sequencing overlapping YAC and PAC clones on chromosome 2p associated with autosomal recessive limb-girdle muscular dystrophy-2 (LGMDR2; <a href="/entry/253601">253601</a>), previously symbolized LGMD2B, <a href="#4" class="mim-tip-reference" title="Bashir, R., Britton, S., Strachan, T., Keers, S., Vafiadaki, E., Lako, M., Richard, I., Marchand, S., Bourg, N., Argov, Z., Sadeh, M., Mahjneh, I., Marconi, G., Passos-Bueno, M. R., Moreira, E. S., Zatz, M., Beckmann, J. S., Bushby, K. <strong>A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B.</strong> Nature Genet. 20: 37-42, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9731527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9731527</a>] [<a href="https://doi.org/10.1038/1689" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9731527">Bashir et al. (1998)</a> cloned a partial dysferlin cDNA. The deduced 1,779-amino acid protein contains 2 C2 domains and a putative transmembrane domain near the C terminus. Northern blot analysis detected a major transcript of approximately 7 kb in skeletal muscle, heart, and placenta, and more weakly in liver, lung, kidney, and pancreas. A transcript of less than 4 kb was present in brain. Analysis of specific brain regions detected the 7-kb transcript only in cerebellum and medulla. The 4-kb transcript was expressed in all brain regions except spinal cord, with highest levels in putamen. No dysferlin was detected in fetal brain. The proposed name 'dysferlin' combined the role of the gene in producing muscular dystrophy with its C. elegans homology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9731527" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Britton, S., Freeman, T., Vafiadaki, E., Keers, S., Harrison, R., Bushby, K., Bashir, R. <strong>The third human FER-1-like protein is highly similar to dysferlin.</strong> Genomics 68: 313-321, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10995573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10995573</a>] [<a href="https://doi.org/10.1006/geno.2000.6290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10995573">Britton et al. (2000)</a> stated that DYSF contains 2,080 amino acids. By sequence analysis, they showed that it has 6 C2 domains, a C-terminal transmembrane domain, and several calcium-binding residues conserved between C. elegans ferlin, myoferlin (MYOF; <a href="/entry/604603">604603</a>), and otoferlin (OTOF; <a href="/entry/603681">603681</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10995573" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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 5-prime RACE of adult skeletal muscle total RNA, <a href="#27" class="mim-tip-reference" title="Pramono, Z. A. D., Lai, P. S., Tan, C. L., Takeda, S., Yee, W. C. <strong>Identification and characterization of novel human dysferlin transcript: dysferlin_v1.</strong> Hum. Genet. 120: 410-419, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16896923/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16896923</a>] [<a href="https://doi.org/10.1007/s00439-006-0230-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16896923">Pramono et al. (2006)</a> identified a splice variant of DYSF, which they called DYSF-v1, that arises from an alternate first exon. The deduced 2,081-amino acid variant differs from DYSF only in the N terminus. Northern blot analysis detected a 7.5-kb DYSF-v1 transcript in skeletal muscle, heart, spleen, small intestine, kidney, liver, placenta, and lung, and a 6-kb transcript in brain. There were also minor transcripts of 2-kb and 1.3-kb. A 7.5-kb DYSF transcript was detected in brain, heart, skeletal muscle, spleen, kidney, liver, small intestine, placenta, lung, and peripheral blood leukocytes. Variable expression of minor transcripts of about 5-, 2-, and 1.3-kb was also detected. The promoter region associated with the variant DYSF-v1 contains 2 CpG islands, a TATA box, and 2 clusters of binding sites for several transcription factors, including those involved in muscle expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16896923" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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 RT-PCR of dysferlin mRNA from blood derived from 50 individuals of Chinese, Malaysian, and Indian origin as well as of skeletal muscle samples from unrelated individuals, <a href="#28" class="mim-tip-reference" title="Pramono, Z. A. D., Tan, C. L., Seah, I. A. L., See, J. S. L., Kam, S. Y., Lai, P. S., Yee, W. C. <strong>Identification and characterisation of human dysferlin transcript variants: implications for dysferlin mutational screening and isoforms.</strong> Hum. Genet. 125: 413-420, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19221801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19221801</a>] [<a href="https://doi.org/10.1007/s00439-009-0632-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19221801">Pramono et al. (2009)</a> identified alternatively spliced variants of the DYSF gene involving novel exons, i.e., exons 5a and 40a. Previously reported alternative splicing of exon 17 was also found. Long-range RT-PCR and subcloning revealed a total of 14 dysferlin transcripts derived from alternative splicing, all of which maintained an open reading frame. The study also characterized the differences in relative frequencies of these dysferlin transcripts in skeletal muscle and blood. <a href="#28" class="mim-tip-reference" title="Pramono, Z. A. D., Tan, C. L., Seah, I. A. L., See, J. S. L., Kam, S. Y., Lai, P. S., Yee, W. C. <strong>Identification and characterisation of human dysferlin transcript variants: implications for dysferlin mutational screening and isoforms.</strong> Hum. Genet. 125: 413-420, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19221801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19221801</a>] [<a href="https://doi.org/10.1007/s00439-009-0632-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19221801">Pramono et al. (2009)</a> suggested that these findings may have clinical relevance in the molecular diagnosis of DYSF-related disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19221801" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#2" class="mim-tip-reference" title="Aoki, M., Liu, J., Richard, I., Bashir, R., Britton, S., Keers, S. M., Oeltjen, J., Brown, H. E., Marchand, S., Bourg, N., Beley, C., McKenna-Yasek, D., and 13 others. <strong>Genomic organization of the dysferlin gene and novel mutations in Miyoshi myopathy.</strong> Neurology 57: 271-278, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11468312/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11468312</a>] [<a href="https://doi.org/10.1212/wnl.57.2.271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11468312">Aoki et al. (2001)</a> reported the genomic organization of the dysferlin gene and determined that it contains 55 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11468312" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="Pramono, Z. A. D., Lai, P. S., Tan, C. L., Takeda, S., Yee, W. C. <strong>Identification and characterization of novel human dysferlin transcript: dysferlin_v1.</strong> Hum. Genet. 120: 410-419, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16896923/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16896923</a>] [<a href="https://doi.org/10.1007/s00439-006-0230-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16896923">Pramono et al. (2006)</a> identified a DYSF-v1 promoter region associated with an alternative first exon located within intron 1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16896923" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#5" class="mim-tip-reference" title="Bashir, R., Strachan, T., Keers, S., Stephenson, A., Mahjneh, I., Marconi, G., Nashef, L., Bushby, K. M. D. <strong>A gene for autosomal recessive limb-girdle muscular dystrophy maps to chromosome 2p.</strong> Hum. Molec. Genet. 3: 455-457, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8012357/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8012357</a>] [<a href="https://doi.org/10.1093/hmg/3.3.455" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8012357">Bashir et al. (1994)</a> mapped the DYSF gene to chromosome 2p13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8012357" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#1" class="mim-tip-reference" title="Anderson, L. V. B., Davison, K., Moss, J. A., Young, C., Cullen, M. J., Walsh, J., Johnson, M. A., Bashir, R., Britton, S., Keers, S., Argov, Z., Mahjneh, I., Fougerousse, F., Beckmann, J. S., Bushby, K. M. D. <strong>Dysferlin is a plasma membrane protein and is expressed early in human development.</strong> Hum. Molec. Genet. 8: 855-861, 1999. Note: Erratum: Hum. Molec. Genet. 8: 1141 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10196375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10196375</a>] [<a href="https://doi.org/10.1093/hmg/8.5.855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10196375">Anderson et al. (1999)</a> raised a monoclonal antibody to dysferlin and studied the expression of the protein. Immunolabeling with the antibody demonstrated a polypeptide of approximately 230 kD on Western blot analysis of skeletal muscle, and microscopy at both the light and electron microscopic levels localized dysferlin to the muscle fiber membrane. A specific loss of labeling of dysferlin was observed in patients with mutations in the DYSF gene. Furthermore, patients with 2 different frameshift mutations demonstrated very low levels of immunoreactive protein in a manner reminiscent of the dystrophin expressed in many Duchenne patients. Analysis of human fetal tissue showed that dysferlin was expressed at the earliest stages of development examined, at Carnegie stage 15 or 16 (embryonic age 5 to 6 weeks). Dysferlin is present, therefore, at a time when the limbs start to form regional differentiation. <a href="#1" class="mim-tip-reference" title="Anderson, L. V. B., Davison, K., Moss, J. A., Young, C., Cullen, M. J., Walsh, J., Johnson, M. A., Bashir, R., Britton, S., Keers, S., Argov, Z., Mahjneh, I., Fougerousse, F., Beckmann, J. S., Bushby, K. M. D. <strong>Dysferlin is a plasma membrane protein and is expressed early in human development.</strong> Hum. Molec. Genet. 8: 855-861, 1999. Note: Erratum: Hum. Molec. Genet. 8: 1141 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10196375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10196375</a>] [<a href="https://doi.org/10.1093/hmg/8.5.855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10196375">Anderson et al. (1999)</a> suggested that lack of dysferlin at this critical time may contribute to the pattern of muscle involvement that develops later, with the onset of a muscular dystrophy primarily affecting proximal or distal muscles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10196375" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Caveolin-3 (CAV3; <a href="/entry/601253">601253</a>) is a skeletal muscle membrane protein important in the formation of caveolae and in which mutations were identified in a form of dominantly inherited limb-girdle muscular dystrophy (LGMD1C), reclassified as rippling muscle disease (RMD2; <a href="/entry/606072">606072</a>) by <a href="#32" class="mim-tip-reference" title="Straub, V., Murphy, A., Udd, B. <strong>229th ENMC international workshop: limb girdle muscular dystrophies--nomenclature and reformed classification, Naarden, the Netherlands, 17-19 March 2017.</strong> Neuromusc. Disord. 28: 702-710, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30055862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30055862</a>] [<a href="https://doi.org/10.1016/j.nmd.2018.05.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30055862">Straub et al. (2018)</a>. <a href="#22" class="mim-tip-reference" title="Matsuda, C., Hayashi, Y. K., Ogawa, M., Aoki, M., Murayama, K., Nishino, I., Nonaka, I., Arahata, K., Brown, R. H., Jr. <strong>The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle.</strong> Hum. Molec. Genet. 10: 1761-1766, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11532985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11532985</a>] [<a href="https://doi.org/10.1093/hmg/10.17.1761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11532985">Matsuda et al. (2001)</a> reported that dysferlin coimmunoprecipitates with caveolin-3 from biopsied normal human skeletal muscles. Using immunofluorescence, they found abnormal localization of dysferlin in muscles from patients with LGMD1C. Amino acid sequence analysis of the dysferlin protein revealed 7 sites that correspond to caveolin-3 scaffold-binding motifs, and 1 site that is a potential target to bind the WW domain of the caveolin-3 protein. The authors hypothesized that one function of dysferlin may be to interact with caveolin-3 to subserve signaling functions of caveolae. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11532985+30055862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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 C2C5 mouse cells, <a href="#10" class="mim-tip-reference" title="Fujita, E., Kouroku, Y., Isoai, A., Kumagai, H., Misutani, A., Matsuda, C., Hayashi, Y. K., Momoi, T. <strong>Two endoplasmic reticulum-associated degradation (ERAD) systems for the novel variant of the mutant dysferlin: ubiquitin/proteasome ERAD(I) and autophagy/lysosome ERAD(II).</strong> Hum. Molec. Genet. 16: 618-629, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17331981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17331981</a>] [<a href="https://doi.org/10.1093/hmg/ddm002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17331981">Fujita et al. (2007)</a> found that wildtype dysferlin was degraded by the ubiquitin/proteasome endoplasmic reticulum (ER)-associated degradation system (ERAD). A proteosome inhibitor induced dysferlin accumulation in the ER. In contrast, mutant dysferlin (see, e.g., W999C; <a href="#0010">603009.0010</a>) spontaneously aggregated in the ER and stimulated autophagosome formation by activation of the ER stress-EIF2-alpha (<a href="/entry/603907">603907</a>) phosphorylation pathway, as well as stimulated ER stress-induced cell death. Lysosomal protease inhibitors resulted in the accumulation of mutant dysferlin aggregates. The authors proposed 2 ERAD models for intracellular dysferlin degradation: ubiquitin/proteasome ERAD(I) and autophagy/lysosome ERAD(II). Mutant dysferlin aggregates in the ER were degraded by the autophagy/lysosome ERAD(II), as an alternative to ERAD(I), when the ERAD(I) system was impaired by mutant aggregates. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17331981" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The finding that Miyoshi myopathy (MMD1; <a href="/entry/254130">254130</a>) and autosomal recessive limb-girdle muscular dystrophy-2 (LGMDR2; previously symbolized LGMD2B) mapped to the same chromosomal region on chromosome 2p13 raised the possibility that they might be allelic disorders. They were in fact shown to be varying expressions of the same mutant gene; 2 large inbred kindreds whose members included both MMD1 and LGMD2B patients were described by <a href="#37" class="mim-tip-reference" title="Weiler, T., Greenberg, C. R., Nylen, E., Halliday, W., Morgan, K., Eggertson, D., Wrogemann, K. <strong>Limb-girdle muscular dystrophy and Miyoshi myopathy in an aboriginal Canadian kindred map to LGMD2B and segregate with the same haplotype.</strong> Am. J. Hum. Genet. 59: 872-878, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8808603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8808603</a>]" pmid="8808603">Weiler et al. (1996)</a> and Illarioshkin et al. (<a href="#18" class="mim-tip-reference" title="Illarioshkin, S. N., Ivanova-Smolenskaya, I. A., Tanaka, H., Vereshchagin, N. V., Markova, E. D., Poleshchuk, V. V., Lozhnikova, S. M., Sukhorukov, V. S., Limborska, S. A., Slominsky, P. A., Bulayeva, K. B., Tsuji, S. <strong>Clinical and molecular analysis of a large family with three distinct phenotypes of progressive muscular dystrophy.</strong> Brain 119: 1895-1909, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9009996/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9009996</a>] [<a href="https://doi.org/10.1093/brain/119.6.1895" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9009996">1996</a>, <a href="#17" class="mim-tip-reference" title="Illarioshkin, S. N., Ivanova-Smolenskaya, I. A., Tanaka, H., Poleshchuk, V. V., Markova, E. D., Tsuji, S. <strong>Refined genetic location of the chromosome 2p-linked progressive muscular dystrophy gene.</strong> Genomics 42: 345-348, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9192858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9192858</a>] [<a href="https://doi.org/10.1006/geno.1997.4725" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9192858">1997</a>). Affected individuals in both pedigrees shared the same haplotype. Differences in the phenotype appeared to be due to additional modifying factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8808603+9192858+9009996" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="#19" class="mim-tip-reference" title="Liu, J., Aoki, M., Illa, I., Wu, C., Fardeau, M., Angelini, C., Serrano, C., Urtizberea, J. A., Hentati, F., Ben Hamida, M., Bohlega, S., Culper, E. J., Amato, A. A., Bossie, K., Oeltjen, J., Bejaoui, K., McKenna-Yasek, D., Hosler, B. A., Schurr, E., Arahata, K., de Jong, P. J., Brown, R. H., Jr. <strong>Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy.</strong> Nature Genet. 20: 31-36, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9731526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9731526</a>] [<a href="https://doi.org/10.1038/1682" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9731526">Liu et al. (1998)</a> described 9 mutations in the DYSF gene (see, e.g., <a href="#0001">603009.0001</a>-<a href="#0004">603009.0004</a>) in 9 families with MMD1, LGMD2B, and/or distal myopathy with anterior tibial onset (DMAT; <a href="/entry/606768">606768</a>); 5 were predicted to prevent dysferlin expression. Identical mutations in the dysferlin gene can produce, they concluded, more than 1 myopathy phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9731526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="Bashir, R., Britton, S., Strachan, T., Keers, S., Vafiadaki, E., Lako, M., Richard, I., Marchand, S., Bourg, N., Argov, Z., Sadeh, M., Mahjneh, I., Marconi, G., Passos-Bueno, M. R., Moreira, E. S., Zatz, M., Beckmann, J. S., Bushby, K. <strong>A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B.</strong> Nature Genet. 20: 37-42, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9731527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9731527</a>] [<a href="https://doi.org/10.1038/1689" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9731527">Bashir et al. (1998)</a> identified 2 homozygous frameshift mutations in the DYSF gene (<a href="#0005">603009.0005</a> and <a href="#0006">603009.0006</a>, respectively), resulting in muscular dystrophy of either proximal or distal onset in 9 families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9731527" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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 patients with Miyoshi myopathy, <a href="#23" class="mim-tip-reference" title="Matsumura, T., Aoki, M., Nagano, A., Hayashi, Y. K., Asada, C., Ogawa, M., Yamanaka, G., Goto, K., Nakagawa, M., Oka, H., Sahashi, K., Kouhara, N., Saito, Y., Brown, R. H., Jr., Nonaka, I., Arahata, K. <strong>Molecular genetic analysis of dysferlin in Japanese patients with Miyoshi myopathy.</strong> Proc. Jpn. Acad. 75B: 207-212, 1999."None>Matsumura et al. (1999)</a> and <a href="#2" class="mim-tip-reference" title="Aoki, M., Liu, J., Richard, I., Bashir, R., Britton, S., Keers, S. M., Oeltjen, J., Brown, H. E., Marchand, S., Bourg, N., Beley, C., McKenna-Yasek, D., and 13 others. <strong>Genomic organization of the dysferlin gene and novel mutations in Miyoshi myopathy.</strong> Neurology 57: 271-278, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11468312/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11468312</a>] [<a href="https://doi.org/10.1212/wnl.57.2.271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11468312">Aoki et al. (2001)</a> identified several mutations in the dysferlin gene (see, e.g., <a href="#0010">603009.0010</a> and <a href="#0011">603009.0011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11468312" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="#36" class="mim-tip-reference" title="Weiler, T., Bashir, R., Anderson, L. V. B., Davison, K., Moss, J. A., Britton, S., Nylen, E., Keers, S., Vafiadaki, E., Greenberg, C. R., Bushby, K. M. D., Wrogemann, K. <strong>Identical mutation in patients with limb girdle muscular dystrophy type 2B or Miyoshi myopathy suggests a role for modifier gene(s).</strong> Hum. Molec. Genet. 8: 871-877, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10196377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10196377</a>] [<a href="https://doi.org/10.1093/hmg/8.5.871" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10196377">Weiler et al. (1999)</a> addressed the issue of the occurrence of both LGMD2B and Miyoshi myopathy in the same family. This had suggested that the same mutation could lead to either LGMD2B or MMD1 and that additional factors were needed to explain the development of the different clinical phenotypes. The discovery of the role of the DYSF gene in these 2 disorders made it possible to test this hypothesis. <a href="#36" class="mim-tip-reference" title="Weiler, T., Bashir, R., Anderson, L. V. B., Davison, K., Moss, J. A., Britton, S., Nylen, E., Keers, S., Vafiadaki, E., Greenberg, C. R., Bushby, K. M. D., Wrogemann, K. <strong>Identical mutation in patients with limb girdle muscular dystrophy type 2B or Miyoshi myopathy suggests a role for modifier gene(s).</strong> Hum. Molec. Genet. 8: 871-877, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10196377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10196377</a>] [<a href="https://doi.org/10.1093/hmg/8.5.871" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10196377">Weiler et al. (1999)</a> reported that, in a large Canadian aboriginal kindred with both LGMD2B and MMD1 patients, all affected individuals were homozygous for a pro791-to-arg (<a href="#0007">603009.0007</a>) mutation of dysferlin and that the mutation resulted in similar reductions of dysferlin expression in the 2 types of patients. Modifier gene(s) or additional factors must account for the differences in the clinical phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10196377" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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 20 of 25 Japanese patients with a clinical diagnosis of Miyoshi myopathy, <a href="#33" class="mim-tip-reference" title="Takahashi, T., Aoki, M., Tateyama, M., Kondo, E., Mizuno, T., Onodera, Y., Takano, R., Kawai, H., Kamakura, K., Mochizuki, H., Shizuka-Ikeda, M., Nakagawa, M., and 21 others. <strong>Dysferlin mutations in Japanese Miyoshi myopathy: relationship to phenotype.</strong> Neurology 60: 1799-1804, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12796534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12796534</a>] [<a href="https://doi.org/10.1212/01.wnl.0000068333.43005.12" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12796534">Takahashi et al. (2003)</a> identified 16 different dysferlin mutations, 10 of which were novel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12796534" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a review of 40 patients with dysferlinopathy, <a href="#25" class="mim-tip-reference" title="Nguyen, K., Bassez, G., Krahn, M., Bernard, R., Laforet, P., Labelle, V., Urtizberea, J. A., Figarella-Branger, D., Romero, N., Attarian, S., Leturcq, F., Pouget, J., Levy, N., Eymard, B. <strong>Phenotypic study in 40 patients with dysferlin gene mutations: high frequency of atypical phenotypes.</strong> Arch. Neurol. 64: 1176-1182, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17698709/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17698709</a>] [<a href="https://doi.org/10.1001/archneur.64.8.1176" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17698709">Nguyen et al. (2007)</a> found that about 50% had typical Miyoshi myopathy or LGMD2B. Other patients had more unusual phenotypes, including mixed proximal and distal onset (35%), distal painful leg swelling without muscle weakness (10%), and asymptomatic increased serum creatine kinase (5%). The disorder could worsen rapidly, and 25% of patients were initially misdiagnosed as having polymyositis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17698709" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In patients with LGMD2B or Miyoshi myopathy, <a href="#31" class="mim-tip-reference" title="Spuler, S., Carl, M., Zabojszcza, J., Straub, V., Bushby, K., Moore, S. A., Bahring, S., Wenzel, K., Vinkemeier, U., Rocken, C. <strong>Dysferlin-deficient muscular dystrophy features amyloidosis.</strong> Ann. Neurol. 63: 323-328, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18306167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18306167</a>] [<a href="https://doi.org/10.1002/ana.21309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18306167">Spuler et al. (2008)</a> identified 3 different mutations in the N terminus of the DYSF gene (<a href="#0017">603009.0017</a>-<a href="#0019">603009.0019</a>) that resulted in deposition of dysferlin-reactive amyloid fibrils within muscle fibers. The authors postulated that amyloid protein is a proteolytic cleavage product of dysferlin, and that the mutations destabilized the protein structure, leading to an increase in the propensity to form amyloid fibrils. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18306167" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The SJL mouse strain (<a href="#9" class="mim-tip-reference" title="Festing, M. F. W. (ed.). <strong>Inbred Strains in Biomedical Research.</strong> New York: Oxford Univ. Press 1979. P. 255."None>Festing, 1979</a>) is susceptible to many induced autoimmune diseases such as experimental autoimmune encephalitis (EAE) and inflammatory muscle disease. Additionally, the skeletal muscle of SJL mice was shown to have an increased regenerative capacity and demonstrates the spontaneous occurrence of what was designated an 'inflammatory myopathy,' accompanied by loss of strength. By histopathologic examinations of muscles in SJL mice of different ages, <a href="#6" class="mim-tip-reference" title="Bittner, R. E., Anderson, L. V. B., Burkhardt, E., Bashir, R., Vafiadaki, E., Ivanova, S., Raffelsberger, T., Maerk, I., Hoger, H., Jung, M., Karbasiyan, M., Storch, M., Lassmann, H., Moss, J. A., Davison, K., Harrison, R., Bushby, K. M. D., Reis, A. <strong>Dysferlin deletion in SJL mice (SJL-Dysf) defines a natural model for limb girdle muscular dystrophy 2B. (Letter)</strong> Nature Genet. 23: 141-142, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508505</a>] [<a href="https://doi.org/10.1038/13770" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508505">Bittner et al. (1999)</a> found features compatible with a progressive muscular dystrophy, including degenerative and regenerative changes of muscle fibers and a progressive fibrosis. Histologically, the changes were observed in mice as young as 3 weeks of age. Changes affected primarily the proximal muscle groups, whereas the distal muscles remained less affected. The morphologic alterations were associated with signs of slowly progressive muscle weakness, which <a href="#6" class="mim-tip-reference" title="Bittner, R. E., Anderson, L. V. B., Burkhardt, E., Bashir, R., Vafiadaki, E., Ivanova, S., Raffelsberger, T., Maerk, I., Hoger, H., Jung, M., Karbasiyan, M., Storch, M., Lassmann, H., Moss, J. A., Davison, K., Harrison, R., Bushby, K. M. D., Reis, A. <strong>Dysferlin deletion in SJL mice (SJL-Dysf) defines a natural model for limb girdle muscular dystrophy 2B. (Letter)</strong> Nature Genet. 23: 141-142, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508505</a>] [<a href="https://doi.org/10.1038/13770" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508505">Bittner et al. (1999)</a> detected as early as 3 weeks after birth when mice were suspended by their tails. The phenotype was found to be inherited as an autosomal recessive trait and was found to map to mouse chromosome 6, in a region syntenic with human 2p13, where the DYSF gene maps. Because of this synteny, <a href="#6" class="mim-tip-reference" title="Bittner, R. E., Anderson, L. V. B., Burkhardt, E., Bashir, R., Vafiadaki, E., Ivanova, S., Raffelsberger, T., Maerk, I., Hoger, H., Jung, M., Karbasiyan, M., Storch, M., Lassmann, H., Moss, J. A., Davison, K., Harrison, R., Bushby, K. M. D., Reis, A. <strong>Dysferlin deletion in SJL mice (SJL-Dysf) defines a natural model for limb girdle muscular dystrophy 2B. (Letter)</strong> Nature Genet. 23: 141-142, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508505</a>] [<a href="https://doi.org/10.1038/13770" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508505">Bittner et al. (1999)</a> studied dysferlin in these mice. They found a reduction to approximately 15% of control levels in SJL mice. They found a 171-bp deletion in the Dysf gene of SJL mice, predicted to result in removal of 57 amino acids, including most of the fourth C2 domain. The last C2 domain is conserved in other members of the fer-like gene family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508505" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="Bansal, D., Miyake, K., Vogel, S. S., Groh, S., Chen, C.-C., Williamson, R., McNeil, P. L., Campbell, K. P. <strong>Defective membrane repair in dysferlin-deficient muscular dystrophy.</strong> Nature 423: 168-172, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12736685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12736685</a>] [<a href="https://doi.org/10.1038/nature01573" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12736685">Bansal et al. (2003)</a> generated dysferlin-null mice by targeted disruption. Although dysferlin-null mice maintain a functional dystrophin-glycoprotein complex they nevertheless develop a progressive muscular dystrophy. In normal muscle, membrane patches enriched in dysferlin can be detected in response to sarcolemma injuries. In contrast, there are subsarcolemmal accumulations of vesicles in dysferlin-null muscle. Membrane repair assays with a 2-photon laser-scanning microscope demonstrated that wildtype muscle fibers efficiently resealed their sarcolemma in the presence of calcium. Interestingly, dysferlin-deficient muscle fibers were defective in calcium-dependent sarcolemma resealing. <a href="#3" class="mim-tip-reference" title="Bansal, D., Miyake, K., Vogel, S. S., Groh, S., Chen, C.-C., Williamson, R., McNeil, P. L., Campbell, K. P. <strong>Defective membrane repair in dysferlin-deficient muscular dystrophy.</strong> Nature 423: 168-172, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12736685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12736685</a>] [<a href="https://doi.org/10.1038/nature01573" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12736685">Bansal et al. (2003)</a> concluded that membrane repair is therefore an active process in skeletal muscle fibers, and that dysferlin has an essential role in this process. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12736685" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Ho, M., Post, C. M., Donahue, L. R., Lidov, H. G. W., Bronson, R. T., Goolsby, H., Watkins, S. C., Cox, G. A., Brown, R. H., Jr. <strong>Disruption of muscle membrane and phenotype divergence in two novel mouse models of dysferlin deficiency.</strong> Hum. Molec. Genet. 13: 1999-2010, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15254015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15254015</a>] [<a href="https://doi.org/10.1093/hmg/ddh212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15254015">Ho et al. (2004)</a> generated 2 novel lines of dysferlin-deficient mice obtained by gene targeting and identification of an inbred strain bearing a retrotransposon insertion in the Dysf gene, respectively. The mutations in these mice were located at the 3-prime and 5-prime ends of the Dysf gene. Both lines of mice lacked dysferlin and developed a progressive muscular dystrophy with histopathologic and ultrastructural features that closely resemble the human disease. Vital staining with Evans blue dye revealed loss of sarcolemmal integrity in both lines of mice, similar to that seen in mdx (DMD; <a href="/entry/300377">300377</a>) and Cav3-deficient mice. However, in contrast to the latter group of animals, the dysferlin-deficient mice had an intact dystrophin glycoprotein complex and normal levels of caveolin-3. <a href="#13" class="mim-tip-reference" title="Ho, M., Post, C. M., Donahue, L. R., Lidov, H. G. W., Bronson, R. T., Goolsby, H., Watkins, S. C., Cox, G. A., Brown, R. H., Jr. <strong>Disruption of muscle membrane and phenotype divergence in two novel mouse models of dysferlin deficiency.</strong> Hum. Molec. Genet. 13: 1999-2010, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15254015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15254015</a>] [<a href="https://doi.org/10.1093/hmg/ddh212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15254015">Ho et al. (2004)</a> concluded that muscle membrane disruption and myofiber degeneration in dysferlinopathy were directly mediated by the loss of dysferlin via a new pathogenic mechanism in muscular dystrophies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15254015" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Han, R., Bansal, D., Miyake, K., Muniz, V. P., Weiss, R. M., McNeil, P. L., Campbell, K. P. <strong>Dysferlin-mediated membrane repair protects the heart from stress-induced left ventricular injury.</strong> J. Clin. Invest. 117: 1805-1813, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17607357/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17607357</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17607357[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/10.1172/JCI30848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17607357">Han et al. (2007)</a> generated dysferlin-null mice and observed the development of mild cardiomyopathy that was exacerbated by stress exercise. Evans blue dye uptake was increased in dysferlin-deficient cardiomyocytes. Dysf/Dmd double-knockout mice developed early-onset cardiomyopathy. <a href="#12" class="mim-tip-reference" title="Han, R., Bansal, D., Miyake, K., Muniz, V. P., Weiss, R. M., McNeil, P. L., Campbell, K. P. <strong>Dysferlin-mediated membrane repair protects the heart from stress-induced left ventricular injury.</strong> J. Clin. Invest. 117: 1805-1813, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17607357/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17607357</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17607357[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/10.1172/JCI30848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17607357">Han et al. (2007)</a> suggested that dysferlin-mediated membrane repair is important for maintaining membrane integrity of cardiomyocytes, particularly under conditions of mechanical stress. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17607357" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Chiu, Y.-H., Hornsey, M. A., Klinge, L., Jorgensen, L. H., Laval, S. H., Charlton, R., Barresi, R., Straub, V., Lochmuller, H., Bushby, K. <strong>Attenuated muscle regeneration is a key factor in dysferlin-deficient muscular dystrophy.</strong> Hum. Molec. Genet. 18: 1976-1989, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19286669/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19286669</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19286669[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19286669">Chiu et al. (2009)</a> observed that muscle regeneration was attenuated in a mouse model of dysferlinopathy, with delayed removal of necrotic fibers, an extended inflammatory phase, and delayed functional recovery. Satellite cell activation and myoblast fusion appeared normal, but there was a reduction in early neutrophil recruitment in regenerating and also needle-wounded muscle in dysferlin-deficient mice. Primary mouse dysferlinopathy myoblast cultures showed reduced cytokine release upon stimulation, indicating that the secretion of chemotactic molecules was impaired. <a href="#8" class="mim-tip-reference" title="Chiu, Y.-H., Hornsey, M. A., Klinge, L., Jorgensen, L. H., Laval, S. H., Charlton, R., Barresi, R., Straub, V., Lochmuller, H., Bushby, K. <strong>Attenuated muscle regeneration is a key factor in dysferlin-deficient muscular dystrophy.</strong> Hum. Molec. Genet. 18: 1976-1989, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19286669/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19286669</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19286669[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19286669">Chiu et al. (2009)</a> suggested an extension to the muscle membrane repair model, where, in addition to fusing patch repair vesicles with the sarcolemma, dysferlin is also involved in the release of chemotactic agents. Reduced neutrophil recruitment may result in incomplete cycles of regeneration in dysferlinopathy, which combines with the membrane repair deficit to ultimately trigger dystrophic pathology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19286669" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="Glover, L. E., Newton, K., Krishnan, G., Bronson, R., Boyle, A., Krivickas, L. S., Brown, R. H., Jr. <strong>Dysferlin overexpression in skeletal muscle produces a progressive myopathy.</strong> Ann. Neurol. 67: 384-393, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20373350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20373350</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20373350[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.21926" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20373350">Glover et al. (2010)</a> generated 3 lines of transgenic mice overexpressing low, mid, and high levels of human dysferlin compared to endogenous levels in wildtype mice. Transgenic mice with high (176-fold) levels of overexpression had muscle atrophy, failure to thrive, severe kyphosis, hind-limb atrophy and weakness, and had to be euthanized between 5 and 7 months of age. Histologic studies of muscle from high and mid (36-fold) dysferlin overexpression mice showed a non-necrotic congenital myopathy with marked reduction in fiber diameter, increased connective tissue, and centralized nuclei. Cardiac muscle was also affected and showed calcifications. These pathogenic changes correlated with increasing dysferlin overexpression. Further analysis of skeletal muscle showed selective loss of the fast type II muscle fibers and abnormal accumulation of vesicular structures at sarcolemmal membranes, although the sarcolemmal membrane was intact. Other findings included evidence of endoplasmic reticulum stress and an increase in the calcium-dependent binding protein annexin-a2 (ANXA2; <a href="/entry/151740">151740</a>). These findings were distinct from abnormalities seen in dysferlin-deficient mice. Low (2-fold) levels of dysferlin overexpression were not associated with cytotoxicity in skeletal muscle. <a href="#11" class="mim-tip-reference" title="Glover, L. E., Newton, K., Krishnan, G., Bronson, R., Boyle, A., Krivickas, L. S., Brown, R. H., Jr. <strong>Dysferlin overexpression in skeletal muscle produces a progressive myopathy.</strong> Ann. Neurol. 67: 384-393, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20373350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20373350</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20373350[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.21926" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20373350">Glover et al. (2010)</a> concluded that attempts at gene replacement therapy for dysferlin need to consider expression levels and dosage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20373350" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a French family with Miyoshi myopathy (MMD1; <a href="/entry/254130">254130</a>), <a href="#19" class="mim-tip-reference" title="Liu, J., Aoki, M., Illa, I., Wu, C., Fardeau, M., Angelini, C., Serrano, C., Urtizberea, J. A., Hentati, F., Ben Hamida, M., Bohlega, S., Culper, E. J., Amato, A. A., Bossie, K., Oeltjen, J., Bejaoui, K., McKenna-Yasek, D., Hosler, B. A., Schurr, E., Arahata, K., de Jong, P. J., Brown, R. H., Jr. <strong>Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy.</strong> Nature Genet. 20: 31-36, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9731526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9731526</a>] [<a href="https://doi.org/10.1038/1682" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9731526">Liu et al. (1998)</a> found that affected members had a homozygous nonsense mutation in codon 605 of the DYSF gene, a CAG-to-TAG transition at nucleotide 2186 (Q605X). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9731526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0002 MYOPATHY, DISTAL, WITH ANTERIOR TIBIAL ONSET</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> rs786205081 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205081;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/rs786205081?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=rs786205081" 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=rs786205081" 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=RCV000007048 OR RCV000700124 OR RCV001781197 OR RCV003466822" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007048, RCV000700124, RCV001781197, RCV003466822" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007048...</a>
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<p>In a consanguineous Spanish family in which members carried the diagnosis of distal myopathy with anterior tibial onset (DMAT; <a href="/entry/606768">606768</a>), <a href="#19" class="mim-tip-reference" title="Liu, J., Aoki, M., Illa, I., Wu, C., Fardeau, M., Angelini, C., Serrano, C., Urtizberea, J. A., Hentati, F., Ben Hamida, M., Bohlega, S., Culper, E. J., Amato, A. A., Bossie, K., Oeltjen, J., Bejaoui, K., McKenna-Yasek, D., Hosler, B. A., Schurr, E., Arahata, K., de Jong, P. J., Brown, R. H., Jr. <strong>Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy.</strong> Nature Genet. 20: 31-36, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9731526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9731526</a>] [<a href="https://doi.org/10.1038/1682" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9731526">Liu et al. (1998)</a> found that the myopathy was associated with deletion of 5966G in the DYSF gene, resulting in a frameshift. <a href="#15" class="mim-tip-reference" title="Illa, I., Serrano-Munuera, C., Gallardo, E., Lasa, A., Rojas-Garcia, R., Palmer, J., Gallano, P., Baiget, M., Matsuda, C., Brown, R. H. <strong>Distal anterior compartment myopathy: a dysferlin mutation causing a new muscular dystrophy phenotype.</strong> Ann. Neurol. 49: 130-134, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11198284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11198284</a>]" pmid="11198284">Illa et al. (2001)</a> reported the same family in greater detail and referred to the disorder as another dysferlinopathy. Affected members of the family were homozygous for the deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11198284+9731526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 MIYOSHI MUSCULAR DYSTROPHY 1</strong>
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MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908954 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908954;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/rs121908954?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=rs121908954" 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=rs121908954" 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=RCV000007049 OR RCV000153183 OR RCV000509353 OR RCV000658868 OR RCV000681611 OR RCV001563901 OR RCV004547461 OR RCV004998077" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007049, RCV000153183, RCV000509353, RCV000658868, RCV000681611, RCV001563901, RCV004547461, RCV004998077" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007049...</a>
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<p>In an Italian family in which some members had Miyoshi myopathy (MMD1; <a href="/entry/254130">254130</a>) and others had limb-girdle muscular dystrophy type 2B (LGMDR2; <a href="/entry/253601">253601</a>), i.e., myopathy with either distal onset or proximal onset, respectively, <a href="#19" class="mim-tip-reference" title="Liu, J., Aoki, M., Illa, I., Wu, C., Fardeau, M., Angelini, C., Serrano, C., Urtizberea, J. A., Hentati, F., Ben Hamida, M., Bohlega, S., Culper, E. J., Amato, A. A., Bossie, K., Oeltjen, J., Bejaoui, K., McKenna-Yasek, D., Hosler, B. A., Schurr, E., Arahata, K., de Jong, P. J., Brown, R. H., Jr. <strong>Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy.</strong> Nature Genet. 20: 31-36, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9731526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9731526</a>] [<a href="https://doi.org/10.1038/1682" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9731526">Liu et al. (1998)</a> found compound heterozygosity for 2 missense mutations in the DYSF gene: an ATG-to-GTC transition at nucleotide 4265 (I1298V) and a CGT-to-TGT transition at nucleotide 6497 (R2042C; <a href="#0004">603009.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9731526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 MIYOSHI MUSCULAR DYSTROPHY 1</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> rs121908955 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908955;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/rs121908955?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=rs121908955" 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=rs121908955" 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=RCV000007051 OR RCV000007052 OR RCV000080320 OR RCV000815134 OR RCV001813961 OR RCV005025020" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007051, RCV000007052, RCV000080320, RCV000815134, RCV001813961, RCV005025020" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007051...</a>
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<p>For discussion of the arg2042-to-cys (R2042C) mutation in the DYSF gene that was found in compound heterozygous state in patients with Miyoshi myopathy (MMD1; <a href="/entry/254130">254130</a>) or limb-girdle muscular dystrophy type 2B (LGMDR2; <a href="/entry/253601">253601</a>) by <a href="#19" class="mim-tip-reference" title="Liu, J., Aoki, M., Illa, I., Wu, C., Fardeau, M., Angelini, C., Serrano, C., Urtizberea, J. A., Hentati, F., Ben Hamida, M., Bohlega, S., Culper, E. J., Amato, A. A., Bossie, K., Oeltjen, J., Bejaoui, K., McKenna-Yasek, D., Hosler, B. A., Schurr, E., Arahata, K., de Jong, P. J., Brown, R. H., Jr. <strong>Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy.</strong> Nature Genet. 20: 31-36, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9731526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9731526</a>] [<a href="https://doi.org/10.1038/1682" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9731526">Liu et al. (1998)</a>, see <a href="#0003">603009.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9731526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 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> rs786200896 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786200896;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/rs786200896?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=rs786200896" 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=rs786200896" 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=RCV000007053 OR RCV000338549 OR RCV000806281 OR RCV003466823 OR RCV005025021" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007053, RCV000338549, RCV000806281, RCV003466823, RCV005025021" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007053...</a>
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<p>In 8 Libyan Jewish families with limb-girdle muscular dystrophy type 2B (LGMDR2; <a href="/entry/253601">253601</a>), <a href="#4" class="mim-tip-reference" title="Bashir, R., Britton, S., Strachan, T., Keers, S., Vafiadaki, E., Lako, M., Richard, I., Marchand, S., Bourg, N., Argov, Z., Sadeh, M., Mahjneh, I., Marconi, G., Passos-Bueno, M. R., Moreira, E. S., Zatz, M., Beckmann, J. S., Bushby, K. <strong>A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B.</strong> Nature Genet. 20: 37-42, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9731527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9731527</a>] [<a href="https://doi.org/10.1038/1689" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9731527">Bashir et al. (1998)</a> found that affected individuals were homozygous for a 1-bp deletion of guanine and a C-G transversion at codon 1322 of the DYSF gene, resulting in a frameshift and premature stop codon at position 1331 (numbering based on a partial DYSF amino acid sequence). Subsequently, <a href="#34" class="mim-tip-reference" title="Therrien, C., Dodig, D., Karpati, G., Sinnreich, M. <strong>Mutation impact on dysferlin inferred from database analysis and computer-based structural predictions.</strong> J. Neurol. Sci. 250: 71-78, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16996541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16996541</a>] [<a href="https://doi.org/10.1016/j.jns.2006.07.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16996541">Therrien et al. (2006)</a> reported the mutation as an insertion/deletion (4872delinsCCCC). In a ninth Libyan Jewish family, with a single affected member, the mutation was detected in single copy; one of the parents (who did not carry the mutation) was of Romanian origin. The 25 patients in these families showed onset of the disease between 12 and 39 years of age (mean 19.5 +/- 5 years). All had lower limb involvement on average 9 years before upper limb symptoms. Thirteen patients (52%) presented with distal lower limb muscle weakness, mostly of the gastrocnemius, with some complaining of transient calf enlargement. Intrafamilial variability was seen in the distribution of muscle weakness. Only 6 patients had lost the ability to walk independently; all of these were older than 35 years. Muscle biopsy showed chronic myopathic changes, and creatine kinase was elevated 10 to 25 times the normal rate in all affected individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9731527+16996541" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 Italian sisters with severe LGMDR2, <a href="#30" class="mim-tip-reference" title="Sinnreich, M., Therrien, C., Karpati, G. <strong>Lariat branch point mutation in the dysferlin gene with mild limb-girdle muscular dystrophy.</strong> Neurology 66: 1114-1116, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16606933/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16606933</a>] [<a href="https://doi.org/10.1212/01.wnl.0000204358.89303.81" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16606933">Sinnreich et al. (2006)</a> identified homozygosity for the insertion/deletion mutation in the DYSF gene, which they characterized as a 1-bp deletion (4872delG) and a 4876G-C transversion, that was previously reported by <a href="#4" class="mim-tip-reference" title="Bashir, R., Britton, S., Strachan, T., Keers, S., Vafiadaki, E., Lako, M., Richard, I., Marchand, S., Bourg, N., Argov, Z., Sadeh, M., Mahjneh, I., Marconi, G., Passos-Bueno, M. R., Moreira, E. S., Zatz, M., Beckmann, J. S., Bushby, K. <strong>A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B.</strong> Nature Genet. 20: 37-42, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9731527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9731527</a>] [<a href="https://doi.org/10.1038/1689" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9731527">Bashir et al. (1998)</a>. Each parent was heterozygous for the insertion/deletion mutation. The girls had onset in the second decade of proximal muscle weakness and wasting. Their 70-year-old mother, who had had mild proximal weakness since her forties, was compound heterozygous for the indel mutation and a splice site mutation (<a href="#0016">603009.0016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9731527+16606933" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs786205082 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205082;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=rs786205082" 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=rs786205082" 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=RCV000007054" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007054" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007054</a>
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<p>In a Palestinian Arab family described by <a href="#21" class="mim-tip-reference" title="Mahjneh, I., Vannelli, G., Bushby, K., Marconi, G. P. <strong>A large inbred Palestinian family with two forms of muscular dystrophy.</strong> Neuromusc. Disord. 2: 277-283, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1483054/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1483054</a>] [<a href="https://doi.org/10.1016/0960-8966(92)90060-j" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1483054">Mahjneh et al. (1992)</a>, <a href="#4" class="mim-tip-reference" title="Bashir, R., Britton, S., Strachan, T., Keers, S., Vafiadaki, E., Lako, M., Richard, I., Marchand, S., Bourg, N., Argov, Z., Sadeh, M., Mahjneh, I., Marconi, G., Passos-Bueno, M. R., Moreira, E. S., Zatz, M., Beckmann, J. S., Bushby, K. <strong>A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B.</strong> Nature Genet. 20: 37-42, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9731527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9731527</a>] [<a href="https://doi.org/10.1038/1689" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9731527">Bashir et al. (1998)</a> demonstrated that autosomal recessive limb-girdle muscular dystrophy type 2B (LGMDR2; <a href="/entry/253601">253601</a>) resulted from a 23-bp insertion at codon 1386 in the DYSF gene. The insertion represented a tandem duplication resulting from replication slippage and was predicted to result in frameshift and premature termination at codon 1427 (numbering based on a partial DYSF amino acid sequence). This kindred also contained individuals with a congenital form of muscular dystrophy (see <a href="/entry/254300">254300</a>); none of these individuals carried the DYSF mutation, indicating that it had a different genetic basis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1483054+9731527" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs121908956 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908956;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/rs121908956?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=rs121908956" 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=rs121908956" 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=RCV000007055 OR RCV000007056 OR RCV000790785 OR RCV000807968" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007055, RCV000007056, RCV000790785, RCV000807968" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007055...</a>
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<p>In a large Canadian aboriginal kindred reported by <a href="#37" class="mim-tip-reference" title="Weiler, T., Greenberg, C. R., Nylen, E., Halliday, W., Morgan, K., Eggertson, D., Wrogemann, K. <strong>Limb-girdle muscular dystrophy and Miyoshi myopathy in an aboriginal Canadian kindred map to LGMD2B and segregate with the same haplotype.</strong> Am. J. Hum. Genet. 59: 872-878, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8808603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8808603</a>]" pmid="8808603">Weiler et al. (1996)</a>, <a href="#36" class="mim-tip-reference" title="Weiler, T., Bashir, R., Anderson, L. V. B., Davison, K., Moss, J. A., Britton, S., Nylen, E., Keers, S., Vafiadaki, E., Greenberg, C. R., Bushby, K. M. D., Wrogemann, K. <strong>Identical mutation in patients with limb girdle muscular dystrophy type 2B or Miyoshi myopathy suggests a role for modifier gene(s).</strong> Hum. Molec. Genet. 8: 871-877, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10196377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10196377</a>] [<a href="https://doi.org/10.1093/hmg/8.5.871" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10196377">Weiler et al. (1999)</a> found that both patients with limb-girdle muscular dystrophy type 2B (LGMDR2; <a href="/entry/253601">253601</a>) and patients with Miyoshi myopathy (MMD1; <a href="/entry/254130">254130</a>) were homozygous for a pro791-to-arg (P791R) missense mutation in the DYSF gene. Four additional patients from 2 previously unpublished families also had this mutation. Haplotype analysis suggested a common origin of the mutation in all of the patients. Western blot analysis of muscle in patients with either Miyoshi myopathy or LGMD2B showed a similar abundance of dysferlin staining of 15% and 11%, respectively. Normal tissue sections showed that dysferlin localizes to the sarcolemma, whereas tissue sections from patients with Miyoshi myopathy or limb-girdle muscular dystrophy showed minimal staining that was indistinguishable between the 2 types. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8808603+10196377" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs745891180 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs745891180;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/rs745891180?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=rs745891180" 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=rs745891180" 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=RCV000007057 OR RCV001781198 OR RCV001851715 OR RCV002298436 OR RCV003466824" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007057, RCV001781198, RCV001851715, RCV002298436, RCV003466824" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007057...</a>
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<p>In a large consanguineous pedigree of Yemenite Jewish descent with limb-girdle muscular dystrophy type 2B (LGMDR2; <a href="/entry/253601">253601</a>), <a href="#24" class="mim-tip-reference" title="McNally, E. M., Ly, C. T., Rosenmann, H., Rosenbaum, S. M., Jiang, W., Anderson, L. V. B., Soffer, D., Argov, Z. <strong>Splicing mutation in dysferlin produces limb-girdle muscular dystrophy with inflammation.</strong> Am. J. Med. Genet. 91: 305-312, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10766988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10766988</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(20000410)91:4<305::aid-ajmg12>3.0.co;2-s" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10766988">McNally et al. (2000)</a> identified a homozygous G-to-A change predicted to affect position 5 in the intron following amino acid 1686 (5711 bp) of the dysferlin cDNA sequence. The phenotype associated with this mutation begins in the late second decade and includes an elevated serum creatine kinase. Biopsy samples from these patients demonstrated an inflammatory process, a finding not previously associated with LGMD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10766988" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs121908957 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908957;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=rs121908957" 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=rs121908957" 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=RCV000007058 OR RCV000681612" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007058, RCV000681612" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007058...</a>
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<p>In a large consanguineous Russian family with both limb-girdle muscular dystrophy type 2B (LGMDR2; <a href="/entry/253601">253601</a>) and Miyoshi myopathy (MMD1; <a href="/entry/254130">254130</a>) reported by <a href="#18" class="mim-tip-reference" title="Illarioshkin, S. N., Ivanova-Smolenskaya, I. A., Tanaka, H., Vereshchagin, N. V., Markova, E. D., Poleshchuk, V. V., Lozhnikova, S. M., Sukhorukov, V. S., Limborska, S. A., Slominsky, P. A., Bulayeva, K. B., Tsuji, S. <strong>Clinical and molecular analysis of a large family with three distinct phenotypes of progressive muscular dystrophy.</strong> Brain 119: 1895-1909, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9009996/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9009996</a>] [<a href="https://doi.org/10.1093/brain/119.6.1895" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9009996">Illarioshkin et al. (1996)</a>, <a href="#16" class="mim-tip-reference" title="Illarioshkin, S. N., Ivanova-Smolenskaya, I. A., Greenberg, C. R., Nylen, E., Sukhorukov, V. S., Poleshchuk, V. V., Markova, E. D., Wrogemann, K. <strong>Identical dysferlin mutation in limb-girdle muscular dystrophy type 2B and distal myopathy.</strong> Neurology 55: 1931-1933, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11134403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11134403</a>] [<a href="https://doi.org/10.1212/wnl.55.12.1931" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11134403">Illarioshkin et al. (2000)</a> found that all affected individuals were homozygous for a TG-to-AT change at nucleotides 573-574 of the DYSF gene, resulting in a val67-to-asp (V67D) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9009996+11134403" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs28937581 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28937581;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/rs28937581?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=rs28937581" 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=rs28937581" 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=RCV000007059 OR RCV000176869 OR RCV000790765 OR RCV001232546 OR RCV004525846 OR RCV005031402" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007059, RCV000176869, RCV000790765, RCV001232546, RCV004525846, RCV005031402" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007059...</a>
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<p>In patients with Miyoshi myopathy (MMD1; <a href="/entry/254130">254130</a>), <a href="#23" class="mim-tip-reference" title="Matsumura, T., Aoki, M., Nagano, A., Hayashi, Y. K., Asada, C., Ogawa, M., Yamanaka, G., Goto, K., Nakagawa, M., Oka, H., Sahashi, K., Kouhara, N., Saito, Y., Brown, R. H., Jr., Nonaka, I., Arahata, K. <strong>Molecular genetic analysis of dysferlin in Japanese patients with Miyoshi myopathy.</strong> Proc. Jpn. Acad. 75B: 207-212, 1999."None>Matsumura et al. (1999)</a> identified a 3370G-T transversion in exon 28 of the DYSF gene, resulting in a trp999-to-cys (W999C) substitution. <a href="#33" class="mim-tip-reference" title="Takahashi, T., Aoki, M., Tateyama, M., Kondo, E., Mizuno, T., Onodera, Y., Takano, R., Kawai, H., Kamakura, K., Mochizuki, H., Shizuka-Ikeda, M., Nakagawa, M., and 21 others. <strong>Dysferlin mutations in Japanese Miyoshi myopathy: relationship to phenotype.</strong> Neurology 60: 1799-1804, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12796534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12796534</a>] [<a href="https://doi.org/10.1212/01.wnl.0000068333.43005.12" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12796534">Takahashi et al. (2003)</a> noted that, in general, patients with the W999C mutation tended to have a later age at disease onset (mean, 32 years) and a milder form of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12796534" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs121908958 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908958;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/rs121908958?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=rs121908958" 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=rs121908958" 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=RCV000007060 OR RCV000176936 OR RCV000763088 OR RCV000790688 OR RCV001229764" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007060, RCV000176936, RCV000763088, RCV000790688, RCV001229764" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007060...</a>
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<p>In a patient with Miyoshi myopathy (MMD1; <a href="/entry/254130">254130</a>), <a href="#2" class="mim-tip-reference" title="Aoki, M., Liu, J., Richard, I., Bashir, R., Britton, S., Keers, S. M., Oeltjen, J., Brown, H. E., Marchand, S., Bourg, N., Beley, C., McKenna-Yasek, D., and 13 others. <strong>Genomic organization of the dysferlin gene and novel mutations in Miyoshi myopathy.</strong> Neurology 57: 271-278, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11468312/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11468312</a>] [<a href="https://doi.org/10.1212/wnl.57.2.271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11468312">Aoki et al. (2001)</a> identified a 3510G-A transition in exon 29 of the DYSF gene, resulting in an arg1046-to-his (R1046H) substitution. <a href="#33" class="mim-tip-reference" title="Takahashi, T., Aoki, M., Tateyama, M., Kondo, E., Mizuno, T., Onodera, Y., Takano, R., Kawai, H., Kamakura, K., Mochizuki, H., Shizuka-Ikeda, M., Nakagawa, M., and 21 others. <strong>Dysferlin mutations in Japanese Miyoshi myopathy: relationship to phenotype.</strong> Neurology 60: 1799-1804, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12796534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12796534</a>] [<a href="https://doi.org/10.1212/01.wnl.0000068333.43005.12" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12796534">Takahashi et al. (2003)</a> noted that patients with the R1046H mutation had a relatively early age at disease onset (mean, 13 years) and a severe form of the disease, with significantly higher serum creatine kinase levels than patients with other mutations in the DYSF gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12796534+11468312" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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MYOPATHY, DISTAL, WITH ANTERIOR TIBIAL ONSET, INCLUDED<br />
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MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908959 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908959;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/rs121908959?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=rs121908959" 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=rs121908959" 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=RCV000007061 OR RCV000007062 OR RCV000007063 OR RCV000080312 OR RCV000808564 OR RCV003114177 OR RCV005025022" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007061, RCV000007062, RCV000007063, RCV000080312, RCV000808564, RCV003114177, RCV005025022" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007061...</a>
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<p>In affected members from 5 families from Sueca, Spain, with a dysferlinopathy, <a href="#35" class="mim-tip-reference" title="Vilchez, J. J., Gallano, P., Gallardo, E., Lasa, A., Rojas-Garcia, R., Freixas, A., De Luna, N., Calafell, F., Sevilla, T., Mayordomo, F., Baiget, M., Illa, I. <strong>Identification of a novel founder mutation in the DYSF gene causing clinical variability in the Spanish population.</strong> Arch. Neurol. 62: 1256-1259, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16087766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16087766</a>] [<a href="https://doi.org/10.1001/archneur.62.8.1256" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16087766">Vilchez et al. (2005)</a> identified a homozygous 6086C-T transition in exon 51 of the DYSF gene, resulting in an arg1905-to-ter (R1905X) substitution. Two families presented with Miyoshi myopathy (MMD1; <a href="/entry/254130">254130</a>), 2 presented with distal myopathy with anterior tibial onset (DMAT; <a href="/entry/606768">606768</a>), and 1 presented with limb-girdle muscular dystrophy type 2B (LGMDR2; <a href="/entry/253601">253601</a>). Although the same mutation resulted in different diagnoses, affected members of each family expressed the same phenotype. The R1905X mutation was not identified in 168 control chromosomes. Haplotype analysis indicated a founder effect. Sueca was founded in 1245 by 17 settlers belonging to the Hospital Order, which received land from King James I of Aragon as a reward for help in reconquering Valencia from the Moors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16087766" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs121908960 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908960;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/rs121908960?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=rs121908960" 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=rs121908960" 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=RCV000007064" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007064" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007064</a>
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<p>In a man with classic limb-girdle muscular dystrophy type 2B (LGMDR2; <a href="/entry/253601">253601</a>), <a href="#14" class="mim-tip-reference" title="Illa, I., De Luna, N., Dominguez-Perles, R., Rojas-Garcia, R., Paradas, C., Palmer, J., Marquez, C., Gallano, P., Gallardo, E. <strong>Symptomatic dysferlin gene mutation carriers: characterization of two cases.</strong> Neurology 68: 1284-1289, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17287450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17287450</a>] [<a href="https://doi.org/10.1212/01.wnl.0000256768.79353.60" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17287450">Illa et al. (2007)</a> identified compound heterozygosity for 2 mutations in the DYSF gene: an 1873G-T transversion in exon 20 resulting in an asp625-to-tyr (D625Y) substitution and a 5201A-G transition in exon 47 resulting in a glu1734-to-gly (E1734G; <a href="#0014">603009.0014</a>) substitution. The patient's 54-year-old sister, who was heterozygous for the D625Y mutation, developed progressive fatigue while walking and difficulty climbing stairs at age 51. She had proximal muscle weakness of the lower limbs, increased serum creatine kinase, and evidence of fatty infiltration of the lower limb muscles on MRI. Although immunostaining and Western blot analysis showed decreased dysferlin levels in the woman's muscle, RT-PCR showed normal levels of DYSF mRNA. The findings indicated that heterozygous DYSF mutation carriers may develop late-onset milder manifestations of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17287450" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 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">rs121908961 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908961;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=rs121908961" 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=rs121908961" 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=RCV000007065" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007065" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007065</a>
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<p>For discussion of the glu1734-to-gly (E1734G) mutation in the DYSF gene that was found in compound heterozygous state in a patient with limb-girdle muscular dystrophy type 2B (LGMDR2; <a href="/entry/253601">253601</a>) by <a href="#14" class="mim-tip-reference" title="Illa, I., De Luna, N., Dominguez-Perles, R., Rojas-Garcia, R., Paradas, C., Palmer, J., Marquez, C., Gallano, P., Gallardo, E. <strong>Symptomatic dysferlin gene mutation carriers: characterization of two cases.</strong> Neurology 68: 1284-1289, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17287450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17287450</a>] [<a href="https://doi.org/10.1212/01.wnl.0000256768.79353.60" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17287450">Illa et al. (2007)</a>, see <a href="#0013">603009.0013</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17287450" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 MIYOSHI MUSCULAR DYSTROPHY 1</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">rs121908962 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908962;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=rs121908962" 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=rs121908962" 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=RCV000007066 OR RCV000342783 OR RCV001048974" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007066, RCV000342783, RCV001048974" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007066...</a>
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<p>In 2 sibs with Miyoshi myopathy (MMD1; <a href="/entry/254130">254130</a>), <a href="#14" class="mim-tip-reference" title="Illa, I., De Luna, N., Dominguez-Perles, R., Rojas-Garcia, R., Paradas, C., Palmer, J., Marquez, C., Gallano, P., Gallardo, E. <strong>Symptomatic dysferlin gene mutation carriers: characterization of two cases.</strong> Neurology 68: 1284-1289, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17287450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17287450</a>] [<a href="https://doi.org/10.1212/01.wnl.0000256768.79353.60" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17287450">Illa et al. (2007)</a> identified a homozygous 1555G-A transition in exon 18 of the DYSF gene, resulting in a gly519-to-arg (G519R) substitution. Age at onset was 18 and 15 years, respectively, of distal weakness of the lower limbs with progression to proximal muscle involvement and later upper limb involvement. Both were wheelchair-bound in their thirties. The patients' father, who was heterozygous for the G519R mutation, developed calf myalgias and mild progressive difficulties in walking at age 65 years. He had moderately increased serum creatine kinase and decreased dysferlin immunostaining on muscle biopsy, although DYSF mRNA levels were normal. The findings indicated that heterozygous DYSF mutation carriers may develop late-onset milder manifestations of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17287450" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0016 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2</strong>
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DYSF, IVS31DS, A-G, -33
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs786205083 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205083;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=rs786205083" 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=rs786205083" 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=RCV000007067" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007067" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007067</a>
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<p>In a woman with mild limb-girdle muscular dystrophy type 2B (LGMDR2; <a href="/entry/253601">253601</a>), <a href="#30" class="mim-tip-reference" title="Sinnreich, M., Therrien, C., Karpati, G. <strong>Lariat branch point mutation in the dysferlin gene with mild limb-girdle muscular dystrophy.</strong> Neurology 66: 1114-1116, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16606933/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16606933</a>] [<a href="https://doi.org/10.1212/01.wnl.0000204358.89303.81" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16606933">Sinnreich et al. (2006)</a> identified compound heterozygosity for 2 mutations in the DYSF gene: an A-to-G transition in intron 31, resulting in the in-frame skipping of exon 32, and an indel mutation (<a href="#0005">603009.0005</a>). The A-to-G mutation was found to lie in the second of 2 putative lariat branch point sequences within the gene. Western blot analysis showed decreased levels of dysferlin, about 10% of normal. The patient's 2 severely affected daughters were homozygous for the indel mutation. <a href="#30" class="mim-tip-reference" title="Sinnreich, M., Therrien, C., Karpati, G. <strong>Lariat branch point mutation in the dysferlin gene with mild limb-girdle muscular dystrophy.</strong> Neurology 66: 1114-1116, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16606933/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16606933</a>] [<a href="https://doi.org/10.1212/01.wnl.0000204358.89303.81" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16606933">Sinnreich et al. (2006)</a> postulated that the mother's milder phenotype resulted from residual protein function due to the splice site mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16606933" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0017 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2</strong>
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DYSF, GLY299ARG
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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> rs121908963 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908963;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/rs121908963?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=rs121908963" 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=rs121908963" 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=RCV000007068 OR RCV000726614 OR RCV001388966 OR RCV003460431" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007068, RCV000726614, RCV001388966, RCV003460431" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007068...</a>
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<p>In 2 sibs with limb-girdle muscular dystrophy type 2B (LGMDR2; <a href="/entry/253601">253601</a>), <a href="#31" class="mim-tip-reference" title="Spuler, S., Carl, M., Zabojszcza, J., Straub, V., Bushby, K., Moore, S. A., Bahring, S., Wenzel, K., Vinkemeier, U., Rocken, C. <strong>Dysferlin-deficient muscular dystrophy features amyloidosis.</strong> Ann. Neurol. 63: 323-328, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18306167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18306167</a>] [<a href="https://doi.org/10.1002/ana.21309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18306167">Spuler et al. (2008)</a> identified compound heterozygosity for 2 mutations in the DYSF gene: an 895G-A transition resulting in a gly299-to-arg (G299R) substitution downstream of the second C2 domain, and a 1-bp deletion (855+1delG; <a href="#0020">603009.0020</a>) predicted to result in nonsense-mediated decay and lack of protein expression. Skeletal muscle biopsy of both patients showed amyloid fibrils that stained with antibodies against the second C2 domain of dysferlin. Amyloid was located in the sarcolemma of muscle cells, in multiple vessel walls, and in the interstitium. The unaffected father was heterozygous for the G299R mutation and showed no amyloid in skeletal muscle. <a href="#31" class="mim-tip-reference" title="Spuler, S., Carl, M., Zabojszcza, J., Straub, V., Bushby, K., Moore, S. A., Bahring, S., Wenzel, K., Vinkemeier, U., Rocken, C. <strong>Dysferlin-deficient muscular dystrophy features amyloidosis.</strong> Ann. Neurol. 63: 323-328, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18306167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18306167</a>] [<a href="https://doi.org/10.1002/ana.21309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18306167">Spuler et al. (2008)</a> postulated that the mutation destabilized the protein structure and increased the propensity to form amyloid fibrils. An unrelated family with myopathy and a different mutation at this codon (G299W; <a href="#0018">603009.0018</a>) also showed amyloidosis in skeletal muscle fibers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18306167" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs121908963 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908963;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/rs121908963?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=rs121908963" 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=rs121908963" 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=RCV000007069 OR RCV000594920 OR RCV003159090" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007069, RCV000594920, RCV003159090" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007069...</a>
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<p>In 2 sibs with Miyoshi myopathy (MMD1; <a href="/entry/254130">254130</a>), <a href="#31" class="mim-tip-reference" title="Spuler, S., Carl, M., Zabojszcza, J., Straub, V., Bushby, K., Moore, S. A., Bahring, S., Wenzel, K., Vinkemeier, U., Rocken, C. <strong>Dysferlin-deficient muscular dystrophy features amyloidosis.</strong> Ann. Neurol. 63: 323-328, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18306167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18306167</a>] [<a href="https://doi.org/10.1002/ana.21309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18306167">Spuler et al. (2008)</a> identified a homozygous 895G-T transversion in the DYSF gene, resulting in a gly299-to-trp (G299W) substitution downstream of the second C2 domain. Skeletal muscle biopsy available from 1 patient showed amyloid fibrils that stained with antibodies against the second C2 domain of dysferlin. Amyloid was located in the sarcolemma of muscle cells, in multiple vessel walls, and in the interstitium. <a href="#31" class="mim-tip-reference" title="Spuler, S., Carl, M., Zabojszcza, J., Straub, V., Bushby, K., Moore, S. A., Bahring, S., Wenzel, K., Vinkemeier, U., Rocken, C. <strong>Dysferlin-deficient muscular dystrophy features amyloidosis.</strong> Ann. Neurol. 63: 323-328, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18306167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18306167</a>] [<a href="https://doi.org/10.1002/ana.21309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18306167">Spuler et al. (2008)</a> postulated that the mutation destabilized the protein structure and increased the propensity to form amyloid fibrils. An unrelated family with myopathy and a different mutation at this codon (G299R; <a href="#0017">603009.0017</a>) also showed amyloidosis in skeletal muscle fibers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18306167" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs786200897 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786200897;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=rs786200897" 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=rs786200897" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an Arab man with limb-girdle muscular dystrophy type 2B (LGMDR2; <a href="/entry/253601">253601</a>), <a href="#31" class="mim-tip-reference" title="Spuler, S., Carl, M., Zabojszcza, J., Straub, V., Bushby, K., Moore, S. A., Bahring, S., Wenzel, K., Vinkemeier, U., Rocken, C. <strong>Dysferlin-deficient muscular dystrophy features amyloidosis.</strong> Ann. Neurol. 63: 323-328, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18306167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18306167</a>] [<a href="https://doi.org/10.1002/ana.21309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18306167">Spuler et al. (2008)</a> identified a homozygous A-to-G transition in intron 14 of the DYSF gene, resulting in a splice site mutation near the third C2 domain. Muscle biopsy showed sarcolemmal defects and deposition of amyloid fibrils. <a href="#31" class="mim-tip-reference" title="Spuler, S., Carl, M., Zabojszcza, J., Straub, V., Bushby, K., Moore, S. A., Bahring, S., Wenzel, K., Vinkemeier, U., Rocken, C. <strong>Dysferlin-deficient muscular dystrophy features amyloidosis.</strong> Ann. Neurol. 63: 323-328, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18306167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18306167</a>] [<a href="https://doi.org/10.1002/ana.21309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18306167">Spuler et al. (2008)</a> postulated that the mutation destabilized the protein structure and increased the propensity to form amyloid fibrils. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18306167" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs786200898 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786200898;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=rs786200898" 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=rs786200898" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the 1-bp deletion in the DYSF gene (855+1delG) that was found in compound heterozygous state in patients with limb-girdle muscular dystrophy type 2B (LGMDR2; <a href="/entry/253601">253601</a>) by <a href="#31" class="mim-tip-reference" title="Spuler, S., Carl, M., Zabojszcza, J., Straub, V., Bushby, K., Moore, S. A., Bahring, S., Wenzel, K., Vinkemeier, U., Rocken, C. <strong>Dysferlin-deficient muscular dystrophy features amyloidosis.</strong> Ann. Neurol. 63: 323-328, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18306167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18306167</a>] [<a href="https://doi.org/10.1002/ana.21309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18306167">Spuler et al. (2008)</a>, see <a href="#0017">603009.0017</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18306167" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs727503909 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs727503909;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=rs727503909" 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=rs727503909" 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=RCV000007072 OR RCV000311139 OR RCV000546602 OR RCV000599552 OR RCV004998078" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007072, RCV000311139, RCV000546602, RCV000599552, RCV004998078" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007072...</a>
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<p>In 2 Spanish sibs, aged 2 and 5 years, with unusual congenital onset of limb-girdle muscular dystrophy type 2B (LGMDR2; <a href="/entry/253601">253601</a>), <a href="#26" class="mim-tip-reference" title="Paradas, C., Gonzalez-Quereda, L., De Luna, N., Gallardo, E., Garcia-Consuegra, I., Gomez, H., Cabello, A., Illa, I., Gallano, P. <strong>A new phenotype of dysferlinopathy with congenital onset.</strong> Neuromusc. Disord. 19: 21-25, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19084402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19084402</a>] [<a href="https://doi.org/10.1016/j.nmd.2008.09.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19084402">Paradas et al. (2009)</a> identified a homozygous 1-bp deletion (2776delG) in exon 26 of the DYSF gene, resulting in a frameshift and premature termination. The parents were not consanguineous, but they came from the same small village, and haplotype analysis suggested an ancient consanguineous relationship. Both patients presented in infancy with hypotonia and delayed motor development. They had difficulty walking, running, and climbing stairs, as well as neck muscle weakness. The patients had almost no expression of dysferlin in muscle, whereas clinically unaffected family members who were heterozygous for the mutation had about a 50% reduction in dysferlin expression. <a href="#26" class="mim-tip-reference" title="Paradas, C., Gonzalez-Quereda, L., De Luna, N., Gallardo, E., Garcia-Consuegra, I., Gomez, H., Cabello, A., Illa, I., Gallano, P. <strong>A new phenotype of dysferlinopathy with congenital onset.</strong> Neuromusc. Disord. 19: 21-25, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19084402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19084402</a>] [<a href="https://doi.org/10.1016/j.nmd.2008.09.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19084402">Paradas et al. (2009)</a> emphasized the early onset of this disorder in these sibs, and suggested that they have a novel phenotype not previously associated with DYSF mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19084402" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs786205084 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205084;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=rs786205084" 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=rs786205084" 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=RCV000007073 OR RCV000723469 OR RCV001215439 OR RCV002476993" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007073, RCV000723469, RCV001215439, RCV002476993" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007073...</a>
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<p>In 6 unrelated Portuguese male patients with limb-girdle muscular dystrophy type 2B (LGMDR2; <a href="/entry/253601">253601</a>), <a href="#29" class="mim-tip-reference" title="Santos, R., Oliveira, J., Vieira, E., Coelho, T., Carneiro, A. L., Evangelista, T., Dias, C., Fortuna, A., Geraldo, A., Negrao, L., Guimaraes, A., Bronze-da-Rocha, E. <strong>Private dysferlin exon skipping mutation (c.5492G-A) with a founder effect reveals further alternative splicing involving exons 49-51.</strong> J. Hum. Genet. 55: 546-549, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20535123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20535123</a>] [<a href="https://doi.org/10.1038/jhg.2010.60" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20535123">Santos et al. (2010)</a> identified a homozygous 5492G-A transition in the last nucleotide of exon 49 of the DYSF gene. Another Portuguese patient was compound heterozygous for this mutation and another pathogenic mutation in the DYSF gene. The 5492G-A mutation was not found in 240 control alleles. Transcript analysis of patient tissue indicated that the 5492G-A mutation resulted in abnormal splicing, skipping of exon 49, and premature termination. Further studies identified several other residually expressed products of alternative splicing involving exons 50 and 51 in both patients and normal controls, particularly in blood. Haplotype analysis supported a founder effect for the mutation. All 7 patients originated or resided in a confined region of the northern interior part of Portugal. Although most patients had a limb-girdle muscular dystrophy, there was some phenotypic variation: 1 patient presented with distal muscle weakness in the lower limbs, and another had cardiac arrhythmia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20535123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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Anderson, L. V. B., Davison, K., Moss, J. A., Young, C., Cullen, M. J., Walsh, J., Johnson, M. A., Bashir, R., Britton, S., Keers, S., Argov, Z., Mahjneh, I., Fougerousse, F., Beckmann, J. S., Bushby, K. M. D.
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<strong>Dysferlin is a plasma membrane protein and is expressed early in human development.</strong>
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Hum. Molec. Genet. 8: 855-861, 1999. Note: Erratum: Hum. Molec. Genet. 8: 1141 only, 1999.
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[<a href="https://doi.org/10.1093/brain/119.6.1895" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/1682" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1998.5204" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/10.17.1761" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(sici)1096-8628(20000410)91:4<305::aid-ajmg12>3.0.co;2-s" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.64.8.1176" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.nmd.2008.09.015" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-006-0230-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-009-0632-y" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/jhg.2010.60" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000204358.89303.81" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.21309" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.nmd.2018.05.007" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000068333.43005.12" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16996541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16996541</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16996541" 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.jns.2006.07.004" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="35" class="mim-anchor"></a>
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<a id="Vilchez2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vilchez, J. J., Gallano, P., Gallardo, E., Lasa, A., Rojas-Garcia, R., Freixas, A., De Luna, N., Calafell, F., Sevilla, T., Mayordomo, F., Baiget, M., Illa, I.
|
|
<strong>Identification of a novel founder mutation in the DYSF gene causing clinical variability in the Spanish population.</strong>
|
|
Arch. Neurol. 62: 1256-1259, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16087766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16087766</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16087766" 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/10.1001/archneur.62.8.1256" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="36" class="mim-anchor"></a>
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<a id="Weiler1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Weiler, T., Bashir, R., Anderson, L. V. B., Davison, K., Moss, J. A., Britton, S., Nylen, E., Keers, S., Vafiadaki, E., Greenberg, C. R., Bushby, K. M. D., Wrogemann, K.
|
|
<strong>Identical mutation in patients with limb girdle muscular dystrophy type 2B or Miyoshi myopathy suggests a role for modifier gene(s).</strong>
|
|
Hum. Molec. Genet. 8: 871-877, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10196377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10196377</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10196377" 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/8.5.871" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="37" class="mim-anchor"></a>
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<a id="Weiler1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Weiler, T., Greenberg, C. R., Nylen, E., Halliday, W., Morgan, K., Eggertson, D., Wrogemann, K.
|
|
<strong>Limb-girdle muscular dystrophy and Miyoshi myopathy in an aboriginal Canadian kindred map to LGMD2B and segregate with the same haplotype.</strong>
|
|
Am. J. Hum. Genet. 59: 872-878, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8808603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8808603</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8808603" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 11/1/2010
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 8/2/2010<br>Cassandra L. Kniffin - updated : 7/12/2010<br>Cassandra L. Kniffin - updated : 3/5/2010<br>George E. Tiller - updated : 2/23/2010<br>Cassandra L. Kniffin - updated : 11/4/2009<br>Cassandra L. Kniffin - updated : 3/24/2009<br>Cassandra L. Kniffin - updated : 3/31/2008<br>Cassandra L. Kniffin - updated : 2/4/2008<br>Cassandra L. Kniffin - updated : 12/5/2007<br>Marla J. F. O'Neill - updated : 8/2/2007<br>George E. Tiller - updated : 3/21/2007<br>Cassandra L. Kniffin - updated : 11/4/2005<br>Ada Hamosh - updated : 5/9/2003<br>Victor A. McKusick updated : 2/22/2002<br>George E. Tiller - updated : 1/23/2002<br>Kathryn R. Wagner - updated : 3/28/2001<br>Carol A. Bocchini - updated : 9/21/2000<br>Victor A. McKusick - updated : 9/27/1999<br>Victor A. McKusick - updated : 5/18/1999<br>Victor A. McKusick - updated : 4/29/1999
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
|
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Creation Date:
|
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
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Victor A. McKusick : 8/28/1998
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 08/09/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
|
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 03/17/2023<br>carol : 06/24/2021<br>carol : 07/15/2020<br>carol : 12/20/2019<br>carol : 12/19/2019<br>carol : 09/26/2018<br>carol : 09/25/2018<br>carol : 09/23/2016<br>alopez : 04/29/2015<br>mcolton : 4/20/2015<br>carol : 3/9/2015<br>carol : 9/30/2013<br>carol : 9/17/2013<br>terry : 11/28/2012<br>wwang : 12/9/2010<br>ckniffin : 11/1/2010<br>wwang : 8/3/2010<br>ckniffin : 8/2/2010<br>wwang : 7/14/2010<br>ckniffin : 7/12/2010<br>carol : 3/9/2010<br>ckniffin : 3/5/2010<br>wwang : 2/26/2010<br>terry : 2/23/2010<br>wwang : 11/18/2009<br>ckniffin : 11/4/2009<br>carol : 6/25/2009<br>wwang : 4/1/2009<br>ckniffin : 3/24/2009<br>wwang : 4/4/2008<br>ckniffin : 3/31/2008<br>wwang : 2/20/2008<br>wwang : 2/20/2008<br>ckniffin : 2/4/2008<br>wwang : 12/11/2007<br>ckniffin : 12/5/2007<br>wwang : 8/15/2007<br>terry : 8/2/2007<br>wwang : 3/22/2007<br>terry : 3/21/2007<br>wwang : 2/15/2007<br>wwang : 11/14/2005<br>ckniffin : 11/4/2005<br>ckniffin : 7/19/2005<br>terry : 11/4/2004<br>carol : 4/1/2004<br>carol : 9/9/2003<br>tkritzer : 8/20/2003<br>ckniffin : 8/12/2003<br>carol : 5/22/2003<br>alopez : 5/9/2003<br>terry : 5/9/2003<br>carol : 3/20/2002<br>cwells : 3/8/2002<br>terry : 2/22/2002<br>cwells : 2/13/2002<br>cwells : 1/23/2002<br>alopez : 8/6/2001<br>cwells : 5/3/2001<br>carol : 3/29/2001<br>carol : 3/29/2001<br>terry : 3/28/2001<br>mcapotos : 9/22/2000<br>carol : 9/21/2000<br>carol : 9/20/2000<br>terry : 11/24/1999<br>alopez : 10/29/1999<br>alopez : 9/30/1999<br>terry : 9/27/1999<br>mgross : 6/4/1999<br>mgross : 5/25/1999<br>terry : 5/18/1999<br>alopez : 5/4/1999<br>terry : 4/29/1999<br>alopez : 12/22/1998<br>dkim : 9/10/1998<br>alopez : 9/2/1998<br>alopez : 9/2/1998<br>alopez : 8/31/1998<br>alopez : 8/28/1998<br>alopez : 8/28/1998
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
|
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<h3>
|
|
<span class="mim-font">
|
|
<strong>*</strong> 603009
|
|
</span>
|
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</h3>
|
|
</div>
|
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|
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<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
DYSFERLIN; DYSF
|
|
|
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</span>
|
|
</h3>
|
|
</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>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: DYSF</em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
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<div>
|
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<p>
|
|
<span class="mim-text-font">
|
|
|
|
<strong>SNOMEDCT:</strong> 718179003, 782675008;
|
|
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|
|
<strong>ICD10CM:</strong> G71.033;
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</span>
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</p>
|
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
|
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<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 2p13.2
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 2:71,453,561-71,686,763 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
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<div>
|
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<br />
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</div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
2p13.2
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Miyoshi muscular dystrophy 1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
254130
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
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</tr>
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Muscular dystrophy, limb-girdle, autosomal recessive 2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
253601
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Myopathy, distal, with anterior tibial onset
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
606768
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
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|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Dysferlin belongs to a family of genes similar to Caenorhabditis elegans ferlin. Members of this family contain a type II transmembrane domain with the majority of the protein facing the cytoplasm, and they have multiple C2 domains, which are implicated in calcium-dependent membrane fusion events (Britton et al., 2000). Dysferlin plays an important role in muscle fiber repair (Bashir et al., 1998). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
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<span class="mim-text-font">
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<p>Liu et al. (1998) constructed a 3-Mb PAC contig spanning the Miyoshi myopathy (MMD1; 254130) candidate region. This clarified the order of genetic markers across the area, provided 5 new polymorphic markers within it, and narrowed the locus to approximately 2 Mb. They found 5 skeletal muscle ESTs that mapped in this region. Liu et al. (1998) reported that 1 of these ESTs is located in a novel, full-length 6.9-kb muscle cDNA; they designated the corresponding protein dysferlin. </p><p>By database analysis and sequencing overlapping YAC and PAC clones on chromosome 2p associated with autosomal recessive limb-girdle muscular dystrophy-2 (LGMDR2; 253601), previously symbolized LGMD2B, Bashir et al. (1998) cloned a partial dysferlin cDNA. The deduced 1,779-amino acid protein contains 2 C2 domains and a putative transmembrane domain near the C terminus. Northern blot analysis detected a major transcript of approximately 7 kb in skeletal muscle, heart, and placenta, and more weakly in liver, lung, kidney, and pancreas. A transcript of less than 4 kb was present in brain. Analysis of specific brain regions detected the 7-kb transcript only in cerebellum and medulla. The 4-kb transcript was expressed in all brain regions except spinal cord, with highest levels in putamen. No dysferlin was detected in fetal brain. The proposed name 'dysferlin' combined the role of the gene in producing muscular dystrophy with its C. elegans homology. </p><p>Britton et al. (2000) stated that DYSF contains 2,080 amino acids. By sequence analysis, they showed that it has 6 C2 domains, a C-terminal transmembrane domain, and several calcium-binding residues conserved between C. elegans ferlin, myoferlin (MYOF; 604603), and otoferlin (OTOF; 603681). </p><p>By 5-prime RACE of adult skeletal muscle total RNA, Pramono et al. (2006) identified a splice variant of DYSF, which they called DYSF-v1, that arises from an alternate first exon. The deduced 2,081-amino acid variant differs from DYSF only in the N terminus. Northern blot analysis detected a 7.5-kb DYSF-v1 transcript in skeletal muscle, heart, spleen, small intestine, kidney, liver, placenta, and lung, and a 6-kb transcript in brain. There were also minor transcripts of 2-kb and 1.3-kb. A 7.5-kb DYSF transcript was detected in brain, heart, skeletal muscle, spleen, kidney, liver, small intestine, placenta, lung, and peripheral blood leukocytes. Variable expression of minor transcripts of about 5-, 2-, and 1.3-kb was also detected. The promoter region associated with the variant DYSF-v1 contains 2 CpG islands, a TATA box, and 2 clusters of binding sites for several transcription factors, including those involved in muscle expression. </p><p>By RT-PCR of dysferlin mRNA from blood derived from 50 individuals of Chinese, Malaysian, and Indian origin as well as of skeletal muscle samples from unrelated individuals, Pramono et al. (2009) identified alternatively spliced variants of the DYSF gene involving novel exons, i.e., exons 5a and 40a. Previously reported alternative splicing of exon 17 was also found. Long-range RT-PCR and subcloning revealed a total of 14 dysferlin transcripts derived from alternative splicing, all of which maintained an open reading frame. The study also characterized the differences in relative frequencies of these dysferlin transcripts in skeletal muscle and blood. Pramono et al. (2009) suggested that these findings may have clinical relevance in the molecular diagnosis of DYSF-related disorders. </p>
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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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<span class="mim-text-font">
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<p>Aoki et al. (2001) reported the genomic organization of the dysferlin gene and determined that it contains 55 exons. </p><p>Pramono et al. (2006) identified a DYSF-v1 promoter region associated with an alternative first exon located within intron 1. </p>
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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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<span class="mim-text-font">
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<p>Bashir et al. (1994) mapped the DYSF gene to chromosome 2p13. </p>
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<br />
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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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<span class="mim-text-font">
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<p>Anderson et al. (1999) raised a monoclonal antibody to dysferlin and studied the expression of the protein. Immunolabeling with the antibody demonstrated a polypeptide of approximately 230 kD on Western blot analysis of skeletal muscle, and microscopy at both the light and electron microscopic levels localized dysferlin to the muscle fiber membrane. A specific loss of labeling of dysferlin was observed in patients with mutations in the DYSF gene. Furthermore, patients with 2 different frameshift mutations demonstrated very low levels of immunoreactive protein in a manner reminiscent of the dystrophin expressed in many Duchenne patients. Analysis of human fetal tissue showed that dysferlin was expressed at the earliest stages of development examined, at Carnegie stage 15 or 16 (embryonic age 5 to 6 weeks). Dysferlin is present, therefore, at a time when the limbs start to form regional differentiation. Anderson et al. (1999) suggested that lack of dysferlin at this critical time may contribute to the pattern of muscle involvement that develops later, with the onset of a muscular dystrophy primarily affecting proximal or distal muscles. </p><p>Caveolin-3 (CAV3; 601253) is a skeletal muscle membrane protein important in the formation of caveolae and in which mutations were identified in a form of dominantly inherited limb-girdle muscular dystrophy (LGMD1C), reclassified as rippling muscle disease (RMD2; 606072) by Straub et al. (2018). Matsuda et al. (2001) reported that dysferlin coimmunoprecipitates with caveolin-3 from biopsied normal human skeletal muscles. Using immunofluorescence, they found abnormal localization of dysferlin in muscles from patients with LGMD1C. Amino acid sequence analysis of the dysferlin protein revealed 7 sites that correspond to caveolin-3 scaffold-binding motifs, and 1 site that is a potential target to bind the WW domain of the caveolin-3 protein. The authors hypothesized that one function of dysferlin may be to interact with caveolin-3 to subserve signaling functions of caveolae. </p><p>In C2C5 mouse cells, Fujita et al. (2007) found that wildtype dysferlin was degraded by the ubiquitin/proteasome endoplasmic reticulum (ER)-associated degradation system (ERAD). A proteosome inhibitor induced dysferlin accumulation in the ER. In contrast, mutant dysferlin (see, e.g., W999C; 603009.0010) spontaneously aggregated in the ER and stimulated autophagosome formation by activation of the ER stress-EIF2-alpha (603907) phosphorylation pathway, as well as stimulated ER stress-induced cell death. Lysosomal protease inhibitors resulted in the accumulation of mutant dysferlin aggregates. The authors proposed 2 ERAD models for intracellular dysferlin degradation: ubiquitin/proteasome ERAD(I) and autophagy/lysosome ERAD(II). Mutant dysferlin aggregates in the ER were degraded by the autophagy/lysosome ERAD(II), as an alternative to ERAD(I), when the ERAD(I) system was impaired by mutant aggregates. </p>
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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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<span class="mim-text-font">
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<p>The finding that Miyoshi myopathy (MMD1; 254130) and autosomal recessive limb-girdle muscular dystrophy-2 (LGMDR2; previously symbolized LGMD2B) mapped to the same chromosomal region on chromosome 2p13 raised the possibility that they might be allelic disorders. They were in fact shown to be varying expressions of the same mutant gene; 2 large inbred kindreds whose members included both MMD1 and LGMD2B patients were described by Weiler et al. (1996) and Illarioshkin et al. (1996, 1997). Affected individuals in both pedigrees shared the same haplotype. Differences in the phenotype appeared to be due to additional modifying factors. </p><p>Liu et al. (1998) described 9 mutations in the DYSF gene (see, e.g., 603009.0001-603009.0004) in 9 families with MMD1, LGMD2B, and/or distal myopathy with anterior tibial onset (DMAT; 606768); 5 were predicted to prevent dysferlin expression. Identical mutations in the dysferlin gene can produce, they concluded, more than 1 myopathy phenotype. </p><p>Bashir et al. (1998) identified 2 homozygous frameshift mutations in the DYSF gene (603009.0005 and 603009.0006, respectively), resulting in muscular dystrophy of either proximal or distal onset in 9 families. </p><p>In patients with Miyoshi myopathy, Matsumura et al. (1999) and Aoki et al. (2001) identified several mutations in the dysferlin gene (see, e.g., 603009.0010 and 603009.0011). </p><p>Weiler et al. (1999) addressed the issue of the occurrence of both LGMD2B and Miyoshi myopathy in the same family. This had suggested that the same mutation could lead to either LGMD2B or MMD1 and that additional factors were needed to explain the development of the different clinical phenotypes. The discovery of the role of the DYSF gene in these 2 disorders made it possible to test this hypothesis. Weiler et al. (1999) reported that, in a large Canadian aboriginal kindred with both LGMD2B and MMD1 patients, all affected individuals were homozygous for a pro791-to-arg (603009.0007) mutation of dysferlin and that the mutation resulted in similar reductions of dysferlin expression in the 2 types of patients. Modifier gene(s) or additional factors must account for the differences in the clinical phenotype. </p><p>In 20 of 25 Japanese patients with a clinical diagnosis of Miyoshi myopathy, Takahashi et al. (2003) identified 16 different dysferlin mutations, 10 of which were novel. </p><p>In a review of 40 patients with dysferlinopathy, Nguyen et al. (2007) found that about 50% had typical Miyoshi myopathy or LGMD2B. Other patients had more unusual phenotypes, including mixed proximal and distal onset (35%), distal painful leg swelling without muscle weakness (10%), and asymptomatic increased serum creatine kinase (5%). The disorder could worsen rapidly, and 25% of patients were initially misdiagnosed as having polymyositis. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</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>In patients with LGMD2B or Miyoshi myopathy, Spuler et al. (2008) identified 3 different mutations in the N terminus of the DYSF gene (603009.0017-603009.0019) that resulted in deposition of dysferlin-reactive amyloid fibrils within muscle fibers. The authors postulated that amyloid protein is a proteolytic cleavage product of dysferlin, and that the mutations destabilized the protein structure, leading to an increase in the propensity to form amyloid fibrils. </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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<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>The SJL mouse strain (Festing, 1979) is susceptible to many induced autoimmune diseases such as experimental autoimmune encephalitis (EAE) and inflammatory muscle disease. Additionally, the skeletal muscle of SJL mice was shown to have an increased regenerative capacity and demonstrates the spontaneous occurrence of what was designated an 'inflammatory myopathy,' accompanied by loss of strength. By histopathologic examinations of muscles in SJL mice of different ages, Bittner et al. (1999) found features compatible with a progressive muscular dystrophy, including degenerative and regenerative changes of muscle fibers and a progressive fibrosis. Histologically, the changes were observed in mice as young as 3 weeks of age. Changes affected primarily the proximal muscle groups, whereas the distal muscles remained less affected. The morphologic alterations were associated with signs of slowly progressive muscle weakness, which Bittner et al. (1999) detected as early as 3 weeks after birth when mice were suspended by their tails. The phenotype was found to be inherited as an autosomal recessive trait and was found to map to mouse chromosome 6, in a region syntenic with human 2p13, where the DYSF gene maps. Because of this synteny, Bittner et al. (1999) studied dysferlin in these mice. They found a reduction to approximately 15% of control levels in SJL mice. They found a 171-bp deletion in the Dysf gene of SJL mice, predicted to result in removal of 57 amino acids, including most of the fourth C2 domain. The last C2 domain is conserved in other members of the fer-like gene family. </p><p>Bansal et al. (2003) generated dysferlin-null mice by targeted disruption. Although dysferlin-null mice maintain a functional dystrophin-glycoprotein complex they nevertheless develop a progressive muscular dystrophy. In normal muscle, membrane patches enriched in dysferlin can be detected in response to sarcolemma injuries. In contrast, there are subsarcolemmal accumulations of vesicles in dysferlin-null muscle. Membrane repair assays with a 2-photon laser-scanning microscope demonstrated that wildtype muscle fibers efficiently resealed their sarcolemma in the presence of calcium. Interestingly, dysferlin-deficient muscle fibers were defective in calcium-dependent sarcolemma resealing. Bansal et al. (2003) concluded that membrane repair is therefore an active process in skeletal muscle fibers, and that dysferlin has an essential role in this process. </p><p>Ho et al. (2004) generated 2 novel lines of dysferlin-deficient mice obtained by gene targeting and identification of an inbred strain bearing a retrotransposon insertion in the Dysf gene, respectively. The mutations in these mice were located at the 3-prime and 5-prime ends of the Dysf gene. Both lines of mice lacked dysferlin and developed a progressive muscular dystrophy with histopathologic and ultrastructural features that closely resemble the human disease. Vital staining with Evans blue dye revealed loss of sarcolemmal integrity in both lines of mice, similar to that seen in mdx (DMD; 300377) and Cav3-deficient mice. However, in contrast to the latter group of animals, the dysferlin-deficient mice had an intact dystrophin glycoprotein complex and normal levels of caveolin-3. Ho et al. (2004) concluded that muscle membrane disruption and myofiber degeneration in dysferlinopathy were directly mediated by the loss of dysferlin via a new pathogenic mechanism in muscular dystrophies. </p><p>Han et al. (2007) generated dysferlin-null mice and observed the development of mild cardiomyopathy that was exacerbated by stress exercise. Evans blue dye uptake was increased in dysferlin-deficient cardiomyocytes. Dysf/Dmd double-knockout mice developed early-onset cardiomyopathy. Han et al. (2007) suggested that dysferlin-mediated membrane repair is important for maintaining membrane integrity of cardiomyocytes, particularly under conditions of mechanical stress. </p><p>Chiu et al. (2009) observed that muscle regeneration was attenuated in a mouse model of dysferlinopathy, with delayed removal of necrotic fibers, an extended inflammatory phase, and delayed functional recovery. Satellite cell activation and myoblast fusion appeared normal, but there was a reduction in early neutrophil recruitment in regenerating and also needle-wounded muscle in dysferlin-deficient mice. Primary mouse dysferlinopathy myoblast cultures showed reduced cytokine release upon stimulation, indicating that the secretion of chemotactic molecules was impaired. Chiu et al. (2009) suggested an extension to the muscle membrane repair model, where, in addition to fusing patch repair vesicles with the sarcolemma, dysferlin is also involved in the release of chemotactic agents. Reduced neutrophil recruitment may result in incomplete cycles of regeneration in dysferlinopathy, which combines with the membrane repair deficit to ultimately trigger dystrophic pathology. </p><p>Glover et al. (2010) generated 3 lines of transgenic mice overexpressing low, mid, and high levels of human dysferlin compared to endogenous levels in wildtype mice. Transgenic mice with high (176-fold) levels of overexpression had muscle atrophy, failure to thrive, severe kyphosis, hind-limb atrophy and weakness, and had to be euthanized between 5 and 7 months of age. Histologic studies of muscle from high and mid (36-fold) dysferlin overexpression mice showed a non-necrotic congenital myopathy with marked reduction in fiber diameter, increased connective tissue, and centralized nuclei. Cardiac muscle was also affected and showed calcifications. These pathogenic changes correlated with increasing dysferlin overexpression. Further analysis of skeletal muscle showed selective loss of the fast type II muscle fibers and abnormal accumulation of vesicular structures at sarcolemmal membranes, although the sarcolemmal membrane was intact. Other findings included evidence of endoplasmic reticulum stress and an increase in the calcium-dependent binding protein annexin-a2 (ANXA2; 151740). These findings were distinct from abnormalities seen in dysferlin-deficient mice. Low (2-fold) levels of dysferlin overexpression were not associated with cytotoxicity in skeletal muscle. Glover et al. (2010) concluded that attempts at gene replacement therapy for dysferlin need to consider expression levels and dosage. </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>ALLELIC VARIANTS</strong>
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</span>
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<strong>22 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 MIYOSHI MUSCULAR DYSTROPHY 1</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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DYSF, GLN605TER
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<br />
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SNP: rs121908953,
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ClinVar: RCV000007047, RCV000301362, RCV003574697
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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 French family with Miyoshi myopathy (MMD1; 254130), Liu et al. (1998) found that affected members had a homozygous nonsense mutation in codon 605 of the DYSF gene, a CAG-to-TAG transition at nucleotide 2186 (Q605X). </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>.0002 MYOPATHY, DISTAL, WITH ANTERIOR TIBIAL ONSET</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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DYSF, 1-BP DEL, 5966G
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<br />
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SNP: rs786205081,
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gnomAD: rs786205081,
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ClinVar: RCV000007048, RCV000700124, RCV001781197, RCV003466822
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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 consanguineous Spanish family in which members carried the diagnosis of distal myopathy with anterior tibial onset (DMAT; 606768), Liu et al. (1998) found that the myopathy was associated with deletion of 5966G in the DYSF gene, resulting in a frameshift. Illa et al. (2001) reported the same family in greater detail and referred to the disorder as another dysferlinopathy. Affected members of the family were homozygous for the deletion. </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>.0003 MIYOSHI MUSCULAR DYSTROPHY 1</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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MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2, 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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DYSF, ILE1298VAL
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<br />
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SNP: rs121908954,
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gnomAD: rs121908954,
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ClinVar: RCV000007049, RCV000153183, RCV000509353, RCV000658868, RCV000681611, RCV001563901, RCV004547461, RCV004998077
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an Italian family in which some members had Miyoshi myopathy (MMD1; 254130) and others had limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), i.e., myopathy with either distal onset or proximal onset, respectively, Liu et al. (1998) found compound heterozygosity for 2 missense mutations in the DYSF gene: an ATG-to-GTC transition at nucleotide 4265 (I1298V) and a CGT-to-TGT transition at nucleotide 6497 (R2042C; 603009.0004). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 MIYOSHI MUSCULAR DYSTROPHY 1</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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MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2, 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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DYSF, ARG2042CYS
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<br />
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SNP: rs121908955,
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gnomAD: rs121908955,
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ClinVar: RCV000007051, RCV000007052, RCV000080320, RCV000815134, RCV001813961, RCV005025020
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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>For discussion of the arg2042-to-cys (R2042C) mutation in the DYSF gene that was found in compound heterozygous state in patients with Miyoshi myopathy (MMD1; 254130) or limb-girdle muscular dystrophy type 2B (LGMDR2; 253601) by Liu et al. (1998), see 603009.0003. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 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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DYSF, 5-BP DEL/4-BP INS, NT4872
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<br />
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SNP: rs786200896,
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gnomAD: rs786200896,
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ClinVar: RCV000007053, RCV000338549, RCV000806281, RCV003466823, RCV005025021
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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 8 Libyan Jewish families with limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), Bashir et al. (1998) found that affected individuals were homozygous for a 1-bp deletion of guanine and a C-G transversion at codon 1322 of the DYSF gene, resulting in a frameshift and premature stop codon at position 1331 (numbering based on a partial DYSF amino acid sequence). Subsequently, Therrien et al. (2006) reported the mutation as an insertion/deletion (4872delinsCCCC). In a ninth Libyan Jewish family, with a single affected member, the mutation was detected in single copy; one of the parents (who did not carry the mutation) was of Romanian origin. The 25 patients in these families showed onset of the disease between 12 and 39 years of age (mean 19.5 +/- 5 years). All had lower limb involvement on average 9 years before upper limb symptoms. Thirteen patients (52%) presented with distal lower limb muscle weakness, mostly of the gastrocnemius, with some complaining of transient calf enlargement. Intrafamilial variability was seen in the distribution of muscle weakness. Only 6 patients had lost the ability to walk independently; all of these were older than 35 years. Muscle biopsy showed chronic myopathic changes, and creatine kinase was elevated 10 to 25 times the normal rate in all affected individuals. </p><p>In 2 Italian sisters with severe LGMDR2, Sinnreich et al. (2006) identified homozygosity for the insertion/deletion mutation in the DYSF gene, which they characterized as a 1-bp deletion (4872delG) and a 4876G-C transversion, that was previously reported by Bashir et al. (1998). Each parent was heterozygous for the insertion/deletion mutation. The girls had onset in the second decade of proximal muscle weakness and wasting. Their 70-year-old mother, who had had mild proximal weakness since her forties, was compound heterozygous for the indel mutation and a splice site mutation (603009.0016). </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>.0006 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 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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DYSF, 23-BP INS
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<br />
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SNP: rs786205082,
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ClinVar: RCV000007054
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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 Palestinian Arab family described by Mahjneh et al. (1992), Bashir et al. (1998) demonstrated that autosomal recessive limb-girdle muscular dystrophy type 2B (LGMDR2; 253601) resulted from a 23-bp insertion at codon 1386 in the DYSF gene. The insertion represented a tandem duplication resulting from replication slippage and was predicted to result in frameshift and premature termination at codon 1427 (numbering based on a partial DYSF amino acid sequence). This kindred also contained individuals with a congenital form of muscular dystrophy (see 254300); none of these individuals carried the DYSF mutation, indicating that it had a different genetic basis. </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>.0007 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 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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MIYOSHI MUSCULAR DYSTROPHY 1, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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DYSF, PRO791ARG
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<br />
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SNP: rs121908956,
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gnomAD: rs121908956,
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ClinVar: RCV000007055, RCV000007056, RCV000790785, RCV000807968
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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 large Canadian aboriginal kindred reported by Weiler et al. (1996), Weiler et al. (1999) found that both patients with limb-girdle muscular dystrophy type 2B (LGMDR2; 253601) and patients with Miyoshi myopathy (MMD1; 254130) were homozygous for a pro791-to-arg (P791R) missense mutation in the DYSF gene. Four additional patients from 2 previously unpublished families also had this mutation. Haplotype analysis suggested a common origin of the mutation in all of the patients. Western blot analysis of muscle in patients with either Miyoshi myopathy or LGMD2B showed a similar abundance of dysferlin staining of 15% and 11%, respectively. Normal tissue sections showed that dysferlin localizes to the sarcolemma, whereas tissue sections from patients with Miyoshi myopathy or limb-girdle muscular dystrophy showed minimal staining that was indistinguishable between the 2 types. </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>.0008 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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DYSF, NT5711, G-A, +5
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<br />
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SNP: rs745891180,
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gnomAD: rs745891180,
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|
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ClinVar: RCV000007057, RCV001781198, RCV001851715, RCV002298436, RCV003466824
|
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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 large consanguineous pedigree of Yemenite Jewish descent with limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), McNally et al. (2000) identified a homozygous G-to-A change predicted to affect position 5 in the intron following amino acid 1686 (5711 bp) of the dysferlin cDNA sequence. The phenotype associated with this mutation begins in the late second decade and includes an elevated serum creatine kinase. Biopsy samples from these patients demonstrated an inflammatory process, a finding not previously associated with LGMD. </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>
|
|
<span class="mim-font">
|
|
<strong>.0009 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
MIYOSHI MUSCULAR DYSTROPHY 1, INCLUDED
|
|
</span>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
|
|
DYSF, VAL67ASP
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|
<br />
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|
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SNP: rs121908957,
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|
|
|
ClinVar: RCV000007058, RCV000681612
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
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<div>
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|
<span class="mim-text-font">
|
|
<p>In a large consanguineous Russian family with both limb-girdle muscular dystrophy type 2B (LGMDR2; 253601) and Miyoshi myopathy (MMD1; 254130) reported by Illarioshkin et al. (1996), Illarioshkin et al. (2000) found that all affected individuals were homozygous for a TG-to-AT change at nucleotides 573-574 of the DYSF gene, resulting in a val67-to-asp (V67D) substitution. </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
|
|
</div>
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|
|
</div>
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|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 MIYOSHI MUSCULAR DYSTROPHY 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
DYSF, TRP999CYS
|
|
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|
|
<br />
|
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|
|
SNP: rs28937581,
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|
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|
|
|
gnomAD: rs28937581,
|
|
|
|
|
|
ClinVar: RCV000007059, RCV000176869, RCV000790765, RCV001232546, RCV004525846, RCV005031402
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In patients with Miyoshi myopathy (MMD1; 254130), Matsumura et al. (1999) identified a 3370G-T transversion in exon 28 of the DYSF gene, resulting in a trp999-to-cys (W999C) substitution. Takahashi et al. (2003) noted that, in general, patients with the W999C mutation tended to have a later age at disease onset (mean, 32 years) and a milder form of the disease. </p>
|
|
</span>
|
|
</div>
|
|
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|
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|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 MIYOSHI MUSCULAR DYSTROPHY 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
DYSF, ARG1046HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908958,
|
|
|
|
|
|
gnomAD: rs121908958,
|
|
|
|
|
|
ClinVar: RCV000007060, RCV000176936, RCV000763088, RCV000790688, RCV001229764
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Miyoshi myopathy (MMD1; 254130), Aoki et al. (2001) identified a 3510G-A transition in exon 29 of the DYSF gene, resulting in an arg1046-to-his (R1046H) substitution. Takahashi et al. (2003) noted that patients with the R1046H mutation had a relatively early age at disease onset (mean, 13 years) and a severe form of the disease, with significantly higher serum creatine kinase levels than patients with other mutations in the DYSF gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 MIYOSHI MUSCULAR DYSTROPHY 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
MYOPATHY, DISTAL, WITH ANTERIOR TIBIAL ONSET, INCLUDED<br />
|
|
MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
DYSF, ARG1905TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908959,
|
|
|
|
|
|
gnomAD: rs121908959,
|
|
|
|
|
|
ClinVar: RCV000007061, RCV000007062, RCV000007063, RCV000080312, RCV000808564, RCV003114177, RCV005025022
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members from 5 families from Sueca, Spain, with a dysferlinopathy, Vilchez et al. (2005) identified a homozygous 6086C-T transition in exon 51 of the DYSF gene, resulting in an arg1905-to-ter (R1905X) substitution. Two families presented with Miyoshi myopathy (MMD1; 254130), 2 presented with distal myopathy with anterior tibial onset (DMAT; 606768), and 1 presented with limb-girdle muscular dystrophy type 2B (LGMDR2; 253601). Although the same mutation resulted in different diagnoses, affected members of each family expressed the same phenotype. The R1905X mutation was not identified in 168 control chromosomes. Haplotype analysis indicated a founder effect. Sueca was founded in 1245 by 17 settlers belonging to the Hospital Order, which received land from King James I of Aragon as a reward for help in reconquering Valencia from the Moors. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
DYSF, ASP625TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908960,
|
|
|
|
|
|
gnomAD: rs121908960,
|
|
|
|
|
|
ClinVar: RCV000007064
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a man with classic limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), Illa et al. (2007) identified compound heterozygosity for 2 mutations in the DYSF gene: an 1873G-T transversion in exon 20 resulting in an asp625-to-tyr (D625Y) substitution and a 5201A-G transition in exon 47 resulting in a glu1734-to-gly (E1734G; 603009.0014) substitution. The patient's 54-year-old sister, who was heterozygous for the D625Y mutation, developed progressive fatigue while walking and difficulty climbing stairs at age 51. She had proximal muscle weakness of the lower limbs, increased serum creatine kinase, and evidence of fatty infiltration of the lower limb muscles on MRI. Although immunostaining and Western blot analysis showed decreased dysferlin levels in the woman's muscle, RT-PCR showed normal levels of DYSF mRNA. The findings indicated that heterozygous DYSF mutation carriers may develop late-onset milder manifestations of the disorder. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
DYSF, GLU1734GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908961,
|
|
|
|
|
|
|
|
ClinVar: RCV000007065
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the glu1734-to-gly (E1734G) mutation in the DYSF gene that was found in compound heterozygous state in a patient with limb-girdle muscular dystrophy type 2B (LGMDR2; 253601) by Illa et al. (2007), see 603009.0013. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 MIYOSHI MUSCULAR DYSTROPHY 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
DYSF, GLY519ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908962,
|
|
|
|
|
|
|
|
ClinVar: RCV000007066, RCV000342783, RCV001048974
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs with Miyoshi myopathy (MMD1; 254130), Illa et al. (2007) identified a homozygous 1555G-A transition in exon 18 of the DYSF gene, resulting in a gly519-to-arg (G519R) substitution. Age at onset was 18 and 15 years, respectively, of distal weakness of the lower limbs with progression to proximal muscle involvement and later upper limb involvement. Both were wheelchair-bound in their thirties. The patients' father, who was heterozygous for the G519R mutation, developed calf myalgias and mild progressive difficulties in walking at age 65 years. He had moderately increased serum creatine kinase and decreased dysferlin immunostaining on muscle biopsy, although DYSF mRNA levels were normal. The findings indicated that heterozygous DYSF mutation carriers may develop late-onset milder manifestations of the disorder. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
DYSF, IVS31DS, A-G, -33
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs786205083,
|
|
|
|
|
|
|
|
ClinVar: RCV000007067
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a woman with mild limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), Sinnreich et al. (2006) identified compound heterozygosity for 2 mutations in the DYSF gene: an A-to-G transition in intron 31, resulting in the in-frame skipping of exon 32, and an indel mutation (603009.0005). The A-to-G mutation was found to lie in the second of 2 putative lariat branch point sequences within the gene. Western blot analysis showed decreased levels of dysferlin, about 10% of normal. The patient's 2 severely affected daughters were homozygous for the indel mutation. Sinnreich et al. (2006) postulated that the mother's milder phenotype resulted from residual protein function due to the splice site mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 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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DYSF, GLY299ARG
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<br />
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SNP: rs121908963,
|
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|
|
|
gnomAD: rs121908963,
|
|
|
|
|
|
ClinVar: RCV000007068, RCV000726614, RCV001388966, RCV003460431
|
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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 2 sibs with limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), Spuler et al. (2008) identified compound heterozygosity for 2 mutations in the DYSF gene: an 895G-A transition resulting in a gly299-to-arg (G299R) substitution downstream of the second C2 domain, and a 1-bp deletion (855+1delG; 603009.0020) predicted to result in nonsense-mediated decay and lack of protein expression. Skeletal muscle biopsy of both patients showed amyloid fibrils that stained with antibodies against the second C2 domain of dysferlin. Amyloid was located in the sarcolemma of muscle cells, in multiple vessel walls, and in the interstitium. The unaffected father was heterozygous for the G299R mutation and showed no amyloid in skeletal muscle. Spuler et al. (2008) postulated that the mutation destabilized the protein structure and increased the propensity to form amyloid fibrils. An unrelated family with myopathy and a different mutation at this codon (G299W; 603009.0018) also showed amyloidosis in skeletal muscle fibers. </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>.0018 MIYOSHI MUSCULAR DYSTROPHY 1</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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DYSF, GLY299TRP
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<br />
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SNP: rs121908963,
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gnomAD: rs121908963,
|
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|
|
|
|
ClinVar: RCV000007069, RCV000594920, RCV003159090
|
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</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
<p>In 2 sibs with Miyoshi myopathy (MMD1; 254130), Spuler et al. (2008) identified a homozygous 895G-T transversion in the DYSF gene, resulting in a gly299-to-trp (G299W) substitution downstream of the second C2 domain. Skeletal muscle biopsy available from 1 patient showed amyloid fibrils that stained with antibodies against the second C2 domain of dysferlin. Amyloid was located in the sarcolemma of muscle cells, in multiple vessel walls, and in the interstitium. Spuler et al. (2008) postulated that the mutation destabilized the protein structure and increased the propensity to form amyloid fibrils. An unrelated family with myopathy and a different mutation at this codon (G299R; 603009.0017) also showed amyloidosis in skeletal muscle fibers. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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DYSF, IVS14AS, A-G, -2
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<br />
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SNP: rs786200897,
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ClinVar: RCV000007070, RCV003574698
|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Arab man with limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), Spuler et al. (2008) identified a homozygous A-to-G transition in intron 14 of the DYSF gene, resulting in a splice site mutation near the third C2 domain. Muscle biopsy showed sarcolemmal defects and deposition of amyloid fibrils. Spuler et al. (2008) postulated that the mutation destabilized the protein structure and increased the propensity to form amyloid fibrils. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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DYSF, 1-BP DEL, 855+1G
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<br />
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SNP: rs786200898,
|
|
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|
|
ClinVar: RCV000007071, RCV001236174, RCV003466825, RCV004525847, RCV005025023
|
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|
</span>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>For discussion of the 1-bp deletion in the DYSF gene (855+1delG) that was found in compound heterozygous state in patients with limb-girdle muscular dystrophy type 2B (LGMDR2; 253601) by Spuler et al. (2008), see 603009.0017. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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DYSF, 1-BP DEL, 2776G
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<br />
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|
|
SNP: rs727503909,
|
|
|
|
|
|
|
|
ClinVar: RCV000007072, RCV000311139, RCV000546602, RCV000599552, RCV004998078
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Spanish sibs, aged 2 and 5 years, with unusual congenital onset of limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), Paradas et al. (2009) identified a homozygous 1-bp deletion (2776delG) in exon 26 of the DYSF gene, resulting in a frameshift and premature termination. The parents were not consanguineous, but they came from the same small village, and haplotype analysis suggested an ancient consanguineous relationship. Both patients presented in infancy with hypotonia and delayed motor development. They had difficulty walking, running, and climbing stairs, as well as neck muscle weakness. The patients had almost no expression of dysferlin in muscle, whereas clinically unaffected family members who were heterozygous for the mutation had about a 50% reduction in dysferlin expression. Paradas et al. (2009) emphasized the early onset of this disorder in these sibs, and suggested that they have a novel phenotype not previously associated with DYSF mutations. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
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<div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
DYSF, 5492G-A
|
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|
|
|
<br />
|
|
|
|
SNP: rs786205084,
|
|
|
|
|
|
|
|
ClinVar: RCV000007073, RCV000723469, RCV001215439, RCV002476993
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 6 unrelated Portuguese male patients with limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), Santos et al. (2010) identified a homozygous 5492G-A transition in the last nucleotide of exon 49 of the DYSF gene. Another Portuguese patient was compound heterozygous for this mutation and another pathogenic mutation in the DYSF gene. The 5492G-A mutation was not found in 240 control alleles. Transcript analysis of patient tissue indicated that the 5492G-A mutation resulted in abnormal splicing, skipping of exon 49, and premature termination. Further studies identified several other residually expressed products of alternative splicing involving exons 50 and 51 in both patients and normal controls, particularly in blood. Haplotype analysis supported a founder effect for the mutation. All 7 patients originated or resided in a confined region of the northern interior part of Portugal. Although most patients had a limb-girdle muscular dystrophy, there was some phenotypic variation: 1 patient presented with distal muscle weakness in the lower limbs, and another had cardiac arrhythmia. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
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|
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|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
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<div>
|
|
<ol>
|
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|
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<li>
|
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<p class="mim-text-font">
|
|
Anderson, L. V. B., Davison, K., Moss, J. A., Young, C., Cullen, M. J., Walsh, J., Johnson, M. A., Bashir, R., Britton, S., Keers, S., Argov, Z., Mahjneh, I., Fougerousse, F., Beckmann, J. S., Bushby, K. M. D.
|
|
<strong>Dysferlin is a plasma membrane protein and is expressed early in human development.</strong>
|
|
Hum. Molec. Genet. 8: 855-861, 1999. Note: Erratum: Hum. Molec. Genet. 8: 1141 only, 1999.
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|
|
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[PubMed: 10196375]
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|
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[Full Text: https://doi.org/10.1093/hmg/8.5.855]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Aoki, M., Liu, J., Richard, I., Bashir, R., Britton, S., Keers, S. M., Oeltjen, J., Brown, H. E., Marchand, S., Bourg, N., Beley, C., McKenna-Yasek, D., and 13 others.
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<strong>Genomic organization of the dysferlin gene and novel mutations in Miyoshi myopathy.</strong>
|
|
Neurology 57: 271-278, 2001.
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[PubMed: 11468312]
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[Full Text: https://doi.org/10.1212/wnl.57.2.271]
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</p>
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<li>
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<p class="mim-text-font">
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Bansal, D., Miyake, K., Vogel, S. S., Groh, S., Chen, C.-C., Williamson, R., McNeil, P. L., Campbell, K. P.
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<strong>Defective membrane repair in dysferlin-deficient muscular dystrophy.</strong>
|
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Nature 423: 168-172, 2003.
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[PubMed: 12736685]
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[Full Text: https://doi.org/10.1038/nature01573]
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<p class="mim-text-font">
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Bashir, R., Britton, S., Strachan, T., Keers, S., Vafiadaki, E., Lako, M., Richard, I., Marchand, S., Bourg, N., Argov, Z., Sadeh, M., Mahjneh, I., Marconi, G., Passos-Bueno, M. R., Moreira, E. S., Zatz, M., Beckmann, J. S., Bushby, K.
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<strong>A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B.</strong>
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Nature Genet. 20: 37-42, 1998.
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[PubMed: 9731527]
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[Full Text: https://doi.org/10.1038/1689]
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<p class="mim-text-font">
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Bashir, R., Strachan, T., Keers, S., Stephenson, A., Mahjneh, I., Marconi, G., Nashef, L., Bushby, K. M. D.
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<strong>A gene for autosomal recessive limb-girdle muscular dystrophy maps to chromosome 2p.</strong>
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Hum. Molec. Genet. 3: 455-457, 1994.
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[PubMed: 8012357]
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[Full Text: https://doi.org/10.1093/hmg/3.3.455]
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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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Bittner, R. E., Anderson, L. V. B., Burkhardt, E., Bashir, R., Vafiadaki, E., Ivanova, S., Raffelsberger, T., Maerk, I., Hoger, H., Jung, M., Karbasiyan, M., Storch, M., Lassmann, H., Moss, J. A., Davison, K., Harrison, R., Bushby, K. M. D., Reis, A.
|
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<strong>Dysferlin deletion in SJL mice (SJL-Dysf) defines a natural model for limb girdle muscular dystrophy 2B. (Letter)</strong>
|
|
Nature Genet. 23: 141-142, 1999.
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[PubMed: 10508505]
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[Full Text: https://doi.org/10.1038/13770]
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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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Britton, S., Freeman, T., Vafiadaki, E., Keers, S., Harrison, R., Bushby, K., Bashir, R.
|
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<strong>The third human FER-1-like protein is highly similar to dysferlin.</strong>
|
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Genomics 68: 313-321, 2000.
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[PubMed: 10995573]
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[Full Text: https://doi.org/10.1006/geno.2000.6290]
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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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Chiu, Y.-H., Hornsey, M. A., Klinge, L., Jorgensen, L. H., Laval, S. H., Charlton, R., Barresi, R., Straub, V., Lochmuller, H., Bushby, K.
|
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<strong>Attenuated muscle regeneration is a key factor in dysferlin-deficient muscular dystrophy.</strong>
|
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Hum. Molec. Genet. 18: 1976-1989, 2009.
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[PubMed: 19286669]
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[Full Text: https://doi.org/10.1093/hmg/ddp121]
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|
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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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Festing, M. F. W. (ed.).
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<strong>Inbred Strains in Biomedical Research.</strong>
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New York: Oxford Univ. Press 1979. P. 255.
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<li>
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<p class="mim-text-font">
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Fujita, E., Kouroku, Y., Isoai, A., Kumagai, H., Misutani, A., Matsuda, C., Hayashi, Y. K., Momoi, T.
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<strong>Two endoplasmic reticulum-associated degradation (ERAD) systems for the novel variant of the mutant dysferlin: ubiquitin/proteasome ERAD(I) and autophagy/lysosome ERAD(II).</strong>
|
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Hum. Molec. Genet. 16: 618-629, 2007.
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[PubMed: 17331981]
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[Full Text: https://doi.org/10.1093/hmg/ddm002]
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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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Glover, L. E., Newton, K., Krishnan, G., Bronson, R., Boyle, A., Krivickas, L. S., Brown, R. H., Jr.
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<strong>Dysferlin overexpression in skeletal muscle produces a progressive myopathy.</strong>
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Ann. Neurol. 67: 384-393, 2010.
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[PubMed: 20373350]
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[Full Text: https://doi.org/10.1002/ana.21926]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Han, R., Bansal, D., Miyake, K., Muniz, V. P., Weiss, R. M., McNeil, P. L., Campbell, K. P.
|
|
<strong>Dysferlin-mediated membrane repair protects the heart from stress-induced left ventricular injury.</strong>
|
|
J. Clin. Invest. 117: 1805-1813, 2007.
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[PubMed: 17607357]
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[Full Text: https://doi.org/10.1172/JCI30848]
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</p>
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</li>
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<li>
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|
<p class="mim-text-font">
|
|
Ho, M., Post, C. M., Donahue, L. R., Lidov, H. G. W., Bronson, R. T., Goolsby, H., Watkins, S. C., Cox, G. A., Brown, R. H., Jr.
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|
<strong>Disruption of muscle membrane and phenotype divergence in two novel mouse models of dysferlin deficiency.</strong>
|
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Hum. Molec. Genet. 13: 1999-2010, 2004.
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|
|
|
[PubMed: 15254015]
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|
|
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|
|
[Full Text: https://doi.org/10.1093/hmg/ddh212]
|
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|
|
</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Illa, I., De Luna, N., Dominguez-Perles, R., Rojas-Garcia, R., Paradas, C., Palmer, J., Marquez, C., Gallano, P., Gallardo, E.
|
|
<strong>Symptomatic dysferlin gene mutation carriers: characterization of two cases.</strong>
|
|
Neurology 68: 1284-1289, 2007.
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|
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|
|
[PubMed: 17287450]
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|
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|
|
|
[Full Text: https://doi.org/10.1212/01.wnl.0000256768.79353.60]
|
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|
|
</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Illa, I., Serrano-Munuera, C., Gallardo, E., Lasa, A., Rojas-Garcia, R., Palmer, J., Gallano, P., Baiget, M., Matsuda, C., Brown, R. H.
|
|
<strong>Distal anterior compartment myopathy: a dysferlin mutation causing a new muscular dystrophy phenotype.</strong>
|
|
Ann. Neurol. 49: 130-134, 2001.
|
|
|
|
|
|
[PubMed: 11198284]
|
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Illarioshkin, S. N., Ivanova-Smolenskaya, I. A., Greenberg, C. R., Nylen, E., Sukhorukov, V. S., Poleshchuk, V. V., Markova, E. D., Wrogemann, K.
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Cassandra L. Kniffin - updated : 11/1/2010<br>Cassandra L. Kniffin - updated : 8/2/2010<br>Cassandra L. Kniffin - updated : 7/12/2010<br>Cassandra L. Kniffin - updated : 3/5/2010<br>George E. Tiller - updated : 2/23/2010<br>Cassandra L. Kniffin - updated : 11/4/2009<br>Cassandra L. Kniffin - updated : 3/24/2009<br>Cassandra L. Kniffin - updated : 3/31/2008<br>Cassandra L. Kniffin - updated : 2/4/2008<br>Cassandra L. Kniffin - updated : 12/5/2007<br>Marla J. F. O'Neill - updated : 8/2/2007<br>George E. Tiller - updated : 3/21/2007<br>Cassandra L. Kniffin - updated : 11/4/2005<br>Ada Hamosh - updated : 5/9/2003<br>Victor A. McKusick updated : 2/22/2002<br>George E. Tiller - updated : 1/23/2002<br>Kathryn R. Wagner - updated : 3/28/2001<br>Carol A. Bocchini - updated : 9/21/2000<br>Victor A. McKusick - updated : 9/27/1999<br>Victor A. McKusick - updated : 5/18/1999<br>Victor A. McKusick - updated : 4/29/1999
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Victor A. McKusick : 8/28/1998
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OMIM<sup>®</sup> and Online Mendelian Inheritance in Man<sup>®</sup> are registered trademarks of the Johns Hopkins University.
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