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Entry
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- *120240 - COLLAGEN, TYPE VI, ALPHA-2; COL6A2
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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">*120240</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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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<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/120240">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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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 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=ENSG00000142173;t=ENST00000300527" 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=1292" 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=120240" 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=ENSG00000142173;t=ENST00000300527" 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_001849,NM_058174,NM_058175" 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_001849" 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=120240" 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=02110&isoform_id=02110_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/COL6A2" 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/30043,179709,179710,179711,179713,242005,1335033,10441950,12803331,13603394,30582665,41350923,49168630,52545536,115527062,115527066,115527070,119629721,119629722,119629723,125987812,308219654" 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/P12110" 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=1292" 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=ENSG00000142173;t=ENST00000300527" 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=COL6A2" 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=COL6A2" 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+1292" 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/COL6A2" 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:1292" 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/1292" 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=chr21&hgg_gene=ENST00000300527.9&hgg_start=46098112&hgg_end=46132848&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:2212" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/col6a2" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=120240[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><a href="https://www.possumcore.com/nuxeo/nxdoc/default/7c347c9b-e836-4aa1-a4e3-eed77984ccb5/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</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=120240[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/COL6A2/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/ENSG00000142173" 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=COL6A2" 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=COL6A2" 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=COL6A2" 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/COL6A2" 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=COL6A2&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/PA26728" 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:2212" 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://www.mousephenotype.org/data/genes/MGI:88460" 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/COL6A2#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:88460" 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/1292/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=1292" 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="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00000653;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00000653 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00000697;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00000697 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00000714;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00000714 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-070501-7" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:120240" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:1292" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=COL6A2&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> 763895001<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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120240
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
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COLLAGEN, TYPE VI, ALPHA-2; COL6A2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=COL6A2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">COL6A2</a></em></strong>
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/21/175?start=-3&limit=10&highlight=175">21q22.3</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr21:46098112-46132848&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'})">21:46,098,112-46,132,848</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</div>
|
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
|
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Location
|
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</th>
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<th>
|
|
Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=255600,620725,620727" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
|
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</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
|
</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
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<tr>
|
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<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/21/175?start=-3&limit=10&highlight=175">
|
|
21q22.3
|
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</a>
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<p>The COL6A2 gene encodes the alpha-2 subunit of type VI collagen, a ubiquitously expressed extracellular matrix protein. It is 1 of the 3 subunits comprising the full collagen VI protein (see also COL6A1, <a href="/entry/120220">120220</a> and COL6A3, <a href="/entry/120250">120250</a>) (summary by <a href="#26" class="mim-tip-reference" title="Zhang, R.-Z., Zou, Y., Pan, T.-C., Markova, D., Fertala, A., Hu, Y., Squarzoni, S., Reed, U. C., Marie, S. K. N., Bonnemann, C. G., Chu, M.-L. <strong>Recessive COL6A2 C-globular missense mutations in Ullrich congenital muscular dystrophy: role of the C2a splice variant.</strong> J. Biol. Chem. 285: 10005-10015, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20106987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20106987</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20106987[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/10.1074/jbc.M109.093666" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20106987">Zhang et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20106987" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#23" class="mim-tip-reference" title="Weil, D., Mattei, M.-G., Passage, E., Van Cong, N., Pribula-Conway, D., Mann, K., Deutzmann, R., Timpl, R., Chu, M.-L. <strong>Cloning and chromosomal localization of human genes encoding the three chains of type VI collagen.</strong> Am. J. Hum. Genet. 42: 435-445, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3348212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3348212</a>]" pmid="3348212">Weil et al. (1988)</a> isolated clones corresponding to the COL6A2 gene from a human placenta expression library. Northern blot analysis detected a 3.5-kb mRNA transcript. The molecular mass of the protein is approximately 140 kD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3348212" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Chu, M.-L., Pan, T.-C., Conway, D., Kuo, H.-J., Glanville, R. W., Timpl, R., Mann, K., Deutzmann, R. <strong>Sequence analysis of alpha 1(VI) and alpha 2(VI) chains of human type VI collagen reveals internal triplication of globular domains similar to the A domains of von Willebrand factor and two alpha-2(VI) chain variants that differ in the carboxy terminus.</strong> EMBO J. 8: 1939-1946, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2551668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2551668</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1989.tb03598.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2551668">Chu et al. (1989)</a> determined that the COL6A2 protein contains 998 amino acids with 31% identity to COL6A1 in the N-terminal and C-terminal globular domains, which are connected by a triple helical segment. Both COL6A1 and COL6A2 contain small signal peptide sequences. Internal alignment of the globular sequences showed a repetitive 200-residue structure (15 to 23% identity) occurring 3 times (N1, C1, C2) in each chain. Sequencing of COL6A2 cDNA clones revealed 2 variant chains with a distinct C2 subdomain and 3-prime noncoding region. The repetitive segments C1, C2 and, to a lesser extent, N1 showed significant identity (15 to 18%) to the collagen-binding A domains of von Willebrand factor (VWF; <a href="/entry/613160">613160</a>). These results suggested that the globular domains of the COL6 proteins bind to collagenous structures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2551668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Saitta, B., Timpl, R., Chu, M.-L. <strong>Human alpha-2(VI) collagen gene: heterogeneity at the 5-prime-untranslated region generated by an alternate exon.</strong> J. Biol. Chem. 267: 6188-6196, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1556127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1556127</a>]" pmid="1556127">Saitta et al. (1992)</a> found that the human COL6A2 gene uses alternative processing to produce multiple mRNA transcripts differing in the 5-prime untranslated region as well as in the 3-prime coding and noncoding sequences. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1556127" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Saitta, B., Timpl, R., Chu, M.-L. <strong>Human alpha-2(VI) collagen gene: heterogeneity at the 5-prime-untranslated region generated by an alternate exon.</strong> J. Biol. Chem. 267: 6188-6196, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1556127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1556127</a>]" pmid="1556127">Saitta et al. (1992)</a> demonstrated that the COL6A2 gene contains 30 exons and spans 36 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1556127" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By somatic cell hybrid and FISH analysis, <a href="#23" class="mim-tip-reference" title="Weil, D., Mattei, M.-G., Passage, E., Van Cong, N., Pribula-Conway, D., Mann, K., Deutzmann, R., Timpl, R., Chu, M.-L. <strong>Cloning and chromosomal localization of human genes encoding the three chains of type VI collagen.</strong> Am. J. Hum. Genet. 42: 435-445, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3348212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3348212</a>]" pmid="3348212">Weil et al. (1988)</a> mapped the COL6A2 gene to chromosome 21q22.3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3348212" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#13" class="mim-tip-reference" title="Klewer, S. E., Krob, S. L., Kolker, S. J., Kitten, G. T. <strong>Expression of type VI collagen in the developing mouse heart.</strong> Dev. Dyn. 211: 248-255, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9520112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9520112</a>] [<a href="https://doi.org/10.1002/(SICI)1097-0177(199803)211:3<248::AID-AJA6>3.0.CO;2-H" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9520112">Klewer et al. (1998)</a> studied COL6A2 gene expression in the developing mammalian heart. The pattern of expression was identical to that of COL6A1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9520112" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Bethlem Myopathy 1B and Ullrich Congenital Muscular Dystrophy 1B</em></strong></p><p>
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In 9 kindreds with the Bethlem form of autosomal dominant myopathy with contractures (see BTHLM1A, <a href="/entry/158810">158810</a> and BTHLM1B, <a href="/entry/620725">620725</a>), <a href="#11" class="mim-tip-reference" title="Jobsis, G. J., Bolhuis, P. A., Boers, J. M., Baas, F., Wolterman, R. A., Hensels, G. W., de Visser, M. <strong>Genetic localization of Bethlem myopathy.</strong> Neurology 46: 779-782, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8618682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8618682</a>] [<a href="https://doi.org/10.1212/wnl.46.3.779" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8618682">Jobsis et al. (1996)</a> demonstrated genetic linkage to the COL6A1-COL6A2 gene cluster on 21q22.3. By sequence analysis in 4 families, <a href="#12" class="mim-tip-reference" title="Jobsis, G. J., Keizers, H., Vreijling, J. P., de Visser, M., Speer, M. C., Wolterman, R. A., Baas, F., Bohlhuis, P. A. <strong>Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures.</strong> Nature Genet. 14: 113-115, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782832</a>] [<a href="https://doi.org/10.1038/ng0996-113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782832">Jobsis et al. (1996)</a> identified heterozygous missense mutations in 3: affected members of family 2 (a Dutch family originally reported by <a href="#5" class="mim-tip-reference" title="Bethlem, J., van Wijngaarden, G. K. <strong>Benign myopathy, with autosomal dominant inheritance--a report on three pedigrees.</strong> Brain 99: 91-100, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/963533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">963533</a>] [<a href="https://doi.org/10.1093/brain/99.1.91" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="963533">Bethlem and van Wijngaarden, 1976</a>) carried a heterozygous missense mutation in the COL6A1 gene (G286V; <a href="/entry/120220#0001">120220.0001</a>) and families 4 and 5 carried the same heterozygous missense mutation in COL6A2 (G250S; <a href="#0001">120240.0001</a>) (family 4 had been reported by <a href="#2" class="mim-tip-reference" title="Arts, W. F., Bethlem, J., Volkers, W. S. <strong>Further investigations on benign myopathy with autosomal dominant inheritance.</strong> J. Neurol. 217: 201-206, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/75955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">75955</a>] [<a href="https://doi.org/10.1007/BF00312962" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="75955">Arts et al., 1978</a>). Both mutations disrupted the Gly-X-Y motif of the triple helical domain by substitution of gly for either val or ser. Analogous to the putative perturbation of the anchoring function of the dystrophin-associated complex in congenital muscular dystrophy with mutations in the alpha-2 subunit of laminin (<a href="/entry/156225">156225</a>), the observation suggested a similar mechanism in Bethlem myopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=963533+75955+8782832+8618682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Ullrich scleroatonic muscular dystrophy, also known as Ullrich congenital muscular dystrophy (see UCMD1B; <a href="/entry/620727">620727</a>), shares some clinical features with Bethlem myopathy, such as joint contractures, but displays a more severe course. <a href="#6" class="mim-tip-reference" title="Camacho Vanegas, O. C., Bertini, E., Zhang, R.-Z., Petrini, S., Minosse, C., Sabatelli, P., Giusti, B., Chu, M.-L., Pepe, G. <strong>Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI.</strong> Proc. Nat. Acad. Sci. 98: 7516-7521, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11381124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11381124</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11381124[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.121027598" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11381124">Camacho Vanegas et al. (2001)</a> demonstrated recessive mutations in the COL6A2 gene (see <a href="#0002">120240.0002</a>) leading to UCMD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11381124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#15" class="mim-tip-reference" title="Lampe, A. K., Dunn, D. M., von Niederhausern, A. C., Hamil, C., Aoyagi, A., Laval, S. H., Marie, S. K., Chu, M.-L., Swoboda, K., Muntoni, F., Bonnemann, C. G., Flanigan, K. M., Bushby, K. M. D., Weiss, R. B. <strong>Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy.</strong> J. Med. Genet. 42: 108-120, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15689448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15689448</a>] [<a href="https://doi.org/10.1136/jmg.2004.023754" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15689448">Lampe et al. (2005)</a> developed a method for rapid direct sequence analysis of all 107 coding exons of the COL6 genes (COL6A1; COL6A2; COL6A3, <a href="/entry/120250">120250</a>) with single condition amplification/internal primer (SCAIP) sequencing. They sequenced all 3 COL6 genes from genomic DNA in 79 patients with UCMD or Bethlem myopathy, and found putative mutations in 1 of the COL6 genes in 62% of patients. Some patients showed changes in more than one of the COL6 genes, and some UCMD patients appeared to have dominant rather than recessive disease. <a href="#15" class="mim-tip-reference" title="Lampe, A. K., Dunn, D. M., von Niederhausern, A. C., Hamil, C., Aoyagi, A., Laval, S. H., Marie, S. K., Chu, M.-L., Swoboda, K., Muntoni, F., Bonnemann, C. G., Flanigan, K. M., Bushby, K. M. D., Weiss, R. B. <strong>Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy.</strong> J. Med. Genet. 42: 108-120, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15689448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15689448</a>] [<a href="https://doi.org/10.1136/jmg.2004.023754" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15689448">Lampe et al. (2005)</a> concluded that these findings may explain some or all of the cases of UCMD that are unlinked to the COL6 gene under a recessive model. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15689448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 unrelated patients with BTHLM1B, <a href="#3" class="mim-tip-reference" title="Baker, N. L., Morgelin, M., Pace, R. A., Peat, R. A., Adams, N. E., Gardner, R. J. M., Rowland, L. P., Miller, G., De Jonghe, P., Ceulemans, B., Hannibal, M. C., Edwards, M., Thompson, E. M., Jacobson, R., Quinlivan, R. C. M., Aftimos, S., Kornberg, A. J., North, K. N., Bateman, J. F., Lamande, S. R. <strong>Molecular consequences of dominant Bethlem myopathy collagen VI mutations.</strong> Ann. Neurol. 62: 390-405, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17886299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17886299</a>] [<a href="https://doi.org/10.1002/ana.21213" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17886299">Baker et al. (2007)</a> identified different heterozygous mutations in the COL6A2 gene (<a href="#0009">120240.0009</a>; <a href="#0010">120240.0010</a>). In vitro studies indicated defective collagen VI synthesis and secretion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17886299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Nadeau, A., Kinali, M., Main, M., Jimenez-Mallebrera, C., Aloysius, A., Clement, E., North, B., Manzur, A. Y., Robb, S. A., Mercuri, E., Muntoni, F. <strong>Natural history of Ullrich congenital muscular dystrophy.</strong> Neurology 73: 25-31, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19564581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19564581</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181aae851" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19564581">Nadeau et al. (2009)</a> identified a homozygous COL6A2 mutation (C777R; <a href="#0012">120240.0012</a>) in 3 patients with autosomal recessive UCMD1B. Two additional patients had different de novo heterozygous COL6A2 mutations (see, e.g., G283R, <a href="#0013">120240.0013</a>), consistent with autosomal dominant inheritance. Another patient was compound heterozygous for a mutation in the COL6A1 gene (G281R; <a href="/entry/120220#0014">120220.0014</a>) and a mutation in the COL6A2 gene (R498H; <a href="#0014">120240.0014</a>), consistent with digenic inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19564581" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 61-year-old man (UCMD65), born of consanguineous parents, with autosomal recessive Bethlem myopathy-1B, <a href="#24" class="mim-tip-reference" title="Zamurs, L. K., Idoate, M. A., Hanssen, E., Gomez-Ibanez, A., Pastor, P., Lamande, S. R. <strong>Aberrant mitochondria in a Bethlem myopathy patient with a homozygous amino acid substitution that destabilizes the collagen VI alpha2(VI) chain.</strong> J. Biol. Chem. 290: 4272-4281, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25533456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25533456</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25533456[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/10.1074/jbc.M114.632208" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25533456">Zamurs et al. (2015)</a> identified a homozygous missense mutation in the COL6A2 gene (D871N; <a href="#0019">120240.0019</a>). His unaffected parents were each heterozygous for the variant. Detailed studies of patient fibroblasts showed that the mutant protein interfered with collagen VI assembly, secretion, and microfibril formation, all of which were reduced compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25533456" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 adult sibs with autosomal recessive Bethlem myopathy-1B, <a href="#7" class="mim-tip-reference" title="Caria, F., Cescon, M., Gualandi, F., Pichiecchio, A., Rossi, R., Rimessi, P., Cotti Piccinelli, S., Gallo Cassarino, S., Gregorio, I., Galvagni, A., Ferlini, A., Padovani, A., Bonaldo, P., Filosto, M. <strong>Autosomal recessive Bethlem myopathy: a clinical, genetic and functional study.</strong> Neuromusc. Disord. 29: 657-663, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31471117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31471117</a>] [<a href="https://doi.org/10.1016/j.nmd.2019.07.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31471117">Caria et al. (2019)</a> identified compound heterozygous mutations in the COL6A2 gene: a nonsense mutation in exon 28, resulting in a gln889-to-ter (Q889X; <a href="#0022">120240.0022</a>), and an in-frame insertion (<a href="#0023">120240.0023</a>) in exon 5. The mutations, which were found by next-generation panel sequencing and confirmed by Sanger sequencing, were each inherited from an unaffected parent. Western blot analysis of patient fibroblasts showed low levels of the canonical 1,019-residue COL6A2 chain and presence of a truncated 889-residue mutant protein; a normal 918-residue splice variant (C2A) was also detected. There were normal amounts of collagen VI dimers and tetramers in the cell layer, but not in the cell media, indicating instability of the secreted protein. Immunofluorescence studies of patient fibroblasts showed markedly reduced expression of collagen VI, which was poorly organized in the extracellular matrix. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31471117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Myosclerosis, Autosomal Recessive</em></strong></p><p>
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In 2 sibs with autosomal recessive myosclerosis (<a href="/entry/255600">255600</a>), <a href="#18" class="mim-tip-reference" title="Merlini, L., Martoni, E., Grumati, P., Sabatelli, P., Squarzoni, S., Urciuolo, A., Ferlini, A., Gualandi, F., Bonaldo, P. <strong>Autosomal recessive myosclerosis myopathy is a collagen VI disorder.</strong> Neurology 71: 1245-1253, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18852439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18852439</a>] [<a href="https://doi.org/10.1212/01.wnl.0000327611.01687.5e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18852439">Merlini et al. (2008)</a> identified a homozygous truncating mutation in the COL6A2 gene (<a href="#0011">120240.0011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18852439" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Role of COL6A2 in Atrioventricular Septal Defect</em></strong></p><p>
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<a href="#1" class="mim-tip-reference" title="Ackerman, C., Locke, A. E., Feingold, E., Reshey, B., Espana, K., Thusberg, J., Mooney, S., Bean, L. J. H., Dooley, K. J., Cua, C. L., Reeves, R. H., Sherman, S. L., Maslen, C. L. <strong>An excess of deleterious variants in VEGF-A pathway genes in Down-syndrome-associated atrioventricular septal defects.</strong> Am. J. Hum. Genet. 91: 646-659, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23040494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23040494</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.08.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23040494">Ackerman et al. (2012)</a> used a candidate gene approach among individuals with Down syndrome and complete atrioventricular septal defect (AVSD) (141 cases) and Down syndrome with no congenital heart defect (141 controls) to determine whether rare genetic variants in genes involved in atrioventricular valvuloseptal morphogenesis contribute to AVSD in this sensitized population. <a href="#1" class="mim-tip-reference" title="Ackerman, C., Locke, A. E., Feingold, E., Reshey, B., Espana, K., Thusberg, J., Mooney, S., Bean, L. J. H., Dooley, K. J., Cua, C. L., Reeves, R. H., Sherman, S. L., Maslen, C. L. <strong>An excess of deleterious variants in VEGF-A pathway genes in Down-syndrome-associated atrioventricular septal defects.</strong> Am. J. Hum. Genet. 91: 646-659, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23040494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23040494</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.08.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23040494">Ackerman et al. (2012)</a> found a significant excess (p less than 0.0001) of variants predicted to be deleterious in cases compared to controls. At the most stringent level of filtering, they found potentially damaging variants in nearly 20% of cases but in fewer than 3% of controls. The variants with the highest probability of being damaging in cases only were found in 6 genes: COL6A1, COL6A2, CRELD1 (<a href="/entry/607170">607170</a>) (already identified as a cause of AVSD; see <a href="/entry/606217">606217</a>), FBLN2 (<a href="/entry/135821">135821</a>), FRZB (<a href="/entry/605083">605083</a>), and GATA5 (<a href="/entry/611496">611496</a>). Several of the case-specific variants were recurrent in unrelated individuals, occurring in 10% of cases studied. No variants with an equal probability of being damaging were found in controls, demonstrating a highly specific association with AVSD. Of note, all of these genes are in the VEGFA (<a href="/entry/192240">192240</a>) pathway, suggesting to <a href="#1" class="mim-tip-reference" title="Ackerman, C., Locke, A. E., Feingold, E., Reshey, B., Espana, K., Thusberg, J., Mooney, S., Bean, L. J. H., Dooley, K. J., Cua, C. L., Reeves, R. H., Sherman, S. L., Maslen, C. L. <strong>An excess of deleterious variants in VEGF-A pathway genes in Down-syndrome-associated atrioventricular septal defects.</strong> Am. J. Hum. Genet. 91: 646-659, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23040494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23040494</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.08.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23040494">Ackerman et al. (2012)</a> that rare variants in this pathway might contribute to the genetic underpinnings of AVSD in humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23040494" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#9" class="mim-tip-reference" title="Gualandi, F., Urciuolo, A., Martoni, E., Sabatelli, P., Squarzoni, S., Bovolenta, M., Messina, S., Mercuri, E., Franchella, A., Ferlini, A., Bonaldo, P, Merlini, L. <strong>Autosomal recessive Bethlem myopathy.</strong> Neurology 73: 1883-1891, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19949035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19949035</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181c3fd2a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19949035">Gualandi et al. (2009)</a> reported 2 unrelated patients with Bethlem myopathy who were each compound heterozygous for a truncating and a missense mutation in the COL6A2 gene (Q819X, <a href="#0011">120240.0011</a> and R830Q/R843W, <a href="#0017">120240.0017</a>; R366X, <a href="#0018">120240.0018</a> and D871N; <a href="#0019">120240.0019</a>, respectively). Both patients remained ambulatory as adults, and muscle biopsies and studies of fibroblasts showed variable degrees of aberrant collagen VI microfilament formation. <a href="#9" class="mim-tip-reference" title="Gualandi, F., Urciuolo, A., Martoni, E., Sabatelli, P., Squarzoni, S., Bovolenta, M., Messina, S., Mercuri, E., Franchella, A., Ferlini, A., Bonaldo, P, Merlini, L. <strong>Autosomal recessive Bethlem myopathy.</strong> Neurology 73: 1883-1891, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19949035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19949035</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181c3fd2a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19949035">Gualandi et al. (2009)</a> noted that autosomal recessive inheritance had not been reported in Bethlem myopathy and suggested that collagen VI-related myopathies comprise a spectrum of conditions with variable severity. In addition, the findings did not support pure haploinsufficiency as a causative mechanism for Bethlem myopathy, and suggested that some previously reported patients may harbor a second missed mutation. The genotype findings in these patients had important implications for genetic counseling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19949035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#17" class="mim-tip-reference" title="Meehan, T. F., Conte, N., West, D. B., Jacobsen, J. O., Mason, J., Warren, J., Chen, C.-K., Tudose, I., Relac, M., Matthews, P., Karp, N., Santos, L., and 52 others. <strong>Disease model discovery from 3,328 gene knockouts by the International Mouse Phenotyping Consortium.</strong> Nature Genet. 49: 1231-1238, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28650483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28650483</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28650483[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.3901" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28650483">Meehan et al. (2017)</a> reported that knockout of Col6a2 in mice caused decreased grip strength. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28650483" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>23 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=120240[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121912940 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912940;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=rs121912940" 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=rs121912940" 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=RCV000018695 OR RCV001781280 OR RCV003764593" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018695, RCV001781280, RCV003764593" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018695...</a>
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<p>In 2 kindreds (families 4 and 5) with Bethlem myopathy-1B (BTHLM1B; <a href="/entry/620725">620725</a>), <a href="#12" class="mim-tip-reference" title="Jobsis, G. J., Keizers, H., Vreijling, J. P., de Visser, M., Speer, M. C., Wolterman, R. A., Baas, F., Bohlhuis, P. A. <strong>Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures.</strong> Nature Genet. 14: 113-115, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782832</a>] [<a href="https://doi.org/10.1038/ng0996-113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782832">Jobsis et al. (1996)</a> demonstrated that affected members had a heterozygous c.898G-A transition in the COL6A2 gene, resulting in a gly250-to-ser (G250S) substitution in the triple helical region. Family 4 was a Polish family originally reported by <a href="#2" class="mim-tip-reference" title="Arts, W. F., Bethlem, J., Volkers, W. S. <strong>Further investigations on benign myopathy with autosomal dominant inheritance.</strong> J. Neurol. 217: 201-206, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/75955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">75955</a>] [<a href="https://doi.org/10.1007/BF00312962" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="75955">Arts et al. (1978)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=75955+8782832" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1B, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1601231322 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1601231322;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=rs1601231322" 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=rs1601231322" 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 Italian family, <a href="#6" class="mim-tip-reference" title="Camacho Vanegas, O. C., Bertini, E., Zhang, R.-Z., Petrini, S., Minosse, C., Sabatelli, P., Giusti, B., Chu, M.-L., Pepe, G. <strong>Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI.</strong> Proc. Nat. Acad. Sci. 98: 7516-7521, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11381124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11381124</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11381124[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.121027598" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11381124">Camacho Vanegas et al. (2001)</a> found that a son with Ullrich congenital muscular dystrophy (UCMD1B; <a href="/entry/620727">620727</a>) had a homozygous insertion of a C leading to a premature termination codon in the triple helical domain of COL6A2 mRNA. Both healthy consanguineous parents were carriers. The insertion of the C was in a stretch of 5 cytosines between nucleotides 1147 and 1151 of the COL6A2 cDNA, causing a slippage of the reading frame with a premature termination codon at nucleotides 1347-1349. The affected patient in this family showed reduced fetal movements. At birth he was unusually long (55 cm), showed multiple joint contractures of his knees and elbows, a kyphotic contracture of the spine, a left hip dislocation, bilateral congenital convex pes valgus, long and slender fingers and toes with adducted thumbs, ogival palate, micrognathia, and a short neck with torticollis. He also showed marked bilateral distal hyperlaxity of fingers, toes, calcanei, and wrists. The child walked at the age of 13 months, but generalized muscle weakness persisted thereafter, and progressive scoliosis and respiratory failure developed. He underwent tracheostomy and nocturnal positive pressure mechanical ventilation at the age of 8 years, with signs of diaphragmatic insufficiency. At the age of 11 years, he was still ambulant and had normal intelligence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11381124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In fibroblasts from the patient reported by <a href="#6" class="mim-tip-reference" title="Camacho Vanegas, O. C., Bertini, E., Zhang, R.-Z., Petrini, S., Minosse, C., Sabatelli, P., Giusti, B., Chu, M.-L., Pepe, G. <strong>Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI.</strong> Proc. Nat. Acad. Sci. 98: 7516-7521, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11381124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11381124</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11381124[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.121027598" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11381124">Camacho Vanegas et al. (2001)</a>, <a href="#25" class="mim-tip-reference" title="Zhang, R.-Z., Sabatelli, P., Pan, T.-C., Squarzoni, S., Mattioli, E., Bertini, E., Pepe, G., Chu, M.-L. <strong>Effects on collagen VI mRNA stability and microfibrillar assembly of three COL6A2 mutations in two families with Ullrich congenital muscular dystrophy.</strong> J. Biol. Chem. 277: 43557-43564, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12218063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12218063</a>] [<a href="https://doi.org/10.1074/jbc.M207696200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12218063">Zhang et al. (2002)</a> showed almost complete absence of COL6A2 mRNA by Northern blot analysis, suggesting that the mutation led to nonsense-mediated mRNA decay. There was complete absence of secreted COL6A2 protein in the medium of the patient's cells, suggesting that the mutation in the triple helical domain prevented microfibrillar assembly and secretion. Although both parents showed decreased levels of COL6A2 mRNA, long-term collagen VI deposition was essentially normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11381124+12218063" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs749974929 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs749974929;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/rs749974929?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=rs749974929" 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=rs749974929" 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=RCV000550156 OR RCV003767089" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000550156, RCV003767089" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000550156...</a>
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<p>In an Italian family, <a href="#6" class="mim-tip-reference" title="Camacho Vanegas, O. C., Bertini, E., Zhang, R.-Z., Petrini, S., Minosse, C., Sabatelli, P., Giusti, B., Chu, M.-L., Pepe, G. <strong>Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI.</strong> Proc. Nat. Acad. Sci. 98: 7516-7521, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11381124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11381124</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11381124[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.121027598" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11381124">Camacho Vanegas et al. (2001)</a> found that 2 brothers with Ullrich scleroatonic muscular dystrophy (UCMD1B; <a href="/entry/620727">620727</a>) had a splice acceptor site mutation in the COL6A2 gene. Deletion of 28 nucleotides was caused by an A-to-G substitution at nucleotide -2 of intron 17, causing activation of a cryptic acceptor site within exon 18. The normal parents were unrelated. Severe contractures of elbows and knees, rigidity of the spine, ogival (gothic) palate, and hypotonia were present. In 1 brother there was distal hyperlaxity and marked weakness of head flexors but almost complete disappearance of limb joint contractures at the age of 2 years. In the brothers, this mutation was found in compound heterozygosity with a splice site mutation in intron 23 (<a href="#0004">120240.0004</a>). The first mutation was present in the healthy mother, whereas the second mutation was carried by the healthy father. In another Italian family, <a href="#6" class="mim-tip-reference" title="Camacho Vanegas, O. C., Bertini, E., Zhang, R.-Z., Petrini, S., Minosse, C., Sabatelli, P., Giusti, B., Chu, M.-L., Pepe, G. <strong>Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI.</strong> Proc. Nat. Acad. Sci. 98: 7516-7521, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11381124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11381124</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11381124[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.121027598" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11381124">Camacho Vanegas et al. (2001)</a> found the same 28-bp deletion but did not find the mutation in the other allele. This mutation occurred de novo in the patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11381124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In fibroblasts from 1 of the patients reported by <a href="#6" class="mim-tip-reference" title="Camacho Vanegas, O. C., Bertini, E., Zhang, R.-Z., Petrini, S., Minosse, C., Sabatelli, P., Giusti, B., Chu, M.-L., Pepe, G. <strong>Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI.</strong> Proc. Nat. Acad. Sci. 98: 7516-7521, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11381124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11381124</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11381124[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.121027598" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11381124">Camacho Vanegas et al. (2001)</a> who was compound heterozygous for mutations in the COL6A2 gene, <a href="#25" class="mim-tip-reference" title="Zhang, R.-Z., Sabatelli, P., Pan, T.-C., Squarzoni, S., Mattioli, E., Bertini, E., Pepe, G., Chu, M.-L. <strong>Effects on collagen VI mRNA stability and microfibrillar assembly of three COL6A2 mutations in two families with Ullrich congenital muscular dystrophy.</strong> J. Biol. Chem. 277: 43557-43564, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12218063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12218063</a>] [<a href="https://doi.org/10.1074/jbc.M207696200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12218063">Zhang et al. (2002)</a> showed decreased levels of COL6A2 mRNA by Northern blot analysis, suggesting that the mutations led to nonsense-mediated mRNA decay. Low levels of COL6A2 protein were detected in the medium of the patient's cells, suggesting that the mutations, which occurred at the distal part of the triple helical domain, allowed secretion of a small amount of mutant collagen VI protein. Further analysis showed that the truncated proteins were able to form triple helical monomers, but unable to assemble into dimers and tetramers for the completed collagen VI protein. <a href="#25" class="mim-tip-reference" title="Zhang, R.-Z., Sabatelli, P., Pan, T.-C., Squarzoni, S., Mattioli, E., Bertini, E., Pepe, G., Chu, M.-L. <strong>Effects on collagen VI mRNA stability and microfibrillar assembly of three COL6A2 mutations in two families with Ullrich congenital muscular dystrophy.</strong> J. Biol. Chem. 277: 43557-43564, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12218063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12218063</a>] [<a href="https://doi.org/10.1074/jbc.M207696200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12218063">Zhang et al. (2002)</a> noted that the IVS23 mutation (<a href="#0004">120240.0004</a>) retains the triple helical domain and thus can assemble into monomers, but has a shorter C-terminal globular domain which prevents further assembly into higher ordered structures. Although both parents showed decreased levels of COL6A2 mRNA, long-term collagen VI deposition was essentially normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11381124+12218063" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs748035948 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs748035948;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=rs748035948" 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=rs748035948" 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=RCV003764595" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003764595" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003764595</a>
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<p><a href="#6" class="mim-tip-reference" title="Camacho Vanegas, O. C., Bertini, E., Zhang, R.-Z., Petrini, S., Minosse, C., Sabatelli, P., Giusti, B., Chu, M.-L., Pepe, G. <strong>Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI.</strong> Proc. Nat. Acad. Sci. 98: 7516-7521, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11381124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11381124</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11381124[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.121027598" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11381124">Camacho Vanegas et al. (2001)</a> described 2 brothers with Ullrich scleroatonic muscular dystrophy (UCMD1B; <a href="/entry/620727">620727</a>) who had compound heterozygous splice site mutations in the COL6A2 gene, one in intron 17 (<a href="#0003">120240.0003</a>) and the other a G-to-A substitution at nucleotide -1 in intron 23. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11381124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs267606750 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606750;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=rs267606750" 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=rs267606750" 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=RCV000018699 OR RCV000725485 OR RCV004574029" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018699, RCV000725485, RCV004574029" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018699...</a>
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<p>In 9 members of a Caucasian family (family 3) from Mississippi and North Carolina with Bethlem myopathy-1B (BTHLM1B; <a href="/entry/620725">620725</a>), who had a limb-girdle muscular dystrophy phenotype, <a href="#21" class="mim-tip-reference" title="Scacheri, P. C., Gillanders, E. M., Subramony, S. H., Vedanarayanan, V., Crowe, C. A., Thakore, N., Bingler, M., Hoffman, E. P. <strong>Novel mutations in collagen VI genes: expansion of the Bethlem myopathy phenotype.</strong> Neurology 58: 593-602, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11865138/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11865138</a>] [<a href="https://doi.org/10.1212/wnl.58.4.593" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11865138">Scacheri et al. (2002)</a> identified a heterozygous c.1858G-A transition in the COL6A2 gene, resulting in an asp620-to-asn (D620N) substitution. This mutation did not overtly affect the expression of proteins of the extracellular matrix (ECM), but did alter the expression of laminin beta-1 (<a href="/entry/150240">150240</a>) in the basement membrane of muscle fibers. Type VI collagen was thought to anchor the basal lamina to the extracellular matrix by interacting with collagen type IV, which in turn was thought to bind laminin beta-1 (<a href="#14" class="mim-tip-reference" title="Kuo, H.-J., Maslen, C. L., Keene, D. R., Glanville, R. W. <strong>Type VI collagen anchors endothelial basement membranes by interacting with type IV collagen.</strong> J. Biol. Chem. 272: 26522-26529, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9334230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9334230</a>] [<a href="https://doi.org/10.1074/jbc.272.42.26522" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9334230">Kuo et al., 1997</a>). <a href="#21" class="mim-tip-reference" title="Scacheri, P. C., Gillanders, E. M., Subramony, S. H., Vedanarayanan, V., Crowe, C. A., Thakore, N., Bingler, M., Hoffman, E. P. <strong>Novel mutations in collagen VI genes: expansion of the Bethlem myopathy phenotype.</strong> Neurology 58: 593-602, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11865138/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11865138</a>] [<a href="https://doi.org/10.1212/wnl.58.4.593" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11865138">Scacheri et al. (2002)</a> suggested that their studies widen the clinical spectrum of Bethlem myopathy and indicated that autosomal dominant limb-girdle muscular dystrophy should be studied for possible collagen VI etiology. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9334230+11865138" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0006 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1B, AUTOSOMAL RECESSIVE</strong>
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COL6A2, 26-BP DEL, NT731
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003764596" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003764596" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003764596</a>
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<p>In a patient with Ullrich congenital muscular dystrophy (UCMD1B; <a href="/entry/620727">620727</a>), <a href="#10" class="mim-tip-reference" title="Higuchi, I., Shiraishi, T., Hashiguchi, T,, Suehara, M., Niiyama, T., Nakagawa, M., Arimura, K., Maruyama, I., Osame, M. <strong>Frameshift mutation in the collagen VI gene causes Ullrich's disease.</strong> Ann. Neurol. 50: 261-265, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11506412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11506412</a>] [<a href="https://doi.org/10.1002/ana.1120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11506412">Higuchi et al. (2001)</a> identified a homozygous 26-bp deletion (nucleotides 731-756) in exon 14 of the COL6A2 gene, causing a frameshift and premature termination codon, and resulting in a truncated collagen VI alpha-2 chain. Collagen VI expression was absent from the patient's skeletal muscle and skin samples. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11506412" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1B, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1568931397 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1568931397;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=rs1568931397" 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=rs1568931397" 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=RCV003764597" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003764597" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003764597</a>
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<p>In a patient with Ullrich congenital muscular dystrophy (UCMD1B; <a href="/entry/620727">620727</a>), <a href="#16" class="mim-tip-reference" title="Lucarini, L., Giusti, B., Zhang, R.-Z., Pan, T.-C., Jimenez-Mallebrera, C., Mercuri, E., Muntoni, F., Pepe, G., Chu, M.-L. <strong>A homozygous COL6A2 intron mutation causes in-frame triple-helical deletion and nonsense-mediated mRNA decay in a patient with Ullrich congenital muscular dystrophy.</strong> Hum. Genet. 117: 460-466, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16075202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16075202</a>] [<a href="https://doi.org/10.1007/s00439-005-1318-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16075202">Lucarini et al. (2005)</a> identified a homozygous A-to-G transition in intron 12 of the COL6A2 gene, resulting in deletion of exon 13, which removed 21 amino acids from the N terminus of the triple helical domain. The misaligned N-terminal region was predicted to interfere with the assembly of collagen VI microfibrils. The intron mutation activated numerous cryptic acceptor sites, generating both normal and exon 13-deleted COL6A2 mRNA as well as multiple transcripts containing frameshifts that were degraded through nonsense-mediated decay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16075202" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003764598" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003764598" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003764598</a>
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<p>In a patient with Ullrich congenital muscular dystrophy (UCMD1B; <a href="/entry/620727">620727</a>), <a href="#4" class="mim-tip-reference" title="Baker, N. L., Morgelin, M., Peat, R., Goemans, N., North, K. N., Bateman, J. F., Lamande, S. R. <strong>Dominant collagen VI mutations are a common cause of Ullrich congenital muscular dystrophy.</strong> Hum. Molec. Genet. 14: 279-293, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15563506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15563506</a>] [<a href="https://doi.org/10.1093/hmg/ddi025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15563506">Baker et al. (2005)</a> identified heterozygosity for a 1,332-bp deletion of the COL6A2 gene, which included part of intron 5, all of exon 6 and intron 6, and part of exon 7 and was predicted to result in loss of 27 amino acids in the triple helical region. The patient's mother was a mosaic carrier of the deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15563506" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 BETHLEM MYOPATHY 1B, AUTOSOMAL DOMINANT</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">rs1555873356 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555873356;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=rs1555873356" 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=rs1555873356" 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=RCV000018703 OR RCV003764599" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018703, RCV003764599" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018703...</a>
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<p>In a 40-year-old man with Bethlem myopathy (BTHLM1B; <a href="/entry/620725">620725</a>), <a href="#3" class="mim-tip-reference" title="Baker, N. L., Morgelin, M., Pace, R. A., Peat, R. A., Adams, N. E., Gardner, R. J. M., Rowland, L. P., Miller, G., De Jonghe, P., Ceulemans, B., Hannibal, M. C., Edwards, M., Thompson, E. M., Jacobson, R., Quinlivan, R. C. M., Aftimos, S., Kornberg, A. J., North, K. N., Bateman, J. F., Lamande, S. R. <strong>Molecular consequences of dominant Bethlem myopathy collagen VI mutations.</strong> Ann. Neurol. 62: 390-405, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17886299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17886299</a>] [<a href="https://doi.org/10.1002/ana.21213" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17886299">Baker et al. (2007)</a> identified a heterozygous A-to-G transition in intron 10 of the COL6A2 gene, resulting in the skipping of exon 11. Exon 11 codes for the only cysteine residue in the triple helical domain of the protein, which is predicted to form a disulfide bond critical for dimerization. This would result in decreased assembly of the collagen VI protein. Further evidence indicated nonsense-mediated decay of an mRNA with a premature stop codon, and reduced secretion of structurally abnormal collagen. The patient had proximal muscle weakness, decreased motor capacity, joint contractures, and dystrophic features on muscle biopsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17886299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 BETHLEM MYOPATHY 1B, AUTOSOMAL DOMINANT</strong>
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COL6A2, PRO932LEU
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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> rs117725825 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs117725825;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/rs117725825?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=rs117725825" 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=rs117725825" 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=RCV000018704 OR RCV000149938 OR RCV000302217 OR RCV000359356 OR RCV000859498 OR RCV003764600 OR RCV004532388" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018704, RCV000149938, RCV000302217, RCV000359356, RCV000859498, RCV003764600, RCV004532388" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018704...</a>
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<p>In a 42-year-old Australian man with Bethlem myopathy (BTHLM1B; <a href="/entry/620725">620725</a>), <a href="#3" class="mim-tip-reference" title="Baker, N. L., Morgelin, M., Pace, R. A., Peat, R. A., Adams, N. E., Gardner, R. J. M., Rowland, L. P., Miller, G., De Jonghe, P., Ceulemans, B., Hannibal, M. C., Edwards, M., Thompson, E. M., Jacobson, R., Quinlivan, R. C. M., Aftimos, S., Kornberg, A. J., North, K. N., Bateman, J. F., Lamande, S. R. <strong>Molecular consequences of dominant Bethlem myopathy collagen VI mutations.</strong> Ann. Neurol. 62: 390-405, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17886299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17886299</a>] [<a href="https://doi.org/10.1002/ana.21213" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17886299">Baker et al. (2007)</a> identified a heterozygous 2795C-T transition in exon 28 of the COL6A2 gene, resulting in a pro932-to-leu (P932L) substitution in the globular C2 A-domain. Three first cousins and a niece were affected and also carried the mutation. The proband had proximal muscle weakness and joint contractures. Further studies indicated that the mutant P932L resulted in reduced intracellular collagen VI assembly and secretion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17886299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 MYOSCLEROSIS, AUTOSOMAL RECESSIVE (1 family)</strong>
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BETHLEM MYOPATHY 1B, AUTOSOMAL RECESSIVE, INCLUDED
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COL6A2, GLN819TER
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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> rs121912942 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912942;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/rs121912942?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=rs121912942" 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=rs121912942" 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=RCV000018705 OR RCV000480797 OR RCV001327989 OR RCV003764601" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018705, RCV000480797, RCV001327989, RCV003764601" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018705...</a>
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<p><strong><em>Myosclerosis, Autosomal Recessive</em></strong></p><p>
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In 2 sibs, born of consanguineous parents, with autosomal recessive myosclerosis (<a href="/entry/255600">255600</a>), <a href="#18" class="mim-tip-reference" title="Merlini, L., Martoni, E., Grumati, P., Sabatelli, P., Squarzoni, S., Urciuolo, A., Ferlini, A., Gualandi, F., Bonaldo, P. <strong>Autosomal recessive myosclerosis myopathy is a collagen VI disorder.</strong> Neurology 71: 1245-1253, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18852439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18852439</a>] [<a href="https://doi.org/10.1212/01.wnl.0000327611.01687.5e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18852439">Merlini et al. (2008)</a> identified a homozygous 2537C-T transition in exon 27 in the COL6A2 gene, resulting in a gln819-to-ter (Q819X) substitution in the C1 domain. RT-PCR studies showed that the mutation did not result in nonsense-mediated mRNA decay; the translated truncated protein lacked the C2 domain. Studies in patient fibroblasts showed decreased COL6A2 transcripts and decreased amounts of collagen VI deposited in the extracellular matrix. The secreted collagen VI microfibrils were abnormally organized and did not assemble properly into tetramers. The heterozygous parents were unaffected, suggesting that the mutation is not pathogenic in the heterozygous state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18852439" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Bethlem Myopathy 1B, Autosomal Recessive</em></strong></p><p>
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<a href="#9" class="mim-tip-reference" title="Gualandi, F., Urciuolo, A., Martoni, E., Sabatelli, P., Squarzoni, S., Bovolenta, M., Messina, S., Mercuri, E., Franchella, A., Ferlini, A., Bonaldo, P, Merlini, L. <strong>Autosomal recessive Bethlem myopathy.</strong> Neurology 73: 1883-1891, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19949035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19949035</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181c3fd2a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19949035">Gualandi et al. (2009)</a> identified compound heterozygosity for the Q819X mutation and a complex missense allele (R830Q/R843W; <a href="#0017">120240.0017</a>) in a 25-year-old woman with Bethlem myopathy (BTHLM1B; <a href="/entry/620725">620725</a>). Although this genotype suggested autosomal recessive inheritance, the R819X mutation escaped nonsense-mediated decay and was thought not to be pathogenic in the heterozygous state, based on the report of <a href="#18" class="mim-tip-reference" title="Merlini, L., Martoni, E., Grumati, P., Sabatelli, P., Squarzoni, S., Urciuolo, A., Ferlini, A., Gualandi, F., Bonaldo, P. <strong>Autosomal recessive myosclerosis myopathy is a collagen VI disorder.</strong> Neurology 71: 1245-1253, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18852439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18852439</a>] [<a href="https://doi.org/10.1212/01.wnl.0000327611.01687.5e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18852439">Merlini et al. (2008)</a>. However, the fact that the woman reported by <a href="#9" class="mim-tip-reference" title="Gualandi, F., Urciuolo, A., Martoni, E., Sabatelli, P., Squarzoni, S., Bovolenta, M., Messina, S., Mercuri, E., Franchella, A., Ferlini, A., Bonaldo, P, Merlini, L. <strong>Autosomal recessive Bethlem myopathy.</strong> Neurology 73: 1883-1891, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19949035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19949035</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181c3fd2a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19949035">Gualandi et al. (2009)</a> carried COL6A2 mutations on both alleles had implications for genetic counseling. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18852439+19949035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1B, AUTOSOMAL RECESSIVE</strong>
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COL6A2, CYS777ARG
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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> rs267606747 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606747;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/rs267606747?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=rs267606747" 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=rs267606747" 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=RCV000529271 OR RCV001091900 OR RCV003764602" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000529271, RCV001091900, RCV003764602" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000529271...</a>
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<p>In 3 patients with Ullrich congenital muscular dystrophy (UCMD1B; <a href="/entry/620727">620727</a>), including 2 cousins, <a href="#19" class="mim-tip-reference" title="Nadeau, A., Kinali, M., Main, M., Jimenez-Mallebrera, C., Aloysius, A., Clement, E., North, B., Manzur, A. Y., Robb, S. A., Mercuri, E., Muntoni, F. <strong>Natural history of Ullrich congenital muscular dystrophy.</strong> Neurology 73: 25-31, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19564581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19564581</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181aae851" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19564581">Nadeau et al. (2009)</a> identified a homozygous 2329T-C transition in exon 26 of the COL6A2 gene, resulting in a cys777-to-arg (C777R) substitution. Onset ranged from birth to 2 years. One child had congenital hip dislocation. All had proximal muscle weakness and learned to walk independently at about 1 year of age, but became wheelchair-bound at ages 6.8, 9, and 11.5 years, respectively. Other features included spinal rigidity, scoliosis, and kyphosis. All also required nocturnal ventilation, and 1 needed gastrostomy for chewing difficulties. Only 1 had follicular hyperkeratosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19564581" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1B, AUTOSOMAL DOMINANT</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">rs267606748 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606748;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=rs267606748" 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=rs267606748" 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=RCV000269898 OR RCV000816890 OR RCV003764603 OR RCV004799747" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000269898, RCV000816890, RCV003764603, RCV004799747" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000269898...</a>
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<p>In a 20-year-old patient with Ullrich congenital muscular dystrophy (UCMD1B; <a href="/entry/620727">620727</a>), <a href="#19" class="mim-tip-reference" title="Nadeau, A., Kinali, M., Main, M., Jimenez-Mallebrera, C., Aloysius, A., Clement, E., North, B., Manzur, A. Y., Robb, S. A., Mercuri, E., Muntoni, F. <strong>Natural history of Ullrich congenital muscular dystrophy.</strong> Neurology 73: 25-31, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19564581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19564581</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181aae851" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19564581">Nadeau et al. (2009)</a> identified a de novo heterozygous 847G-A transition in exon 6 of the COL6A2 gene, resulting in a gly283-to-arg (G283R) substitution. The patient had onset at birth with hypotonia, contractures, scoliosis, and delayed motor development. Walking with support was achieved at age 3.3 years, but the patient became wheelchair-bound at age 10. Nocturnal ventilation was also required. Skin changes included follicular hyperkeratosis and keloid formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19564581" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1B, DIGENIC, COL6A1/COL6A2</strong>
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COL6A2, ARG498HIS
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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> rs267606749 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606749;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/rs267606749?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=rs267606749" 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=rs267606749" 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=RCV000653500 OR RCV000710888 OR RCV001138980 OR RCV001138981 OR RCV003764604" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000653500, RCV000710888, RCV001138980, RCV001138981, RCV003764604" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000653500...</a>
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<p>In a 25-year-old patient with Ullrich congenital muscular dystrophy (UCMD1B; <a href="/entry/620727">620727</a>), <a href="#19" class="mim-tip-reference" title="Nadeau, A., Kinali, M., Main, M., Jimenez-Mallebrera, C., Aloysius, A., Clement, E., North, B., Manzur, A. Y., Robb, S. A., Mercuri, E., Muntoni, F. <strong>Natural history of Ullrich congenital muscular dystrophy.</strong> Neurology 73: 25-31, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19564581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19564581</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181aae851" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19564581">Nadeau et al. (2009)</a> identified compound heterozygosity for 2 mutations in 2 different genes: a 1493G-A transition in exon 18 of the COL6A2 gene, resulting in an arg498-to-his (R498H) substitution, and a substitution in the COL6A1 gene (G281R; <a href="/entry/120220#0014">120220.0014</a>). The findings were consistent with digenic inheritance. The patient had onset at age 1.5 years of delayed motor development with proximal muscle weakness. Independent walking was achieved, but the patient became wheelchair-bound at age 19. Spinal rigidity, scoliosis, and contractures were also present, as well as follicular hyperkeratosis and a requirement for nocturnal ventilation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19564581" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1B, AUTOSOMAL RECESSIVE</strong>
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COL6A2, GLU624LYS
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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> rs387906607 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906607;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/rs387906607?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=rs387906607" 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=rs387906607" 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=RCV000726381 OR RCV000822059 OR RCV003764618" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000726381, RCV000822059, RCV003764618" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000726381...</a>
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<p>In a Brazilian girl with Ullrich congenital muscular dystrophy (UCMD1B; <a href="/entry/620727">620727</a>), <a href="#26" class="mim-tip-reference" title="Zhang, R.-Z., Zou, Y., Pan, T.-C., Markova, D., Fertala, A., Hu, Y., Squarzoni, S., Reed, U. C., Marie, S. K. N., Bonnemann, C. G., Chu, M.-L. <strong>Recessive COL6A2 C-globular missense mutations in Ullrich congenital muscular dystrophy: role of the C2a splice variant.</strong> J. Biol. Chem. 285: 10005-10015, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20106987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20106987</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20106987[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/10.1074/jbc.M109.093666" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20106987">Zhang et al. (2010)</a> identified a homozygous 1870G-A transition in the COL6A2 gene, resulting in a glu624-to-lys (E624K) substitution in the C1 globular subdomain. Sequence alignment and molecular modeling indicated that the mutation occurred in a consensus metal ion-dependent adhesion site (MIDAS). Patient fibroblasts deposited abundant collagen VI microfibrils that were thick and abnormally knotty. HEK293 cells transfected with the mutation assembled low levels of short collagen VI microfibrils. The E624K mutation did not affect collagen VI formation and assembly and did not exert a dominant-negative effect, as heterozygous family members were unaffected. However, the E624K-mutant chain was less efficient in supporting microfibrillar assembly than wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20106987" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1B, AUTOSOMAL RECESSIVE</strong>
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COL6A2, ARG876SER
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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> rs387906608 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906608;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/rs387906608?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=rs387906608" 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=rs387906608" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a young man, born of consanguineous Filipino parents, with Ullrich congenital muscular dystrophy (UCMD1B; <a href="/entry/620727">620727</a>), <a href="#26" class="mim-tip-reference" title="Zhang, R.-Z., Zou, Y., Pan, T.-C., Markova, D., Fertala, A., Hu, Y., Squarzoni, S., Reed, U. C., Marie, S. K. N., Bonnemann, C. G., Chu, M.-L. <strong>Recessive COL6A2 C-globular missense mutations in Ullrich congenital muscular dystrophy: role of the C2a splice variant.</strong> J. Biol. Chem. 285: 10005-10015, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20106987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20106987</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20106987[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/10.1074/jbc.M109.093666" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20106987">Zhang et al. (2010)</a> identified a homozygous 2626C-A transversion in the COL6A2 gene, resulting in an arg876-to-ser (R876S) substitution in the beta-2 strand of the C2 globular subdomain. Patient fibroblasts produced almost no collagen VI microfibrils in the extracellular matrix. The minute amounts of COL6A2 that were produced consisted of the C2a splice variant with a shorter alternative C2 subdomain not affected by the missense mutation. The C2a splice variant COL6A2 was not assembled into a triple-helical collagen VI molecule. HEK293 cells transfected with the R876S mutation showed intracellular retention of the mutant chain and were unable to synthesize normal collagen VI microfibrils. However, the patient showed a slightly less severe phenotype than another affected patient with a different mutation (see <a href="#0015">120240.0015</a>), suggesting that the low levels of COL6A2 with alternatively spliced C2a may have functionally compensated for loss of normal COL6A2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20106987" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 BETHLEM MYOPATHY 1B, AUTOSOMAL RECESSIVE</strong>
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COL6A2, ARG830GLN AND ARG843TRP
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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> rs139552940 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs139552940;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/rs139552940?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=rs139552940" 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=rs139552940" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <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> rs376880198 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs376880198;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/rs376880198?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=rs376880198" 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=rs376880198" 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=RCV000193161 OR RCV000387708 OR RCV000597570 OR RCV000801298 OR RCV001208362 OR RCV003764620" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000193161, RCV000387708, RCV000597570, RCV000801298, RCV001208362, RCV003764620" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000193161...</a>
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<p>In a 25-year-old woman with Bethlem myopathy (BTHLM1B; <a href="/entry/620725">620725</a>), <a href="#9" class="mim-tip-reference" title="Gualandi, F., Urciuolo, A., Martoni, E., Sabatelli, P., Squarzoni, S., Bovolenta, M., Messina, S., Mercuri, E., Franchella, A., Ferlini, A., Bonaldo, P, Merlini, L. <strong>Autosomal recessive Bethlem myopathy.</strong> Neurology 73: 1883-1891, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19949035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19949035</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181c3fd2a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19949035">Gualandi et al. (2009)</a> identified compound heterozygosity for variations in the COL6A2 gene. The maternal allele carried a 2571G-A and a 2609C-T transition, both in exon 28, resulting in an arg830-to-gln (R830Q) and an arg843-to-trp (R843W) substitution, respectively, in the C2 domain. Both mutations affected highly conserved residues. The paternal allele carried a Q819X (<a href="#0011">120240.0011</a>) substitution. The patient had onset of progressive proximal muscle weakness at age 2 years. During the course of the disorder, she developed prominent joint contractures and decreased forced vital capacity (65% of predicted), but retained independent ambulation. Muscle biopsy showed a myopathic pattern and fibrosis with mildly decreased collagen VI staining. Studies of fibroblasts showed absence of collagen VI tetramer formation, but electron microscopy showed correct filamentous and interconnected collagen VI microfilaments. <a href="#9" class="mim-tip-reference" title="Gualandi, F., Urciuolo, A., Martoni, E., Sabatelli, P., Squarzoni, S., Bovolenta, M., Messina, S., Mercuri, E., Franchella, A., Ferlini, A., Bonaldo, P, Merlini, L. <strong>Autosomal recessive Bethlem myopathy.</strong> Neurology 73: 1883-1891, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19949035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19949035</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181c3fd2a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19949035">Gualandi et al. (2009)</a> concluded that this woman showed rare autosomal recessive inheritance of Bethlem myopathy based on her genotype. However, the authors noted that the R819X mutation escaped nonsense-mediated decay and was thought not to be pathogenic in the heterozygous state, based on the report of <a href="#18" class="mim-tip-reference" title="Merlini, L., Martoni, E., Grumati, P., Sabatelli, P., Squarzoni, S., Urciuolo, A., Ferlini, A., Gualandi, F., Bonaldo, P. <strong>Autosomal recessive myosclerosis myopathy is a collagen VI disorder.</strong> Neurology 71: 1245-1253, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18852439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18852439</a>] [<a href="https://doi.org/10.1212/01.wnl.0000327611.01687.5e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18852439">Merlini et al. (2008)</a>. The fact that the woman reported by <a href="#9" class="mim-tip-reference" title="Gualandi, F., Urciuolo, A., Martoni, E., Sabatelli, P., Squarzoni, S., Bovolenta, M., Messina, S., Mercuri, E., Franchella, A., Ferlini, A., Bonaldo, P, Merlini, L. <strong>Autosomal recessive Bethlem myopathy.</strong> Neurology 73: 1883-1891, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19949035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19949035</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181c3fd2a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19949035">Gualandi et al. (2009)</a> carried COL6A2 mutations on both alleles had implications for genetic counseling. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18852439+19949035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs387906609 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906609;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/rs387906609?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=rs387906609" 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=rs387906609" 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=RCV000254747 OR RCV000796659 OR RCV003764621" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000254747, RCV000796659, RCV003764621" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000254747...</a>
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<p>In a 47-year-old man with Bethlem myopathy (BTHLM1B; <a href="/entry/620725">620725</a>), <a href="#9" class="mim-tip-reference" title="Gualandi, F., Urciuolo, A., Martoni, E., Sabatelli, P., Squarzoni, S., Bovolenta, M., Messina, S., Mercuri, E., Franchella, A., Ferlini, A., Bonaldo, P, Merlini, L. <strong>Autosomal recessive Bethlem myopathy.</strong> Neurology 73: 1883-1891, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19949035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19949035</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181c3fd2a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19949035">Gualandi et al. (2009)</a> identified compound heterozygous mutations in the COL6A2 gene: a 1178C-T transition in exon 12, resulting in an arg366-to-ter (R366X) substitution, and a de novo 2693G-A transition in exon 28, resulting in an asp871-to-asn (D871N; <a href="#0019">120240.0019</a>) substitution in a conserved region of the C2 domain. The nonsense mutation was demonstrated to undergo nonsense-mediated decay. The patient's unaffected mother carried the heterozygous R366X mutation, suggesting that it is not pathogenic in the heterozygous state. The patient was born with talipes equinovarus and had Achilles contractures in childhood. He had limb-girdle weakness with joint contractures and reduced vital capacity (64% of predicted). At age 47, he could walk with aid, but could no longer rise from the floor. Muscle biopsy showed dystrophic features and decreased collagen VI. Studies of fibroblasts showed severely decreased levels of all forms of collagen VI, and electron microscopy showed irregular collagen VI microfilaments with absence of normal network structure. <a href="#9" class="mim-tip-reference" title="Gualandi, F., Urciuolo, A., Martoni, E., Sabatelli, P., Squarzoni, S., Bovolenta, M., Messina, S., Mercuri, E., Franchella, A., Ferlini, A., Bonaldo, P, Merlini, L. <strong>Autosomal recessive Bethlem myopathy.</strong> Neurology 73: 1883-1891, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19949035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19949035</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181c3fd2a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19949035">Gualandi et al. (2009)</a> concluded that this patient had autosomal recessive Bethlem myopathy because of the genotype and his ability to remain ambulatory. The authors stated that the combination of a missense and a nonsense mutation in the COL6A2 gene had not previously been reported, yielding implications for genetic counseling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19949035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0019 BETHLEM MYOPATHY 1B, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387906610 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906610;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/rs387906610?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=rs387906610" 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=rs387906610" 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=RCV000591047 OR RCV000778644 OR RCV001054018 OR RCV003764622" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000591047, RCV000778644, RCV001054018, RCV003764622" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000591047...</a>
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<p>For discussion of the 2693G-A transition in exon 28 of the COL6A2 gene, resulting in an asp871-to-asn (D871N; <a href="#0019">120240.0019</a>) substitution, that was found in compound heterozygous state in a patient with autosomal recessive Bethlem myopathy-1B (BTHLM1B; <a href="/entry/620725">620725</a>) by <a href="#9" class="mim-tip-reference" title="Gualandi, F., Urciuolo, A., Martoni, E., Sabatelli, P., Squarzoni, S., Bovolenta, M., Messina, S., Mercuri, E., Franchella, A., Ferlini, A., Bonaldo, P, Merlini, L. <strong>Autosomal recessive Bethlem myopathy.</strong> Neurology 73: 1883-1891, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19949035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19949035</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181c3fd2a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19949035">Gualandi et al. (2009)</a>, see <a href="#0018">120240.0018</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19949035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 61-year-old man (UCMD65), born of consanguineous parents, with autosomal recessive Bethlem myopathy-1B, <a href="#24" class="mim-tip-reference" title="Zamurs, L. K., Idoate, M. A., Hanssen, E., Gomez-Ibanez, A., Pastor, P., Lamande, S. R. <strong>Aberrant mitochondria in a Bethlem myopathy patient with a homozygous amino acid substitution that destabilizes the collagen VI alpha2(VI) chain.</strong> J. Biol. Chem. 290: 4272-4281, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25533456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25533456</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25533456[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/10.1074/jbc.M114.632208" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25533456">Zamurs et al. (2015)</a> identified a homozygous c.2611G-A transition in the COL6A2 gene, resulting in an asp871-to-asn (D871N) substitution in the C2 domain. His unaffected parents were each heterozygous for the variant. Detailed studies of patient fibroblasts showed that the mutant protein interfered with collagen VI assembly, secretion, and microfibril formation, all of which were reduced compared to controls. Some collagen VI was assembled, albeit more slowly than normal, and was secreted; these molecules contained the minor COL6A2 C2a splice form that has an alternative C terminus and does not contain the mutation. When expressed in HEK293 cells, the mutant D871N protein was retained in the endoplasmic reticulum due to abnormal protein folding and was selectively degraded by the proteosome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25533456" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0020 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1B, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122821 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122821;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=rs398122821" 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=rs398122821" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a girl with Ullrich congenital muscular dystrophy (UCMD1B; <a href="/entry/620727">620727</a>), <a href="#22" class="mim-tip-reference" title="Tooley, L. D., Zamurs, L. K., Beecher, N., Baker, N. L., Peat, R. A., Adams, N. E., Bateman, J. F., North, K. N., Baldock, C., Lamande, S. R. <strong>Collagen VI microfibril formation is abolished by an alpha-2(VI) von Willebrand factor type A domain mutation in a patient with Ullrich congenital muscular dystrophy.</strong> J. Biol. Chem. 285: 33567-33576, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20729548/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20729548</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20729548[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/10.1074/jbc.M110.152520" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20729548">Tooley et al. (2010)</a> identified compound heterozygous mutations in the COL6A2 gene: a 6-bp deletion in exon 25 (1855_1860del6), causing an in-frame deletion of 2 amino acids in the N-terminal C1 VWA domain (V619_I620del2), and a G-to-T transversion in intron 23 (1771-1G-T; <a href="#0021">120240.0021</a>), resulting in the skipping of exon 24, a frameshift, and premature termination. Each mutation was inherited from an unaffected parent. Northern blot analysis of patient fibroblasts showed that the intron 23 mutation resulted in nonsense-mediated mRNA decay. Patient fibroblasts showed reduced, but present, collagen VI production, indicating that the COL6A1 and COL6A3 chains could associate with mutant COL6A2, forming monomers, dimers, and tetramers. However, kinetic studies showed that the mutation delayed the assembly and secretion of collagen VI compared to controls, and several additional approaches showed that the mutation prevented the association of secreted tetramers into collagen VI microfibrils. Recombinant C1 domains containing the mutation were insoluble and retained intracellularly as disulfide-bonded aggregates, consistent with misfolding. The findings indicated that a correctly folded COL6A2 C1 domain is important for microfibril assembly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20729548" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0021 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1B, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs748035948 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs748035948;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=rs748035948" 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=rs748035948" 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=RCV003764645" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003764645" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003764645</a>
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<p>For discussion of the G-to-T transversion in intron 23 (1771-1G-T) of the COL6A2 gene that was found in compound heterozygous state in a patient with Ullrich congenital muscular dystrophy (UCMD1B; <a href="/entry/620727">620727</a>) by <a href="#22" class="mim-tip-reference" title="Tooley, L. D., Zamurs, L. K., Beecher, N., Baker, N. L., Peat, R. A., Adams, N. E., Bateman, J. F., North, K. N., Baldock, C., Lamande, S. R. <strong>Collagen VI microfibril formation is abolished by an alpha-2(VI) von Willebrand factor type A domain mutation in a patient with Ullrich congenital muscular dystrophy.</strong> J. Biol. Chem. 285: 33567-33576, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20729548/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20729548</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20729548[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/10.1074/jbc.M110.152520" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20729548">Tooley et al. (2010)</a>, see <a href="#0020">120240.0020</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20729548" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0022 BETHLEM MYOPATHY 1B, AUTOSOMAL RECESSIVE</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV004588596" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV004588596" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV004588596</a>
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<p>In 2 adult sibs with autosomal recessive Bethlem myopathy-1B (BTHLM1B; <a href="/entry/620725">620725</a>), <a href="#7" class="mim-tip-reference" title="Caria, F., Cescon, M., Gualandi, F., Pichiecchio, A., Rossi, R., Rimessi, P., Cotti Piccinelli, S., Gallo Cassarino, S., Gregorio, I., Galvagni, A., Ferlini, A., Padovani, A., Bonaldo, P., Filosto, M. <strong>Autosomal recessive Bethlem myopathy: a clinical, genetic and functional study.</strong> Neuromusc. Disord. 29: 657-663, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31471117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31471117</a>] [<a href="https://doi.org/10.1016/j.nmd.2019.07.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31471117">Caria et al. (2019)</a> identified compound heterozygous mutations in the COL6A2 gene: a c.2665C-T transition in exon 28, resulting in a gln889-to-ter (Q889X) substitution, and a 6-bp in-frame insertion (c.780_781insCCCCCC) in exon 5, resulting in a Pro260_Lys261insProPro substitution (<a href="#0023">120240.0023</a>). The mutations, which were found by next-generation panel sequencing and confirmed by Sanger sequencing, were each inherited from an unaffected parent. Neither mutation was present in control population databases, including Exome Sequencing Project, ExAC, 1000 Genomes Project, and gnomAD. Western blot analysis of patient fibroblasts showed low levels of the canonical 1,019-residue COL6A2 chain and presence of a truncated 889-residue mutant protein; a normal 918-residue splice variant (C2A) was also detected. There were normal amounts of collagen VI dimers and tetramers in the cell layer, but not in the cell media, indicating instability of the secreted protein. Immunofluorescence studies of patient fibroblasts showed markedly reduced expression of collagen VI, which was poorly organized in the extracellular matrix. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31471117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0023 BETHLEM MYOPATHY 1B, AUTOSOMAL RECESSIVE</strong>
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COL6A2, 6-BP INS, 780CCCCCC
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV004588597" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV004588597" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV004588597</a>
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<p>For discussion of the 6-bp in-frame insertion (c.780_781insCCCCCC) in exon 5 of the COL6A2 gene, resulting in a Pro260_Lys261insProPro substitution, that was found in compound heterozygous state in 2 sibs with autosomal recessive Bethlem myopathy-1B (BTHLM1B; <a href="/entry/620725">620725</a>) by <a href="#7" class="mim-tip-reference" title="Caria, F., Cescon, M., Gualandi, F., Pichiecchio, A., Rossi, R., Rimessi, P., Cotti Piccinelli, S., Gallo Cassarino, S., Gregorio, I., Galvagni, A., Ferlini, A., Padovani, A., Bonaldo, P., Filosto, M. <strong>Autosomal recessive Bethlem myopathy: a clinical, genetic and functional study.</strong> Neuromusc. Disord. 29: 657-663, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31471117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31471117</a>] [<a href="https://doi.org/10.1016/j.nmd.2019.07.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31471117">Caria et al. (2019)</a>, see <a href="#0022">120240.0022</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31471117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Ackerman2012" class="mim-anchor"></a>
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Ackerman, C., Locke, A. E., Feingold, E., Reshey, B., Espana, K., Thusberg, J., Mooney, S., Bean, L. J. H., Dooley, K. J., Cua, C. L., Reeves, R. H., Sherman, S. L., Maslen, C. L.
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<strong>An excess of deleterious variants in VEGF-A pathway genes in Down-syndrome-associated atrioventricular septal defects.</strong>
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Am. J. Hum. Genet. 91: 646-659, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23040494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23040494</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23040494" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2012.08.017" target="_blank">Full Text</a>]
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<a id="Arts1978" class="mim-anchor"></a>
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Arts, W. F., Bethlem, J., Volkers, W. S.
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<strong>Further investigations on benign myopathy with autosomal dominant inheritance.</strong>
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J. Neurol. 217: 201-206, 1978.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/75955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">75955</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=75955" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF00312962" target="_blank">Full Text</a>]
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Baker, N. L., Morgelin, M., Pace, R. A., Peat, R. A., Adams, N. E., Gardner, R. J. M., Rowland, L. P., Miller, G., De Jonghe, P., Ceulemans, B., Hannibal, M. C., Edwards, M., Thompson, E. M., Jacobson, R., Quinlivan, R. C. M., Aftimos, S., Kornberg, A. J., North, K. N., Bateman, J. F., Lamande, S. R.
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<strong>Molecular consequences of dominant Bethlem myopathy collagen VI mutations.</strong>
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Ann. Neurol. 62: 390-405, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17886299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17886299</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17886299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.21213" target="_blank">Full Text</a>]
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Baker, N. L., Morgelin, M., Peat, R., Goemans, N., North, K. N., Bateman, J. F., Lamande, S. R.
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<strong>Dominant collagen VI mutations are a common cause of Ullrich congenital muscular dystrophy.</strong>
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Hum. Molec. Genet. 14: 279-293, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15563506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15563506</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15563506" 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/ddi025" target="_blank">Full Text</a>]
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Bethlem, J., van Wijngaarden, G. K.
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<strong>Benign myopathy, with autosomal dominant inheritance--a report on three pedigrees.</strong>
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Brain 99: 91-100, 1976.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/963533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">963533</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=963533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/99.1.91" target="_blank">Full Text</a>]
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Camacho Vanegas, O. C., Bertini, E., Zhang, R.-Z., Petrini, S., Minosse, C., Sabatelli, P., Giusti, B., Chu, M.-L., Pepe, G.
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<strong>Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI.</strong>
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Proc. Nat. Acad. Sci. 98: 7516-7521, 2001.
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[<a href="https://doi.org/10.1073/pnas.121027598" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e3181c3fd2a" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.46.3.779" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2004.023754" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000327611.01687.5e" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20729548/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20729548</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20729548[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20729548" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M110.152520" target="_blank">Full Text</a>]
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</p>
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</li>
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<li>
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<a id="23" class="mim-anchor"></a>
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<a id="Weil1988" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Weil, D., Mattei, M.-G., Passage, E., Van Cong, N., Pribula-Conway, D., Mann, K., Deutzmann, R., Timpl, R., Chu, M.-L.
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|
<strong>Cloning and chromosomal localization of human genes encoding the three chains of type VI collagen.</strong>
|
|
Am. J. Hum. Genet. 42: 435-445, 1988.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3348212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3348212</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3348212" 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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<li>
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<a id="24" class="mim-anchor"></a>
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<a id="Zamurs2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zamurs, L. K., Idoate, M. A., Hanssen, E., Gomez-Ibanez, A., Pastor, P., Lamande, S. R.
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<strong>Aberrant mitochondria in a Bethlem myopathy patient with a homozygous amino acid substitution that destabilizes the collagen VI alpha2(VI) chain.</strong>
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J. Biol. Chem. 290: 4272-4281, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25533456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25533456</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25533456[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25533456" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M114.632208" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="25" class="mim-anchor"></a>
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<a id="Zhang2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, R.-Z., Sabatelli, P., Pan, T.-C., Squarzoni, S., Mattioli, E., Bertini, E., Pepe, G., Chu, M.-L.
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<strong>Effects on collagen VI mRNA stability and microfibrillar assembly of three COL6A2 mutations in two families with Ullrich congenital muscular dystrophy.</strong>
|
|
J. Biol. Chem. 277: 43557-43564, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12218063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12218063</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12218063" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M207696200" 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="26" class="mim-anchor"></a>
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<a id="Zhang2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, R.-Z., Zou, Y., Pan, T.-C., Markova, D., Fertala, A., Hu, Y., Squarzoni, S., Reed, U. C., Marie, S. K. N., Bonnemann, C. G., Chu, M.-L.
|
|
<strong>Recessive COL6A2 C-globular missense mutations in Ullrich congenital muscular dystrophy: role of the C2a splice variant.</strong>
|
|
J. Biol. Chem. 285: 10005-10015, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20106987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20106987</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20106987[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20106987" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M109.093666" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 07/10/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="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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Patricia A. Hartz - updated : 08/25/2017<br>Ada Hamosh - updated : 2/14/2013<br>Cassandra L. Kniffin - updated : 7/17/2012<br>Cassandra L. Kniffin - updated : 1/28/2011<br>Cassandra L. Kniffin - updated : 12/14/2010<br>Cassandra L. Kniffin - updated : 12/15/2009<br>Cassandra L. Kniffin - updated : 3/30/2009<br>Cassandra L. Kniffin - updated : 5/23/2008<br>George E. Tiller - updated : 11/8/2007<br>Cassandra L. Kniffin - updated : 10/11/2005<br>Marla J. F. O'Neill - updated : 3/1/2005<br>Cassandra L. Kniffin - updated : 1/8/2003<br>Cassandra L. Kniffin - updated : 11/8/2002<br>Victor A. McKusick - updated : 4/8/2002<br>Victor A. McKusick - updated : 7/3/2001<br>Paul Brennan - updated : 5/21/1998
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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="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 : 6/4/1986
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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 : 08/15/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 07/16/2024<br>carol : 07/15/2024<br>ckniffin : 07/10/2024<br>carol : 06/07/2024<br>carol : 06/06/2024<br>ckniffin : 06/05/2024<br>carol : 02/21/2024<br>carol : 09/08/2017<br>carol : 08/28/2017<br>mgross : 08/25/2017<br>carol : 07/20/2015<br>mcolton : 3/3/2015<br>carol : 11/12/2014<br>carol : 12/19/2013<br>joanna : 12/19/2013<br>carol : 9/18/2013<br>joanna : 8/21/2013<br>alopez : 2/14/2013<br>carol : 8/2/2012<br>ckniffin : 7/17/2012<br>terry : 2/18/2011<br>wwang : 2/18/2011<br>ckniffin : 1/28/2011<br>wwang : 1/6/2011<br>ckniffin : 12/14/2010<br>alopez : 6/8/2010<br>carol : 12/23/2009<br>ckniffin : 12/15/2009<br>wwang : 4/13/2009<br>ckniffin : 3/30/2009<br>wwang : 7/8/2008<br>ckniffin : 5/23/2008<br>wwang : 11/30/2007<br>terry : 11/8/2007<br>wwang : 10/26/2005<br>ckniffin : 10/11/2005<br>wwang : 3/14/2005<br>wwang : 3/8/2005<br>terry : 3/1/2005<br>cwells : 1/15/2003<br>ckniffin : 1/8/2003<br>carol : 11/13/2002<br>ckniffin : 11/8/2002<br>terry : 6/26/2002<br>cwells : 4/19/2002<br>cwells : 4/17/2002<br>cwells : 4/17/2002<br>terry : 4/8/2002<br>carol : 7/19/2001<br>joanna : 7/18/2001<br>alopez : 7/17/2001<br>mcapotos : 7/3/2001<br>dkim : 12/10/1998<br>dkim : 12/9/1998<br>carol : 5/21/1998<br>mark : 9/6/1996<br>terry : 9/5/1996<br>terry : 9/3/1996<br>mimadm : 4/18/1994<br>warfield : 4/8/1994<br>carol : 4/6/1993<br>carol : 6/17/1992<br>supermim : 3/16/1992<br>supermim : 3/20/1990
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 120240
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</span>
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</h3>
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</div>
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<div>
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<h3>
|
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<span class="mim-font">
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|
COLLAGEN, TYPE VI, ALPHA-2; COL6A2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: COL6A2</em></strong>
|
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 763895001;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 21q22.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 21:46,098,112-46,132,848 </span>
|
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</em>
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</strong>
|
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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|
Phenotype <br /> MIM number
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</th>
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<th>
|
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="3">
|
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<span class="mim-font">
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21q22.3
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
?Myosclerosis, congenital
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
255600
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
Autosomal recessive
|
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</span>
|
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</td>
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<td>
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<span class="mim-font">
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3
|
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
|
Bethlem myopathy 1B
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
620725
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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Autosomal dominant; Autosomal recessive
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
|
Ullrich congenital muscular dystrophy 1B
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
620727
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Autosomal dominant; Autosomal recessive
|
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</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
3
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<span class="mim-text-font">
|
|
<p>The COL6A2 gene encodes the alpha-2 subunit of type VI collagen, a ubiquitously expressed extracellular matrix protein. It is 1 of the 3 subunits comprising the full collagen VI protein (see also COL6A1, 120220 and COL6A3, 120250) (summary by Zhang et al., 2010). </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>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Weil et al. (1988) isolated clones corresponding to the COL6A2 gene from a human placenta expression library. Northern blot analysis detected a 3.5-kb mRNA transcript. The molecular mass of the protein is approximately 140 kD. </p><p>Chu et al. (1989) determined that the COL6A2 protein contains 998 amino acids with 31% identity to COL6A1 in the N-terminal and C-terminal globular domains, which are connected by a triple helical segment. Both COL6A1 and COL6A2 contain small signal peptide sequences. Internal alignment of the globular sequences showed a repetitive 200-residue structure (15 to 23% identity) occurring 3 times (N1, C1, C2) in each chain. Sequencing of COL6A2 cDNA clones revealed 2 variant chains with a distinct C2 subdomain and 3-prime noncoding region. The repetitive segments C1, C2 and, to a lesser extent, N1 showed significant identity (15 to 18%) to the collagen-binding A domains of von Willebrand factor (VWF; 613160). These results suggested that the globular domains of the COL6 proteins bind to collagenous structures. </p><p>Saitta et al. (1992) found that the human COL6A2 gene uses alternative processing to produce multiple mRNA transcripts differing in the 5-prime untranslated region as well as in the 3-prime coding and noncoding sequences. </p>
|
|
</span>
|
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<div>
|
|
<br />
|
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Saitta et al. (1992) demonstrated that the COL6A2 gene contains 30 exons and spans 36 kb. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By somatic cell hybrid and FISH analysis, Weil et al. (1988) mapped the COL6A2 gene to chromosome 21q22.3. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Klewer et al. (1998) studied COL6A2 gene expression in the developing mammalian heart. The pattern of expression was identical to that of COL6A1. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Bethlem Myopathy 1B and Ullrich Congenital Muscular Dystrophy 1B</em></strong></p><p>
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In 9 kindreds with the Bethlem form of autosomal dominant myopathy with contractures (see BTHLM1A, 158810 and BTHLM1B, 620725), Jobsis et al. (1996) demonstrated genetic linkage to the COL6A1-COL6A2 gene cluster on 21q22.3. By sequence analysis in 4 families, Jobsis et al. (1996) identified heterozygous missense mutations in 3: affected members of family 2 (a Dutch family originally reported by Bethlem and van Wijngaarden, 1976) carried a heterozygous missense mutation in the COL6A1 gene (G286V; 120220.0001) and families 4 and 5 carried the same heterozygous missense mutation in COL6A2 (G250S; 120240.0001) (family 4 had been reported by Arts et al., 1978). Both mutations disrupted the Gly-X-Y motif of the triple helical domain by substitution of gly for either val or ser. Analogous to the putative perturbation of the anchoring function of the dystrophin-associated complex in congenital muscular dystrophy with mutations in the alpha-2 subunit of laminin (156225), the observation suggested a similar mechanism in Bethlem myopathy. </p><p>Ullrich scleroatonic muscular dystrophy, also known as Ullrich congenital muscular dystrophy (see UCMD1B; 620727), shares some clinical features with Bethlem myopathy, such as joint contractures, but displays a more severe course. Camacho Vanegas et al. (2001) demonstrated recessive mutations in the COL6A2 gene (see 120240.0002) leading to UCMD. </p><p>Lampe et al. (2005) developed a method for rapid direct sequence analysis of all 107 coding exons of the COL6 genes (COL6A1; COL6A2; COL6A3, 120250) with single condition amplification/internal primer (SCAIP) sequencing. They sequenced all 3 COL6 genes from genomic DNA in 79 patients with UCMD or Bethlem myopathy, and found putative mutations in 1 of the COL6 genes in 62% of patients. Some patients showed changes in more than one of the COL6 genes, and some UCMD patients appeared to have dominant rather than recessive disease. Lampe et al. (2005) concluded that these findings may explain some or all of the cases of UCMD that are unlinked to the COL6 gene under a recessive model. </p><p>In 2 unrelated patients with BTHLM1B, Baker et al. (2007) identified different heterozygous mutations in the COL6A2 gene (120240.0009; 120240.0010). In vitro studies indicated defective collagen VI synthesis and secretion. </p><p>Nadeau et al. (2009) identified a homozygous COL6A2 mutation (C777R; 120240.0012) in 3 patients with autosomal recessive UCMD1B. Two additional patients had different de novo heterozygous COL6A2 mutations (see, e.g., G283R, 120240.0013), consistent with autosomal dominant inheritance. Another patient was compound heterozygous for a mutation in the COL6A1 gene (G281R; 120220.0014) and a mutation in the COL6A2 gene (R498H; 120240.0014), consistent with digenic inheritance. </p><p>In a 61-year-old man (UCMD65), born of consanguineous parents, with autosomal recessive Bethlem myopathy-1B, Zamurs et al. (2015) identified a homozygous missense mutation in the COL6A2 gene (D871N; 120240.0019). His unaffected parents were each heterozygous for the variant. Detailed studies of patient fibroblasts showed that the mutant protein interfered with collagen VI assembly, secretion, and microfibril formation, all of which were reduced compared to controls. </p><p>In 2 adult sibs with autosomal recessive Bethlem myopathy-1B, Caria et al. (2019) identified compound heterozygous mutations in the COL6A2 gene: a nonsense mutation in exon 28, resulting in a gln889-to-ter (Q889X; 120240.0022), and an in-frame insertion (120240.0023) in exon 5. The mutations, which were found by next-generation panel sequencing and confirmed by Sanger sequencing, were each inherited from an unaffected parent. Western blot analysis of patient fibroblasts showed low levels of the canonical 1,019-residue COL6A2 chain and presence of a truncated 889-residue mutant protein; a normal 918-residue splice variant (C2A) was also detected. There were normal amounts of collagen VI dimers and tetramers in the cell layer, but not in the cell media, indicating instability of the secreted protein. Immunofluorescence studies of patient fibroblasts showed markedly reduced expression of collagen VI, which was poorly organized in the extracellular matrix. </p><p><strong><em>Myosclerosis, Autosomal Recessive</em></strong></p><p>
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|
In 2 sibs with autosomal recessive myosclerosis (255600), Merlini et al. (2008) identified a homozygous truncating mutation in the COL6A2 gene (120240.0011). </p><p><strong><em>Role of COL6A2 in Atrioventricular Septal Defect</em></strong></p><p>
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|
Ackerman et al. (2012) used a candidate gene approach among individuals with Down syndrome and complete atrioventricular septal defect (AVSD) (141 cases) and Down syndrome with no congenital heart defect (141 controls) to determine whether rare genetic variants in genes involved in atrioventricular valvuloseptal morphogenesis contribute to AVSD in this sensitized population. Ackerman et al. (2012) found a significant excess (p less than 0.0001) of variants predicted to be deleterious in cases compared to controls. At the most stringent level of filtering, they found potentially damaging variants in nearly 20% of cases but in fewer than 3% of controls. The variants with the highest probability of being damaging in cases only were found in 6 genes: COL6A1, COL6A2, CRELD1 (607170) (already identified as a cause of AVSD; see 606217), FBLN2 (135821), FRZB (605083), and GATA5 (611496). Several of the case-specific variants were recurrent in unrelated individuals, occurring in 10% of cases studied. No variants with an equal probability of being damaging were found in controls, demonstrating a highly specific association with AVSD. Of note, all of these genes are in the VEGFA (192240) pathway, suggesting to Ackerman et al. (2012) that rare variants in this pathway might contribute to the genetic underpinnings of AVSD in humans. </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>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>Gualandi et al. (2009) reported 2 unrelated patients with Bethlem myopathy who were each compound heterozygous for a truncating and a missense mutation in the COL6A2 gene (Q819X, 120240.0011 and R830Q/R843W, 120240.0017; R366X, 120240.0018 and D871N; 120240.0019, respectively). Both patients remained ambulatory as adults, and muscle biopsies and studies of fibroblasts showed variable degrees of aberrant collagen VI microfilament formation. Gualandi et al. (2009) noted that autosomal recessive inheritance had not been reported in Bethlem myopathy and suggested that collagen VI-related myopathies comprise a spectrum of conditions with variable severity. In addition, the findings did not support pure haploinsufficiency as a causative mechanism for Bethlem myopathy, and suggested that some previously reported patients may harbor a second missed mutation. The genotype findings in these patients had important implications for genetic counseling. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Meehan et al. (2017) reported that knockout of Col6a2 in mice caused decreased grip strength. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
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</span>
|
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<strong>23 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 BETHLEM MYOPATHY 1B, AUTOSOMAL DOMINANT</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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COL6A2, GLY250SER
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<br />
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SNP: rs121912940,
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ClinVar: RCV000018695, RCV001781280, RCV003764593
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In 2 kindreds (families 4 and 5) with Bethlem myopathy-1B (BTHLM1B; 620725), Jobsis et al. (1996) demonstrated that affected members had a heterozygous c.898G-A transition in the COL6A2 gene, resulting in a gly250-to-ser (G250S) substitution in the triple helical region. Family 4 was a Polish family originally reported by Arts et al. (1978). </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>.0002 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1B, AUTOSOMAL RECESSIVE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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COL6A2, 1-BP INS, 1151C
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<br />
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SNP: rs1601231322,
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ClinVar: RCV003764594
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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, Camacho Vanegas et al. (2001) found that a son with Ullrich congenital muscular dystrophy (UCMD1B; 620727) had a homozygous insertion of a C leading to a premature termination codon in the triple helical domain of COL6A2 mRNA. Both healthy consanguineous parents were carriers. The insertion of the C was in a stretch of 5 cytosines between nucleotides 1147 and 1151 of the COL6A2 cDNA, causing a slippage of the reading frame with a premature termination codon at nucleotides 1347-1349. The affected patient in this family showed reduced fetal movements. At birth he was unusually long (55 cm), showed multiple joint contractures of his knees and elbows, a kyphotic contracture of the spine, a left hip dislocation, bilateral congenital convex pes valgus, long and slender fingers and toes with adducted thumbs, ogival palate, micrognathia, and a short neck with torticollis. He also showed marked bilateral distal hyperlaxity of fingers, toes, calcanei, and wrists. The child walked at the age of 13 months, but generalized muscle weakness persisted thereafter, and progressive scoliosis and respiratory failure developed. He underwent tracheostomy and nocturnal positive pressure mechanical ventilation at the age of 8 years, with signs of diaphragmatic insufficiency. At the age of 11 years, he was still ambulant and had normal intelligence. </p><p>In fibroblasts from the patient reported by Camacho Vanegas et al. (2001), Zhang et al. (2002) showed almost complete absence of COL6A2 mRNA by Northern blot analysis, suggesting that the mutation led to nonsense-mediated mRNA decay. There was complete absence of secreted COL6A2 protein in the medium of the patient's cells, suggesting that the mutation in the triple helical domain prevented microfibrillar assembly and secretion. Although both parents showed decreased levels of COL6A2 mRNA, long-term collagen VI deposition was essentially normal. </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>.0003 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1B, AUTOSOMAL RECESSIVE</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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COL6A2, IVS17AS, A-G, -2
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<br />
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SNP: rs749974929,
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gnomAD: rs749974929,
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ClinVar: RCV000550156, RCV003767089
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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 an Italian family, Camacho Vanegas et al. (2001) found that 2 brothers with Ullrich scleroatonic muscular dystrophy (UCMD1B; 620727) had a splice acceptor site mutation in the COL6A2 gene. Deletion of 28 nucleotides was caused by an A-to-G substitution at nucleotide -2 of intron 17, causing activation of a cryptic acceptor site within exon 18. The normal parents were unrelated. Severe contractures of elbows and knees, rigidity of the spine, ogival (gothic) palate, and hypotonia were present. In 1 brother there was distal hyperlaxity and marked weakness of head flexors but almost complete disappearance of limb joint contractures at the age of 2 years. In the brothers, this mutation was found in compound heterozygosity with a splice site mutation in intron 23 (120240.0004). The first mutation was present in the healthy mother, whereas the second mutation was carried by the healthy father. In another Italian family, Camacho Vanegas et al. (2001) found the same 28-bp deletion but did not find the mutation in the other allele. This mutation occurred de novo in the patient. </p><p>In fibroblasts from 1 of the patients reported by Camacho Vanegas et al. (2001) who was compound heterozygous for mutations in the COL6A2 gene, Zhang et al. (2002) showed decreased levels of COL6A2 mRNA by Northern blot analysis, suggesting that the mutations led to nonsense-mediated mRNA decay. Low levels of COL6A2 protein were detected in the medium of the patient's cells, suggesting that the mutations, which occurred at the distal part of the triple helical domain, allowed secretion of a small amount of mutant collagen VI protein. Further analysis showed that the truncated proteins were able to form triple helical monomers, but unable to assemble into dimers and tetramers for the completed collagen VI protein. Zhang et al. (2002) noted that the IVS23 mutation (120240.0004) retains the triple helical domain and thus can assemble into monomers, but has a shorter C-terminal globular domain which prevents further assembly into higher ordered structures. Although both parents showed decreased levels of COL6A2 mRNA, long-term collagen VI deposition was essentially normal. </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>.0004 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1B, AUTOSOMAL RECESSIVE</strong>
|
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</span>
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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COL6A2, IVS23AS, G-A, -1
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<br />
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SNP: rs748035948,
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ClinVar: RCV003764595
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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>Camacho Vanegas et al. (2001) described 2 brothers with Ullrich scleroatonic muscular dystrophy (UCMD1B; 620727) who had compound heterozygous splice site mutations in the COL6A2 gene, one in intron 17 (120240.0003) and the other a G-to-A substitution at nucleotide -1 in intron 23. </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>.0005 BETHLEM MYOPATHY 1B, AUTOSOMAL DOMINANT</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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COL6A2, ASP620ASN
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<br />
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SNP: rs267606750,
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ClinVar: RCV000018699, RCV000725485, RCV004574029
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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 9 members of a Caucasian family (family 3) from Mississippi and North Carolina with Bethlem myopathy-1B (BTHLM1B; 620725), who had a limb-girdle muscular dystrophy phenotype, Scacheri et al. (2002) identified a heterozygous c.1858G-A transition in the COL6A2 gene, resulting in an asp620-to-asn (D620N) substitution. This mutation did not overtly affect the expression of proteins of the extracellular matrix (ECM), but did alter the expression of laminin beta-1 (150240) in the basement membrane of muscle fibers. Type VI collagen was thought to anchor the basal lamina to the extracellular matrix by interacting with collagen type IV, which in turn was thought to bind laminin beta-1 (Kuo et al., 1997). Scacheri et al. (2002) suggested that their studies widen the clinical spectrum of Bethlem myopathy and indicated that autosomal dominant limb-girdle muscular dystrophy should be studied for possible collagen VI etiology. </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 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1B, AUTOSOMAL RECESSIVE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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COL6A2, 26-BP DEL, NT731
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<br />
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ClinVar: RCV003764596
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In a patient with Ullrich congenital muscular dystrophy (UCMD1B; 620727), Higuchi et al. (2001) identified a homozygous 26-bp deletion (nucleotides 731-756) in exon 14 of the COL6A2 gene, causing a frameshift and premature termination codon, and resulting in a truncated collagen VI alpha-2 chain. Collagen VI expression was absent from the patient's skeletal muscle and skin samples. </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 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1B, AUTOSOMAL RECESSIVE</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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COL6A2, IVS12AS, A-G, -10
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<br />
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SNP: rs1568931397,
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ClinVar: RCV003764597
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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 a patient with Ullrich congenital muscular dystrophy (UCMD1B; 620727), Lucarini et al. (2005) identified a homozygous A-to-G transition in intron 12 of the COL6A2 gene, resulting in deletion of exon 13, which removed 21 amino acids from the N terminus of the triple helical domain. The misaligned N-terminal region was predicted to interfere with the assembly of collagen VI microfibrils. The intron mutation activated numerous cryptic acceptor sites, generating both normal and exon 13-deleted COL6A2 mRNA as well as multiple transcripts containing frameshifts that were degraded through nonsense-mediated decay. </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>.0008 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1B, AUTOSOMAL DOMINANT</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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COL6A2, 1.3-KB DEL
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<br />
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ClinVar: RCV003764598
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with Ullrich congenital muscular dystrophy (UCMD1B; 620727), Baker et al. (2005) identified heterozygosity for a 1,332-bp deletion of the COL6A2 gene, which included part of intron 5, all of exon 6 and intron 6, and part of exon 7 and was predicted to result in loss of 27 amino acids in the triple helical region. The patient's mother was a mosaic carrier of 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>.0009 BETHLEM MYOPATHY 1B, AUTOSOMAL DOMINANT</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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COL6A2, IVS10AS, A-G, -2
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<br />
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SNP: rs1555873356,
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ClinVar: RCV000018703, RCV003764599
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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 40-year-old man with Bethlem myopathy (BTHLM1B; 620725), Baker et al. (2007) identified a heterozygous A-to-G transition in intron 10 of the COL6A2 gene, resulting in the skipping of exon 11. Exon 11 codes for the only cysteine residue in the triple helical domain of the protein, which is predicted to form a disulfide bond critical for dimerization. This would result in decreased assembly of the collagen VI protein. Further evidence indicated nonsense-mediated decay of an mRNA with a premature stop codon, and reduced secretion of structurally abnormal collagen. The patient had proximal muscle weakness, decreased motor capacity, joint contractures, and dystrophic features on muscle biopsy. </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>.0010 BETHLEM MYOPATHY 1B, AUTOSOMAL DOMINANT</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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COL6A2, PRO932LEU
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<br />
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SNP: rs117725825,
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gnomAD: rs117725825,
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ClinVar: RCV000018704, RCV000149938, RCV000302217, RCV000359356, RCV000859498, RCV003764600, RCV004532388
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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 42-year-old Australian man with Bethlem myopathy (BTHLM1B; 620725), Baker et al. (2007) identified a heterozygous 2795C-T transition in exon 28 of the COL6A2 gene, resulting in a pro932-to-leu (P932L) substitution in the globular C2 A-domain. Three first cousins and a niece were affected and also carried the mutation. The proband had proximal muscle weakness and joint contractures. Further studies indicated that the mutant P932L resulted in reduced intracellular collagen VI assembly and secretion. </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>.0011 MYOSCLEROSIS, AUTOSOMAL RECESSIVE (1 family)</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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BETHLEM MYOPATHY 1B, AUTOSOMAL RECESSIVE, 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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COL6A2, GLN819TER
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<br />
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SNP: rs121912942,
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gnomAD: rs121912942,
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ClinVar: RCV000018705, RCV000480797, RCV001327989, RCV003764601
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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 />
|
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<p><strong><em>Myosclerosis, Autosomal Recessive</em></strong></p><p>
|
|
In 2 sibs, born of consanguineous parents, with autosomal recessive myosclerosis (255600), Merlini et al. (2008) identified a homozygous 2537C-T transition in exon 27 in the COL6A2 gene, resulting in a gln819-to-ter (Q819X) substitution in the C1 domain. RT-PCR studies showed that the mutation did not result in nonsense-mediated mRNA decay; the translated truncated protein lacked the C2 domain. Studies in patient fibroblasts showed decreased COL6A2 transcripts and decreased amounts of collagen VI deposited in the extracellular matrix. The secreted collagen VI microfibrils were abnormally organized and did not assemble properly into tetramers. The heterozygous parents were unaffected, suggesting that the mutation is not pathogenic in the heterozygous state. </p><p><strong><em>Bethlem Myopathy 1B, Autosomal Recessive</em></strong></p><p>
|
|
Gualandi et al. (2009) identified compound heterozygosity for the Q819X mutation and a complex missense allele (R830Q/R843W; 120240.0017) in a 25-year-old woman with Bethlem myopathy (BTHLM1B; 620725). Although this genotype suggested autosomal recessive inheritance, the R819X mutation escaped nonsense-mediated decay and was thought not to be pathogenic in the heterozygous state, based on the report of Merlini et al. (2008). However, the fact that the woman reported by Gualandi et al. (2009) carried COL6A2 mutations on both alleles had implications for genetic counseling. </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>.0012 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1B, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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COL6A2, CYS777ARG
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<br />
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SNP: rs267606747,
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gnomAD: rs267606747,
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ClinVar: RCV000529271, RCV001091900, RCV003764602
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|
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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 3 patients with Ullrich congenital muscular dystrophy (UCMD1B; 620727), including 2 cousins, Nadeau et al. (2009) identified a homozygous 2329T-C transition in exon 26 of the COL6A2 gene, resulting in a cys777-to-arg (C777R) substitution. Onset ranged from birth to 2 years. One child had congenital hip dislocation. All had proximal muscle weakness and learned to walk independently at about 1 year of age, but became wheelchair-bound at ages 6.8, 9, and 11.5 years, respectively. Other features included spinal rigidity, scoliosis, and kyphosis. All also required nocturnal ventilation, and 1 needed gastrostomy for chewing difficulties. Only 1 had follicular hyperkeratosis. </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>.0013 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1B, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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COL6A2, GLY283ARG
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<br />
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SNP: rs267606748,
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ClinVar: RCV000269898, RCV000816890, RCV003764603, RCV004799747
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|
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|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 20-year-old patient with Ullrich congenital muscular dystrophy (UCMD1B; 620727), Nadeau et al. (2009) identified a de novo heterozygous 847G-A transition in exon 6 of the COL6A2 gene, resulting in a gly283-to-arg (G283R) substitution. The patient had onset at birth with hypotonia, contractures, scoliosis, and delayed motor development. Walking with support was achieved at age 3.3 years, but the patient became wheelchair-bound at age 10. Nocturnal ventilation was also required. Skin changes included follicular hyperkeratosis and keloid formation. </p>
|
|
</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>.0014 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1B, DIGENIC, COL6A1/COL6A2</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
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|
COL6A2, ARG498HIS
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<br />
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SNP: rs267606749,
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gnomAD: rs267606749,
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ClinVar: RCV000653500, RCV000710888, RCV001138980, RCV001138981, RCV003764604
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 25-year-old patient with Ullrich congenital muscular dystrophy (UCMD1B; 620727), Nadeau et al. (2009) identified compound heterozygosity for 2 mutations in 2 different genes: a 1493G-A transition in exon 18 of the COL6A2 gene, resulting in an arg498-to-his (R498H) substitution, and a substitution in the COL6A1 gene (G281R; 120220.0014). The findings were consistent with digenic inheritance. The patient had onset at age 1.5 years of delayed motor development with proximal muscle weakness. Independent walking was achieved, but the patient became wheelchair-bound at age 19. Spinal rigidity, scoliosis, and contractures were also present, as well as follicular hyperkeratosis and a requirement for nocturnal ventilation. </p>
|
|
</span>
|
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</div>
|
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<div>
|
|
<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>.0015 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1B, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
COL6A2, GLU624LYS
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906607,
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|
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|
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gnomAD: rs387906607,
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|
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|
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ClinVar: RCV000726381, RCV000822059, RCV003764618
|
|
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|
|
</span>
|
|
</div>
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Brazilian girl with Ullrich congenital muscular dystrophy (UCMD1B; 620727), Zhang et al. (2010) identified a homozygous 1870G-A transition in the COL6A2 gene, resulting in a glu624-to-lys (E624K) substitution in the C1 globular subdomain. Sequence alignment and molecular modeling indicated that the mutation occurred in a consensus metal ion-dependent adhesion site (MIDAS). Patient fibroblasts deposited abundant collagen VI microfibrils that were thick and abnormally knotty. HEK293 cells transfected with the mutation assembled low levels of short collagen VI microfibrils. The E624K mutation did not affect collagen VI formation and assembly and did not exert a dominant-negative effect, as heterozygous family members were unaffected. However, the E624K-mutant chain was less efficient in supporting microfibrillar assembly than wildtype. </p>
|
|
</span>
|
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</div>
|
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1B, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
COL6A2, ARG876SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906608,
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|
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|
|
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gnomAD: rs387906608,
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|
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|
|
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ClinVar: RCV003764619
|
|
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|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a young man, born of consanguineous Filipino parents, with Ullrich congenital muscular dystrophy (UCMD1B; 620727), Zhang et al. (2010) identified a homozygous 2626C-A transversion in the COL6A2 gene, resulting in an arg876-to-ser (R876S) substitution in the beta-2 strand of the C2 globular subdomain. Patient fibroblasts produced almost no collagen VI microfibrils in the extracellular matrix. The minute amounts of COL6A2 that were produced consisted of the C2a splice variant with a shorter alternative C2 subdomain not affected by the missense mutation. The C2a splice variant COL6A2 was not assembled into a triple-helical collagen VI molecule. HEK293 cells transfected with the R876S mutation showed intracellular retention of the mutant chain and were unable to synthesize normal collagen VI microfibrils. However, the patient showed a slightly less severe phenotype than another affected patient with a different mutation (see 120240.0015), suggesting that the low levels of COL6A2 with alternatively spliced C2a may have functionally compensated for loss of normal COL6A2. </p>
|
|
</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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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 BETHLEM MYOPATHY 1B, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
COL6A2, ARG830GLN AND ARG843TRP
|
|
|
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<br />
|
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|
|
SNP: rs139552940, rs376880198,
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|
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gnomAD: rs139552940, rs376880198,
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|
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ClinVar: RCV000193161, RCV000387708, RCV000597570, RCV000801298, RCV001208362, RCV003764620
|
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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 a 25-year-old woman with Bethlem myopathy (BTHLM1B; 620725), Gualandi et al. (2009) identified compound heterozygosity for variations in the COL6A2 gene. The maternal allele carried a 2571G-A and a 2609C-T transition, both in exon 28, resulting in an arg830-to-gln (R830Q) and an arg843-to-trp (R843W) substitution, respectively, in the C2 domain. Both mutations affected highly conserved residues. The paternal allele carried a Q819X (120240.0011) substitution. The patient had onset of progressive proximal muscle weakness at age 2 years. During the course of the disorder, she developed prominent joint contractures and decreased forced vital capacity (65% of predicted), but retained independent ambulation. Muscle biopsy showed a myopathic pattern and fibrosis with mildly decreased collagen VI staining. Studies of fibroblasts showed absence of collagen VI tetramer formation, but electron microscopy showed correct filamentous and interconnected collagen VI microfilaments. Gualandi et al. (2009) concluded that this woman showed rare autosomal recessive inheritance of Bethlem myopathy based on her genotype. However, the authors noted that the R819X mutation escaped nonsense-mediated decay and was thought not to be pathogenic in the heterozygous state, based on the report of Merlini et al. (2008). The fact that the woman reported by Gualandi et al. (2009) carried COL6A2 mutations on both alleles had implications for genetic counseling. </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>.0018 BETHLEM MYOPATHY 1B, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
|
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COL6A2, ARG366TER
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<br />
|
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SNP: rs387906609,
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gnomAD: rs387906609,
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ClinVar: RCV000254747, RCV000796659, RCV003764621
|
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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 a 47-year-old man with Bethlem myopathy (BTHLM1B; 620725), Gualandi et al. (2009) identified compound heterozygous mutations in the COL6A2 gene: a 1178C-T transition in exon 12, resulting in an arg366-to-ter (R366X) substitution, and a de novo 2693G-A transition in exon 28, resulting in an asp871-to-asn (D871N; 120240.0019) substitution in a conserved region of the C2 domain. The nonsense mutation was demonstrated to undergo nonsense-mediated decay. The patient's unaffected mother carried the heterozygous R366X mutation, suggesting that it is not pathogenic in the heterozygous state. The patient was born with talipes equinovarus and had Achilles contractures in childhood. He had limb-girdle weakness with joint contractures and reduced vital capacity (64% of predicted). At age 47, he could walk with aid, but could no longer rise from the floor. Muscle biopsy showed dystrophic features and decreased collagen VI. Studies of fibroblasts showed severely decreased levels of all forms of collagen VI, and electron microscopy showed irregular collagen VI microfilaments with absence of normal network structure. Gualandi et al. (2009) concluded that this patient had autosomal recessive Bethlem myopathy because of the genotype and his ability to remain ambulatory. The authors stated that the combination of a missense and a nonsense mutation in the COL6A2 gene had not previously been reported, yielding implications for genetic counseling. </p>
|
|
</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>.0019 BETHLEM MYOPATHY 1B, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
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<span class="mim-text-font">
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COL6A2, ASP871ASN
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<br />
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SNP: rs387906610,
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gnomAD: rs387906610,
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ClinVar: RCV000591047, RCV000778644, RCV001054018, RCV003764622
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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 2693G-A transition in exon 28 of the COL6A2 gene, resulting in an asp871-to-asn (D871N; 120240.0019) substitution, that was found in compound heterozygous state in a patient with autosomal recessive Bethlem myopathy-1B (BTHLM1B; 620725) by Gualandi et al. (2009), see 120240.0018. </p><p>In a 61-year-old man (UCMD65), born of consanguineous parents, with autosomal recessive Bethlem myopathy-1B, Zamurs et al. (2015) identified a homozygous c.2611G-A transition in the COL6A2 gene, resulting in an asp871-to-asn (D871N) substitution in the C2 domain. His unaffected parents were each heterozygous for the variant. Detailed studies of patient fibroblasts showed that the mutant protein interfered with collagen VI assembly, secretion, and microfibril formation, all of which were reduced compared to controls. Some collagen VI was assembled, albeit more slowly than normal, and was secreted; these molecules contained the minor COL6A2 C2a splice form that has an alternative C terminus and does not contain the mutation. When expressed in HEK293 cells, the mutant D871N protein was retained in the endoplasmic reticulum due to abnormal protein folding and was selectively degraded by the proteosome. </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>.0020 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1B, AUTOSOMAL RECESSIVE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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COL6A2, 6-BP DEL, NT1855
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<br />
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SNP: rs398122821,
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ClinVar: RCV003764644
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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 girl with Ullrich congenital muscular dystrophy (UCMD1B; 620727), Tooley et al. (2010) identified compound heterozygous mutations in the COL6A2 gene: a 6-bp deletion in exon 25 (1855_1860del6), causing an in-frame deletion of 2 amino acids in the N-terminal C1 VWA domain (V619_I620del2), and a G-to-T transversion in intron 23 (1771-1G-T; 120240.0021), resulting in the skipping of exon 24, a frameshift, and premature termination. Each mutation was inherited from an unaffected parent. Northern blot analysis of patient fibroblasts showed that the intron 23 mutation resulted in nonsense-mediated mRNA decay. Patient fibroblasts showed reduced, but present, collagen VI production, indicating that the COL6A1 and COL6A3 chains could associate with mutant COL6A2, forming monomers, dimers, and tetramers. However, kinetic studies showed that the mutation delayed the assembly and secretion of collagen VI compared to controls, and several additional approaches showed that the mutation prevented the association of secreted tetramers into collagen VI microfibrils. Recombinant C1 domains containing the mutation were insoluble and retained intracellularly as disulfide-bonded aggregates, consistent with misfolding. The findings indicated that a correctly folded COL6A2 C1 domain is important for microfibril assembly. </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>.0021 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1B, AUTOSOMAL RECESSIVE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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COL6A2, IVS23AS, G-T, -1
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<br />
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SNP: rs748035948,
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ClinVar: RCV003764645
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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 G-to-T transversion in intron 23 (1771-1G-T) of the COL6A2 gene that was found in compound heterozygous state in a patient with Ullrich congenital muscular dystrophy (UCMD1B; 620727) by Tooley et al. (2010), see 120240.0020. </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>.0022 BETHLEM MYOPATHY 1B, AUTOSOMAL RECESSIVE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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COL6A2, GLN889TER
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<br />
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ClinVar: RCV004588596
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 adult sibs with autosomal recessive Bethlem myopathy-1B (BTHLM1B; 620725), Caria et al. (2019) identified compound heterozygous mutations in the COL6A2 gene: a c.2665C-T transition in exon 28, resulting in a gln889-to-ter (Q889X) substitution, and a 6-bp in-frame insertion (c.780_781insCCCCCC) in exon 5, resulting in a Pro260_Lys261insProPro substitution (120240.0023). The mutations, which were found by next-generation panel sequencing and confirmed by Sanger sequencing, were each inherited from an unaffected parent. Neither mutation was present in control population databases, including Exome Sequencing Project, ExAC, 1000 Genomes Project, and gnomAD. Western blot analysis of patient fibroblasts showed low levels of the canonical 1,019-residue COL6A2 chain and presence of a truncated 889-residue mutant protein; a normal 918-residue splice variant (C2A) was also detected. There were normal amounts of collagen VI dimers and tetramers in the cell layer, but not in the cell media, indicating instability of the secreted protein. Immunofluorescence studies of patient fibroblasts showed markedly reduced expression of collagen VI, which was poorly organized in the extracellular matrix. </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>.0023 BETHLEM MYOPATHY 1B, AUTOSOMAL RECESSIVE</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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COL6A2, 6-BP INS, 780CCCCCC
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<br />
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ClinVar: RCV004588597
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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>For discussion of the 6-bp in-frame insertion (c.780_781insCCCCCC) in exon 5 of the COL6A2 gene, resulting in a Pro260_Lys261insProPro substitution, that was found in compound heterozygous state in 2 sibs with autosomal recessive Bethlem myopathy-1B (BTHLM1B; 620725) by Caria et al. (2019), see 120240.0022. </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>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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Ackerman, C., Locke, A. E., Feingold, E., Reshey, B., Espana, K., Thusberg, J., Mooney, S., Bean, L. J. H., Dooley, K. J., Cua, C. L., Reeves, R. H., Sherman, S. L., Maslen, C. L.
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<strong>An excess of deleterious variants in VEGF-A pathway genes in Down-syndrome-associated atrioventricular septal defects.</strong>
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Am. J. Hum. Genet. 91: 646-659, 2012.
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Arts, W. F., Bethlem, J., Volkers, W. S.
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<strong>Further investigations on benign myopathy with autosomal dominant inheritance.</strong>
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J. Neurol. 217: 201-206, 1978.
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Baker, N. L., Morgelin, M., Pace, R. A., Peat, R. A., Adams, N. E., Gardner, R. J. M., Rowland, L. P., Miller, G., De Jonghe, P., Ceulemans, B., Hannibal, M. C., Edwards, M., Thompson, E. M., Jacobson, R., Quinlivan, R. C. M., Aftimos, S., Kornberg, A. J., North, K. N., Bateman, J. F., Lamande, S. R.
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<strong>Molecular consequences of dominant Bethlem myopathy collagen VI mutations.</strong>
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Baker, N. L., Morgelin, M., Peat, R., Goemans, N., North, K. N., Bateman, J. F., Lamande, S. R.
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<strong>Dominant collagen VI mutations are a common cause of Ullrich congenital muscular dystrophy.</strong>
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Hum. Molec. Genet. 14: 279-293, 2005.
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Bethlem, J., van Wijngaarden, G. K.
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<strong>Benign myopathy, with autosomal dominant inheritance--a report on three pedigrees.</strong>
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Brain 99: 91-100, 1976.
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Camacho Vanegas, O. C., Bertini, E., Zhang, R.-Z., Petrini, S., Minosse, C., Sabatelli, P., Giusti, B., Chu, M.-L., Pepe, G.
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<strong>Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI.</strong>
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Proc. Nat. Acad. Sci. 98: 7516-7521, 2001.
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Caria, F., Cescon, M., Gualandi, F., Pichiecchio, A., Rossi, R., Rimessi, P., Cotti Piccinelli, S., Gallo Cassarino, S., Gregorio, I., Galvagni, A., Ferlini, A., Padovani, A., Bonaldo, P., Filosto, M.
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<strong>Autosomal recessive Bethlem myopathy: a clinical, genetic and functional study.</strong>
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Chu, M.-L., Pan, T.-C., Conway, D., Kuo, H.-J., Glanville, R. W., Timpl, R., Mann, K., Deutzmann, R.
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<strong>Sequence analysis of alpha 1(VI) and alpha 2(VI) chains of human type VI collagen reveals internal triplication of globular domains similar to the A domains of von Willebrand factor and two alpha-2(VI) chain variants that differ in the carboxy terminus.</strong>
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EMBO J. 8: 1939-1946, 1989.
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[PubMed: 2551668]
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[Full Text: https://doi.org/10.1002/j.1460-2075.1989.tb03598.x]
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<p class="mim-text-font">
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Gualandi, F., Urciuolo, A., Martoni, E., Sabatelli, P., Squarzoni, S., Bovolenta, M., Messina, S., Mercuri, E., Franchella, A., Ferlini, A., Bonaldo, P, Merlini, L.
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<strong>Autosomal recessive Bethlem myopathy.</strong>
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Neurology 73: 1883-1891, 2009.
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[PubMed: 19949035]
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<p class="mim-text-font">
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Higuchi, I., Shiraishi, T., Hashiguchi, T,, Suehara, M., Niiyama, T., Nakagawa, M., Arimura, K., Maruyama, I., Osame, M.
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<strong>Frameshift mutation in the collagen VI gene causes Ullrich's disease.</strong>
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Ann. Neurol. 50: 261-265, 2001.
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[PubMed: 11506412]
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<p class="mim-text-font">
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Jobsis, G. J., Bolhuis, P. A., Boers, J. M., Baas, F., Wolterman, R. A., Hensels, G. W., de Visser, M.
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<strong>Genetic localization of Bethlem myopathy.</strong>
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Neurology 46: 779-782, 1996.
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[PubMed: 8618682]
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[Full Text: https://doi.org/10.1212/wnl.46.3.779]
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</p>
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<p class="mim-text-font">
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Jobsis, G. J., Keizers, H., Vreijling, J. P., de Visser, M., Speer, M. C., Wolterman, R. A., Baas, F., Bohlhuis, P. A.
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<strong>Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures.</strong>
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Nature Genet. 14: 113-115, 1996.
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[PubMed: 8782832]
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[Full Text: https://doi.org/10.1038/ng0996-113]
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</p>
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<li>
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<p class="mim-text-font">
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Klewer, S. E., Krob, S. L., Kolker, S. J., Kitten, G. T.
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<strong>Expression of type VI collagen in the developing mouse heart.</strong>
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Dev. Dyn. 211: 248-255, 1998.
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[PubMed: 9520112]
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[Full Text: https://doi.org/10.1002/(SICI)1097-0177(199803)211:3<248::AID-AJA6>3.0.CO;2-H]
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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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|
Kuo, H.-J., Maslen, C. L., Keene, D. R., Glanville, R. W.
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<strong>Type VI collagen anchors endothelial basement membranes by interacting with type IV collagen.</strong>
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J. Biol. Chem. 272: 26522-26529, 1997.
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[PubMed: 9334230]
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[Full Text: https://doi.org/10.1074/jbc.272.42.26522]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Lampe, A. K., Dunn, D. M., von Niederhausern, A. C., Hamil, C., Aoyagi, A., Laval, S. H., Marie, S. K., Chu, M.-L., Swoboda, K., Muntoni, F., Bonnemann, C. G., Flanigan, K. M., Bushby, K. M. D., Weiss, R. B.
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<strong>Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy.</strong>
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J. Med. Genet. 42: 108-120, 2005.
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[PubMed: 15689448]
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[Full Text: https://doi.org/10.1136/jmg.2004.023754]
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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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Lucarini, L., Giusti, B., Zhang, R.-Z., Pan, T.-C., Jimenez-Mallebrera, C., Mercuri, E., Muntoni, F., Pepe, G., Chu, M.-L.
|
|
<strong>A homozygous COL6A2 intron mutation causes in-frame triple-helical deletion and nonsense-mediated mRNA decay in a patient with Ullrich congenital muscular dystrophy.</strong>
|
|
Hum. Genet. 117: 460-466, 2005.
|
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|
|
[PubMed: 16075202]
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[Full Text: https://doi.org/10.1007/s00439-005-1318-8]
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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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Meehan, T. F., Conte, N., West, D. B., Jacobsen, J. O., Mason, J., Warren, J., Chen, C.-K., Tudose, I., Relac, M., Matthews, P., Karp, N., Santos, L., and 52 others.
|
|
<strong>Disease model discovery from 3,328 gene knockouts by the International Mouse Phenotyping Consortium.</strong>
|
|
Nature Genet. 49: 1231-1238, 2017.
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|
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|
|
|
[PubMed: 28650483]
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[Full Text: https://doi.org/10.1038/ng.3901]
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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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Merlini, L., Martoni, E., Grumati, P., Sabatelli, P., Squarzoni, S., Urciuolo, A., Ferlini, A., Gualandi, F., Bonaldo, P.
|
|
<strong>Autosomal recessive myosclerosis myopathy is a collagen VI disorder.</strong>
|
|
Neurology 71: 1245-1253, 2008.
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|
|
[PubMed: 18852439]
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Zhang, R.-Z., Zou, Y., Pan, T.-C., Markova, D., Fertala, A., Hu, Y., Squarzoni, S., Reed, U. C., Marie, S. K. N., Bonnemann, C. G., Chu, M.-L.
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