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Entry
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- *120220 - COLLAGEN, TYPE VI, ALPHA-1; COL6A1
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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">*120220</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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<a href="#mapping">Mapping</a>
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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="#animalModel">Animal Model</a>
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<a href="#history">History</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/120220">Table View</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<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=ENSG00000142156;t=ENST00000361866" 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=1291" 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=120220" 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=ENSG00000142156;t=ENST00000361866" 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_001848" 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_001848" 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=120220" 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=00370&isoform_id=00370_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/COL6A1" 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/30030,30032,291916,1335031,1915900,1915902,8176524,18490111,30851190,38197044,87196339,116283832,119629725,119629726,119629727,125987811,194386506,194387934,308219652" 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/P12109" 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=1291" 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=ENSG00000142156;t=ENST00000361866" 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=COL6A1" 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=COL6A1" 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+1291" 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/COL6A1" 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:1291" 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/1291" 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=ENST00000361866.8&hgg_start=45981770&hgg_end=46005048&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 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:2211" 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/col6a1" 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=120220[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=120220[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/COL6A1/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/ENSG00000142156" 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=COL6A1" 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=COL6A1" 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=COL6A1" 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/COL6A1" 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=COL6A1&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/PA26727" 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:2211" 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:88459" 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/COL6A1#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:88459" 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/1291/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA001967/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=1291" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-070501-6" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
|
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:120220" 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:1291" 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=COL6A1&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> 718572004<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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120220
|
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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-1; COL6A1
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</span>
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</h3>
|
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
COLLAGEN, INTIMAL<br />
|
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SHORT-CHAIN COLLAGEN
|
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</span>
|
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</h4>
|
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</div>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=COL6A1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">COL6A1</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>
|
|
<span class="mim-text-font">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/21/174?start=-3&limit=10&highlight=174">21q22.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr21:45981770-46005048&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'})">21:45,981,770-46,005,048</a> </span>
|
|
</em>
|
|
</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>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=158810,254090" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/21/174?start=-3&limit=10&highlight=174">
|
|
21q22.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Bethlem myopathy 1A
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/158810"> 158810 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
|
</td>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p>Collagens play important roles in maintaining extracellular matrix structure and function. Members of the collagen VI family, like COL6A1, form distinct networks of microfibrils in connective tissue and interact with other extracellular matrix components (summary by <a href="#14" class="mim-tip-reference" title="Gara, S. K., Grumati, P., Urciuolo, A., Bonaldo, P., Kobbe, B., Koch, M., Paulsson, M., Wagener, R. <strong>Three novel collagen VI chains with high homology to the alpha-3 chain.</strong> J. Biol. Chem. 283: 10658-10670, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18276594/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18276594</a>] [<a href="https://doi.org/10.1074/jbc.M709540200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18276594">Gara et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18276594" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#6" class="mim-tip-reference" title="Chung, E., Rhodes, R. K., Miller, E. J. <strong>Isolation of three collagenous components of probable basement membrane origin from several tissues.</strong> Biochem. Biophys. Res. Commun. 71: 1167-1174, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/971306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">971306</a>] [<a href="https://doi.org/10.1016/0006-291x(76)90776-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="971306">Chung et al. (1976)</a> isolated a collagen from the intima of human aorta that differed from types IV and V collagen. Seemingly, the same collagen was isolated from bovine placenta by <a href="#20" class="mim-tip-reference" title="Jander, R., Rauterberg, J., Voss, B., von Bassewitz, D. B. <strong>A cysteine-rich collagenous protein from bovine placenta: isolation of its constituent polypeptide chains and some properties of the non-denatured protein.</strong> Europ. J. Biochem. 114: 17-25, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6783402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6783402</a>]" pmid="6783402">Jander et al. (1981)</a> and from human placenta by <a href="#13" class="mim-tip-reference" title="Furuto, D. K., Miller, E. J. <strong>Characterization of a unique collagenous fraction from limited pepsin digests of human placental tissue: molecular organization of the native aggregate.</strong> Biochemistry 20: 1635-1640, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6261803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6261803</a>] [<a href="https://doi.org/10.1021/bi00509a035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6261803">Furuto and Miller (1981)</a>. It is cysteine-rich and appears to have 3 peptides: a single relatively acidic peptide plus 2 more basic peptides. Type VI collagen appears to be unusual among collagens in the small size of its collagenous domains and in its supramolecular structure. It has been called 'short-chain collagen.' It is relatively resistant to bacterial collagenase and has a glycine content less than one-third of the protein, suggesting interrupted helical regions. Electron microscopy shows additional unique features. Collagen VI is a component of microfibrillar structures in many tissues (<a href="#11" class="mim-tip-reference" title="Engel, J., Furthmayr, H., Odermatt, E., Von der Mark, H., Aumailley, M., Fleishmajer, R., Timpl, R. <strong>Structure and macromolecular organization of type VI collagen.</strong> Ann. N.Y. Acad. Sci. 460: 25-37, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3938630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3938630</a>] [<a href="https://doi.org/10.1111/j.1749-6632.1985.tb51154.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3938630">Engel et al., 1985</a>). These microfibrils localize close to cells, nerves, blood vessels, and large collagen fibrils and are considered to have an anchoring function. Consistent with such a function are the biochemical findings that type VI collagen binds cells and that its fusion protein binds type I collagen. The binding activity also implies that, in addition to a structural role, type VI collagen may be involved in cell migration and differentiation and embryonic development. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6783402+6261803+3938630+971306" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#41" class="mim-tip-reference" title="Trueb, B., Winterhalter, K. H. <strong>Type VI collagen is composed of a 200 kD subunit and two 140 kD subunits.</strong> EMBO J. 5: 2815-2819, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3792302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3792302</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1986.tb04573.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3792302">Trueb and Winterhalter (1986)</a> showed that type VI collagen consists of 2 different 140-kD subunits (alpha-1 and alpha-2) and a 200-kD subunit (alpha-3). The alpha-3(VI) chain is synthesized by cells in culture as a precursor of 260 kD, while no precursor forms of the other 2 chains could be detected. Working with pepsin-solubilized collagen VI from human placenta, <a href="#5" class="mim-tip-reference" title="Chu, M.-L., Mann, K., Deutzmann, R., Pribula-Conway, D., Hsu-Chen, C.-C., Bernard, M. P., Timpl, R. <strong>Characterization of three constituent chains of collagen type VI by peptide sequences and cDNA clones.</strong> Europ. J. Biochem. 168: 309-317, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3665927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3665927</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1987.tb13422.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3665927">Chu et al. (1987)</a> characterized the 3 constituent chains by peptide-sequences and cDNA clones. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3792302+3665927" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 analysis and in situ hybridization, <a href="#43" 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> localized the alpha-1 and alpha-2 (COL6A2) collagen VI genes to chromosome 21q22.3 and the alpha-3(VI) gene (COL6A3; <a href="/entry/120250">120250</a>) to chromosome 2q37. By Southern hybridization analysis of DNA from Chinese hamster-human somatic cell hybrids segregating different portions of human chromosome 21, <a href="#7" class="mim-tip-reference" title="Cutting, G., Francomano, C. A., Chu, M. L., Timpl, R., McCormick, M. K., Warren, A. C., Hong, H. K., Pyeritz, R. E., Antonarakis, S. E. <strong>Genetic linkage analysis and macrorestriction mapping of COL6A1 and COL6A2, structural genes of type VI collagen. (Abstract)</strong> Am. J. Hum. Genet. 43: A141 only, 1988."None>Cutting et al. (1988)</a> showed that COL6A1 and COL6A2 map distal to the locus D21S3. Linkage analysis in 40 CEPH families showed 12.5% recombination between COL6A1 and ETS2 (<a href="/entry/164740">164740</a>). No recombinants were observed between COL6A1 and COL6A2. Recombinants between the Marfan phenotype (<a href="/entry/154700">154700</a>) and COL6A1 markers in 3 families excluded mutation of COL6A1 and COL6A2 as the cause of the Marfan syndrome. By pulsed field gel electrophoresis (PFGE), <a href="#7" class="mim-tip-reference" title="Cutting, G., Francomano, C. A., Chu, M. L., Timpl, R., McCormick, M. K., Warren, A. C., Hong, H. K., Pyeritz, R. E., Antonarakis, S. E. <strong>Genetic linkage analysis and macrorestriction mapping of COL6A1 and COL6A2, structural genes of type VI collagen. (Abstract)</strong> Am. J. Hum. Genet. 43: A141 only, 1988."None>Cutting et al. (1988)</a> showed that COL6A1 and COL6A2 hybridized to the same size restriction fragments, the smallest of which was 205 kb. <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="#36" class="mim-tip-reference" title="Petersen, M. B., Slaugenhaupt, S. A., Lewis, J. G., Warren, A. C., Chakravarti, A., Antonarakis, S. E. <strong>A genetic linkage map of 27 markers on human chromosome 21.</strong> Genomics 9: 407-419, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1674496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1674496</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90406-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1674496">Petersen et al. (1991)</a> presented a genetic linkage map of chromosome 21 involving 27 markers (10 genes and 17 anonymous sequences). The length of the male map was 132 cM and of the female map 161 cM. In both sexes, approximately one-half of the crossovers occurred distally in terminal band 21q22.3, which also contained 16 of the markers studied, including 8 of the 10 genes. Band 21q22.3 spans about 75 cM in the female map. The Petersen map illustrated the homogeneity in the distribution of genes in the genome, with a concentration of genes in Giemsa-light bands and near the ends of chromosomes. <a href="#12" class="mim-tip-reference" title="Francomano, C. A., Cutting, G. R., McCormick, M. K., Chu, M. L., Timpl, R., Hong, H. K., Antonarakis, S. E. <strong>The COL6A1 and COL6A2 genes exist as a gene cluster and detect highly informative DNA polymorphisms in the telomeric region of human chromosome 21q.</strong> Hum. Genet. 87: 162-166, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1676701/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1676701</a>] [<a href="https://doi.org/10.1007/BF00204174" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1676701">Francomano et al. (1991)</a> used PFGE and somatic cell hybrids to demonstrate that COL6A1 and COL6A2 form a gene cluster on the most distal part of chromosome 21. They detected several DNA polymorphisms (both restriction site and VNTRs) associated with these loci. Using a slot-blot method for the dosage of single-copy sequences, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1674496+1676701" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#9" class="mim-tip-reference" title="Delabar, J.-M., Chettouh, Z., Rahmani, Z., Theophile, D., Blouin, J.-L., Bono, R., Kraus, J., Barton, J., Patterson, D., Sinet, P.-M. <strong>Gene-dosage mapping of 30 DNA markers on chromosome 21.</strong> Genomics 13: 887-889, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1639420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1639420</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90177-t" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1639420">Delabar et al. (1992)</a> assessed the copy number of 30 chromosome 21 markers in the blood DNA of 11 patients with partial trisomy or monosomy 21. The physical order of the markers on chromosome 21 was thereby determined. The results showed that COL6A1 and S100B (<a href="/entry/176990">176990</a>) were in the most terminal region, with CD18 (<a href="/entry/600065">600065</a>) in the penultimate segment of 21q and PFKL (<a href="/entry/171860">171860</a>) in the next segment toward the centromere. Using a single interspecific backcross, <a href="#22" class="mim-tip-reference" title="Justice, M. J., Siracusa, L. D., Gilbert, D. J., Heisterkamp, N., Groffen, J., Chada, K., Silan, C. M., Copeland, N. G., Jenkins, N. A. <strong>A genetic linkage map of mouse chromosome 10: localization of eighteen molecular markers using a single interspecific backcross.</strong> Genetics 125: 855-866, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1975791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1975791</a>] [<a href="https://doi.org/10.1093/genetics/125.4.855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1975791">Justice et al. (1990)</a> mapped the homologous gene to mouse chromosome 10 and determined its location relative to 17 other markers. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1639420+1975791" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By high-resolution fluorescence in situ hybridization (FISH) techniques, <a href="#17" class="mim-tip-reference" title="Heiskanen, M., Saitta, B., Palotie, A., Chu, M.-L. <strong>Head to tail organization of the human COL6A1 and COL6A2 genes by fiber-FISH.</strong> Genomics 29: 801-803, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8575781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8575781</a>] [<a href="https://doi.org/10.1006/geno.1995.9008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8575781">Heiskanen et al. (1995)</a> determined the distance separating the COL6A1 and COL6A2 genes (150 kb), the size of the COL6A1 gene (29 kb), and the 5-prime/3-prime orientation of these genes. By fiber-FISH, they showed that the orientation is 5-prime COL6A1 3-prime/5-prime COL6A2 3-prime. This appeared to be the first collagen gene pair found to be in a head-to-tail configuration. Other closely located collagen gene pairs are either in a head-to-head configuration (type IV collagen genes) with a common promoter region or in a tail-to-tail configuration (COL3A1 and COL5A2) on chromosome 2q. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8575781" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 immunohistochemical analysis, <a href="#14" class="mim-tip-reference" title="Gara, S. K., Grumati, P., Urciuolo, A., Bonaldo, P., Kobbe, B., Koch, M., Paulsson, M., Wagener, R. <strong>Three novel collagen VI chains with high homology to the alpha-3 chain.</strong> J. Biol. Chem. 283: 10658-10670, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18276594/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18276594</a>] [<a href="https://doi.org/10.1074/jbc.M709540200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18276594">Gara et al. (2008)</a> detected expression of Col6a5 (<a href="/entry/611916">611916</a>) and Col6a6 (<a href="/entry/616613">616613</a>) in quadriceps femoris and diaphragm of wildtype mice, but not in Col6a1-deficient mice, suggesting that the alpha-1 chain is a prerequisite for trimeric assembly of collagens containing Col6a5 and Col6a6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18276594" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 1 and Ullrich Congenital Muscular Dystrophy 1</em></strong></p><p>
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In affected members of a family with autosomal dominant Bethlem myopathy-1 (BTHLM1A; <a href="/entry/158810">158810</a>), <a href="#21" 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 a heterozygous missense mutation in the COL6A1 gene (G286V; <a href="#0001">120220.0001</a>). The mutation 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 to the authors a similar mechanism in Bethlem myopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=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><p><a href="#25" class="mim-tip-reference" title="Lamande, S. R., Bateman, J. F., Hutchison, W., Gardner, R. J. M., Bower, S. P., Byrne, E., Dahl, H.-H. M. <strong>Reduced collagen VI causes Bethlem myopathy: a heterozygous COL6A1 nonsense mutation results in mRNA decay and functional haploinsufficiency.</strong> Hum. Molec. Genet. 7: 981-989, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9580662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9580662</a>] [<a href="https://doi.org/10.1093/hmg/7.6.981" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9580662">Lamande et al. (1998)</a> found that functional haploinsufficiency of collagen VI causes Bethlem myopathy. They identified a heterozygous COL6A1 mutation (<a href="#0002">120220.0002</a>) resulting in a 1-bp deletion from the mRNA and a premature stop codon. Mutant mRNA was unstable, subject to nonsense-mediated mRNA decay and was almost completely absent both from patient fibroblasts and skeletal muscle. They stated that Bethlem myopathy is the first example of a muscular dystrophy caused by haploinsufficiency of a structural protein or member of the dystrophin-glycoprotein complex, and identifies collagen VI as a critical contributor to cell-matrix adhesion in skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9580662" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 large families with an autosomal dominant limb-girdle muscular dystrophy phenotype, <a href="#38" 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> studied the COL6A1 and COL6A2 (<a href="/entry/120240">120240</a>) genes and found 2 novel missense mutations (<a href="#0004">120220.0004</a>; <a href="#0005">120220.0005</a>) in the former and 1 (<a href="/entry/120240#0005">120240.0005</a>) in the latter; 2 of these mutations were in regions of the proteins not previously associated with disease. To address the question of why symptoms in limb-girdle muscular dystrophy and Bethlem myopathy are restricted to skeletal muscle although collagen VI is ubiquitously expressed in connective tissue, the authors studied protein expression in 3 patient muscle biopsies. A marked reduction of laminin beta-1 protein (LAMB1; <a href="/entry/150240">150240</a>) was found in the myofiber basal lamina in all biopsies, although this protein was expressed normally in the neighboring capillary basal laminae. <a href="#38" 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. They hypothesized that collagen VI mutations lead to muscle-specific defects of the basal lamina, thus explaining the muscle-specific symptoms of Bethlem and limb-girdle muscular dystrophy in patients with collagen VI mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=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><p><a href="#33" class="mim-tip-reference" title="Pan, T.-C., Zhang, R.-Z., Sudano, D. G., Marie, S. K., Bonnemann, C. G., Chu, M.-L. <strong>New molecular mechanism for Ullrich congenital muscular dystrophy: a heterozygous in-frame deletion in the COL6A1 gene causes a severe phenotype.</strong> Am. J. Hum. Genet. 73: 355-369, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12840783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12840783</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12840783[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/377107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12840783">Pan et al. (2003)</a> reported a 12-year-old boy with a de novo heterozygous deletion near a minisatellite DNA sequence in intron 8 of the COL6A1 gene that removed 1.1 kb of genomic DNA encompassing exons 9 and 10 (<a href="#0007">120220.0007</a>), resulting in a severe phenotype of classic Ullrich congenital muscular dystrophy (UCMD1A; <a href="/entry/254090">254090</a>). UCMD had previously been shown to be caused by recessive mutations in COL6A2 and COL6A3. <a href="#33" class="mim-tip-reference" title="Pan, T.-C., Zhang, R.-Z., Sudano, D. G., Marie, S. K., Bonnemann, C. G., Chu, M.-L. <strong>New molecular mechanism for Ullrich congenital muscular dystrophy: a heterozygous in-frame deletion in the COL6A1 gene causes a severe phenotype.</strong> Am. J. Hum. Genet. 73: 355-369, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12840783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12840783</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12840783[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/377107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12840783">Pan et al. (2003)</a> stated that heterozygous skipping of exon 14 in the COL6A1 transcript is a recurring mutation, as it had been identified in 2 unrelated patients with Bethlem myopathy resulting from mutations in either the first (<a href="#0006">120220.0006</a>) or second (<a href="#0003">120220.0003</a>) nucleotide of the splice donor site in intron 14. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12840783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="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) using 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="#27" 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><a href="#28" class="mim-tip-reference" title="Lucioli, S., Giusti, B., Mercuri, E., Vanegas, O. C., Lucarini, L., Pietroni, V., Urtizberea, A., Ben Yaou, R., de Visser, M., van der Kooi, A. J., Bonnemann, C., Iannaccone, S. T., Merlini, L., Bushby, K., Muntoni, F., Bertini, E., Chu, M.-L., Pepe, G. <strong>Detection of common and private mutations in the COL6A1 gene of patients with Bethlem myopathy.</strong> Neurology 64: 1931-1937, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15955946/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15955946</a>] [<a href="https://doi.org/10.1212/01.WNL.0000163990.00057.66" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15955946">Lucioli et al. (2005)</a> identified 8 different mutations in the COL6A1 gene in 16 unrelated patients with Bethlem myopathy. The most common mutation was a splice site mutation (<a href="#0006">120220.0006</a>), which was found in 6 unrelated patients. All the mutations were localized between exons 3 and 14, corresponding to the COOH end of the NH2-globular domain and the NH2-end of the triple-helical domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15955946" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 unrelated patients with Ullrich congenital muscular dystrophy, <a href="#15" class="mim-tip-reference" title="Giusti, B., Lucarini, L., Pietroni, V., Lucioli, S., Bandinelli, B., Sabatelli, P., Squarzoni, S., Petrini, S., Gartioux, C., Talim, B., Roelens, F., Merlini, L., Topaloglu, H., Bertini, E., Guicheney, P., Pepe, G. <strong>Dominant and recessive COL6A1 mutations in Ullrich scleroatonic muscular dystrophy.</strong> Ann. Neurol. 58: 400-410, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16130093/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16130093</a>] [<a href="https://doi.org/10.1002/ana.20586" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16130093">Giusti et al. (2005)</a> identified 3 different homozygous mutations in the COL6A1 gene (<a href="#0009">120220.0009</a>-<a href="#0011">120220.0011</a>). Two additional patients with a relatively milder form of UCMD had de novo heterozygous missense mutations (G284R; <a href="#0012">120220.0012</a> and G290R; <a href="#0013">120220.0013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16130093" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#35" class="mim-tip-reference" title="Pepe, G., Lucarini, L., Zhang, R.-Z., Pan, T.-C., Giusti, B., Quijano-Roy, S., Gartioux, C., Bushby, K. M. D., Guicheney, P., Chu, M.-L. <strong>COL6A1 genomic deletions in Bethlem myopathy and Ullrich muscular dystrophy.</strong> Ann. Neurol. 59: 190-195, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16278855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16278855</a>] [<a href="https://doi.org/10.1002/ana.20705" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16278855">Pepe et al. (2006)</a> reported 2 unrelated patients with a mild form of UCMD and Bethlem myopathy, respectively, who had similar heterozygous deletions in the COL6A1 gene spanning from intron 8 to exon 13 or intron 13. The 5-prime breakpoints of both deletions were located within a minisatellite in intron 8. Coimmunoprecipitation studies of fibroblasts derived from the 2 patients showed that mutant proteins were inefficiently secreted, thus preventing a strong dominant effect. <a href="#35" class="mim-tip-reference" title="Pepe, G., Lucarini, L., Zhang, R.-Z., Pan, T.-C., Giusti, B., Quijano-Roy, S., Gartioux, C., Bushby, K. M. D., Guicheney, P., Chu, M.-L. <strong>COL6A1 genomic deletions in Bethlem myopathy and Ullrich muscular dystrophy.</strong> Ann. Neurol. 59: 190-195, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16278855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16278855</a>] [<a href="https://doi.org/10.1002/ana.20705" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16278855">Pepe et al. (2006)</a> concluded that the minisatellite region in intron 8 predisposes that area of the COL6A1 gene to multiexon deletions and noted that this type of mutation is often not detectable by standard DNA analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16278855" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#31" 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> reported heterozygous mutations in the COL6A1 gene (G284R, <a href="#0012">120220.0012</a>; G290R, <a href="#0013">120220.0013</a>) in 2 twin sisters and 2 unrelated patients, respectively, with UCMD. <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><strong><em>Associations Pending Confirmation</em></strong></p><p>
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<a href="#8" class="mim-tip-reference" title="Davies, G. E., Howard, C. M., Farrer, M. J., Coleman, M. M., Bennett, L. B., Cullen, L. M., Wyse, R. K. H., Burn, J., Williamson, R., Kessling, A. M. <strong>Genetic variation in the COL6A1 region is associated with congenital heart defects in trisomy 21 (Down's syndrome).</strong> Ann. Hum. Genet. 59: 253-269, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7486833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7486833</a>] [<a href="https://doi.org/10.1111/j.1469-1809.1995.tb00746.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7486833">Davies et al. (1995)</a> studied genetic variation in the COL6A1/COL6A2 gene cluster on chromosome 21 in 113 controls and 58 European families (including control and family subgroups of British/Irish origin) having a child with trisomy 21. They found statistically significant differences among subgroups of trisomy children with and without congenital heart defects in distributions of definitive, 3-RFLP haplotype classes received from their nondisjoining and disjoining parents. The haplotypes received by trisomy children with congenital heart defects from the disjoining parents were not a random sample of controls' haplotypes. Analysis of parental single-RFLP genotypes and linkage disequilibrium patterns confirmed this parent subgroup differed from a random sample of controls. There was no significant difference in parent subgroup genotype distribution at any of 9 control loci distributed along chromosome 21q. The study by <a href="#8" class="mim-tip-reference" title="Davies, G. E., Howard, C. M., Farrer, M. J., Coleman, M. M., Bennett, L. B., Cullen, L. M., Wyse, R. K. H., Burn, J., Williamson, R., Kessling, A. M. <strong>Genetic variation in the COL6A1 region is associated with congenital heart defects in trisomy 21 (Down's syndrome).</strong> Ann. Hum. Genet. 59: 253-269, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7486833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7486833</a>] [<a href="https://doi.org/10.1111/j.1469-1809.1995.tb00746.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7486833">Davies et al. (1995)</a> showed an association between genetic variation in the COL6A1 region and congenital heart defects in trisomy 21. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7486833" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="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 (<a href="/entry/120240">120240</a>), 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><p>Ossification of the posterior longitudinal ligament of the spine (OPLL; <a href="/entry/602475">602475</a>) is a subset of 'bone-forming' diseases, characterized by ectopic ossification in the spinal ligaments. OPLL is a common disorder among elderly populations in eastern Asia and is a leading cause of spinal myelopathy in Japan. <a href="#39" class="mim-tip-reference" title="Tanaka, T., Ikari, K., Furushima, K., Okada, A., Tanaka, H., Furukawa, K.-I., Yoshida, K., Ikeda, T., Ikegawa, S., Hunt, S. C., Takeda, J., Toh, S., Harata, S., Nakajima, T., Inoue, I. <strong>Genomewide linkage and linkage disequilibrium analyses identify COL6A1, on chromosome 21, as the locus for ossification of the posterior longitudinal ligament of the spine.</strong> Am. J. Hum. Genet. 73: 812-822, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12958705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12958705</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12958705[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/378593" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12958705">Tanaka et al. (2003)</a> performed a genomewide linkage study of 142 affected sib pairs to identify genetic loci related to OPLL. The best evidence of linkage was detected near marker D21S1903 on 21q22.3; the linkage region was therefore extensively investigated for linkage disequilibrium with SNPs covering 20 Mb. Haplotype analysis with 3 SNPs in the COL6A1 gene gave a single-point P value of 0.0000007. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12958705" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using in situ hybridization to sectioned embryonic mouse hearts, <a href="#24" 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> delineated the developmental expression pattern of the COL6A1, COL6A2, and COL6A3 genes. COL6A1 mRNA was first detected at embryonic day 11-11.5 in endothelial cells overlying the atrioventricular endocardial cushions. Expression was seen throughout the atrioventricular endocardial cushions following epithelial-mesenchymal transition. High expression levels were seen after embryonic day 13 in the remodeling atrioventricular endocardial cushions as they contributed to the developing atrioventricular valves and atrioventricular septum. The authors noted that type VI collagen is present in higher amounts than usual in the extracellular matrix of skin from individuals with trisomy 21, but commented that it is uncertain whether overexpression of COL6A1 and COL6A2 is sufficient to disrupt normal atrioventricular valvuloseptal morphogenesis and lead to the congenital heart malformations typical of trisomy 21. <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><p>To gain insight into the function of type VI collagen, <a href="#4" class="mim-tip-reference" title="Bonaldo, P., Braghetta, P., Zanetti, M., Piccolo, S., Volpin, D., Bressan, G. M. <strong>Collagen VI deficiency induces early onset myopathy in the mouse: an animal model for Bethlem myopathy.</strong> Hum. Molec. Genet. 7: 2135-2140, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9817932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9817932</a>] [<a href="https://doi.org/10.1093/hmg/7.13.2135" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9817932">Bonaldo et al. (1998)</a> inactivated the Col6a1 gene by targeted gene disruption in the mouse. The homozygous mutants lacked collagen VI in the tissues and showed histologic features of myopathy such as fiber necrosis and phagocytosis and a pronounced variation in muscle fiber diameter. Muscles also showed signs of stimulated regeneration of fibers. Necrotic fibers were particularly frequent in the diaphragm at all ages examined. Similar, although milder, alterations were detected in heterozygous mutant mice, indicating haploinsufficiency of the Col6a1 gene function. The authors concluded that collagen VI is necessary for maintenance of the integrity of muscle fibers and that the Col6a1-deficient mouse can be considered an animal model of Bethlem myopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9817932" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Irwin, W. A., Bergamin, N., Sabatelli, P., Reggiani, C., Megighian, A., Merlini, L., Braghetta, P., Columbaro, M., Volpin, D., Bressan, G. M., Bernardi, P., Bonaldo, P. <strong>Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency.</strong> Nature Genet. 35: 367-371, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14625552/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14625552</a>] [<a href="https://doi.org/10.1038/ng1270" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14625552">Irwin et al. (2003)</a> showed that muscles of the Col6a1 -/- mice have a loss of contractile strength associated with ultrastructural alterations of sarcoplasmic reticulum (SR) and mitochondria and spontaneous apoptosis. They found a latent mitochondrial dysfunction in myofibers of Col6a1 -/- mice on incubation with oligomycin, which caused mitochondrial depolarization, Ca(2+) deregulation, and increased apoptosis. These defects were reversible, as they could be normalized by plating Col6a1 -/- myofibers on collagen VI or by addition of cyclosporin A, the inhibitor of mitochondrial permeability transition pore. Treatment of Col6a1 -/- mice with cyclosporin A rescued the muscle ultrastructural defects and markedly decreased the number of apoptotic nuclei in vivo. These findings indicated that collagen VI myopathies have an unexpected mitochondrial pathogenesis that could be exploited for therapeutic intervention. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14625552" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Palma, E., Tiepolo, T., Angelin, A., Sabatelli, P., Maraldi, N. M., Basso, E., Forte, M. A., Bernardi, P., Bonaldo, P. <strong>Genetic ablation of cyclophilin D rescues mitochondrial defects and prevents muscle apoptosis in collagen VI myopathic mice.</strong> Hum. Molec. Genet. 18: 2024-2031, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19293339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19293339</a>] [<a href="https://doi.org/10.1093/hmg/ddp126" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19293339">Palma et al. (2009)</a> showed that inactivation of the Ppid gene (<a href="/entry/601753">601753</a>), which encodes cyclophilin D (CypD), rescued the disease phenotype of Col6a1 deficiency. In the absence of CypD, Col6a1-null mice showed negligible myofiber degeneration, rescue from mitochondrial dysfunction and ultrastructural defects, and normalized incidence of apoptosis. <a href="#32" class="mim-tip-reference" title="Palma, E., Tiepolo, T., Angelin, A., Sabatelli, P., Maraldi, N. M., Basso, E., Forte, M. A., Bernardi, P., Bonaldo, P. <strong>Genetic ablation of cyclophilin D rescues mitochondrial defects and prevents muscle apoptosis in collagen VI myopathic mice.</strong> Hum. Molec. Genet. 18: 2024-2031, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19293339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19293339</a>] [<a href="https://doi.org/10.1093/hmg/ddp126" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19293339">Palma et al. (2009)</a> concluded that lack of CypD is equivalent to its inhibition with cyclosporin A at curing the mouse dystrophic phenotype and that there is a cause and effect relationship between CypD-dependent permeability transition pore (PTP) regulation and pathogenesis of Bethlem myopathy and UCMD, suggesting CypD and PTP as a pharmacologic target for therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19293339" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Grumati, P., Coletto, L., Sabatelli, P., Cescon, M., Angelin, A., Bertaggia, E., Blaauw, B., Urciuolo, A., Tiepolo, T., Merlini, L., Maraldi, N. M., Bernardi, P., Sandri, M., Bonaldo, P. <strong>Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration.</strong> Nature Med. 16: 1313-1320, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21037586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21037586</a>] [<a href="https://doi.org/10.1038/nm.2247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21037586">Grumati et al. (2010)</a> found that Col6a1 -/- mice showed impaired autophagic flux that matched the lower induction of Becn1 (<a href="/entry/604378">604378</a>) and Bnip3 (<a href="/entry/603293">603293</a>) and lack of autophagosomes after starvation. Forced activation of autophagy by genetic, dietary, and pharmacologic approaches restored myofiber survival and ameliorated the dystrophic phenotype of Col6a1 -/- mice. Western blot analysis showed that muscle biopsies from 4 individuals with Bethlem myopathy and 5 individuals with UMCD had reduced protein expression of BECN1 and BNIP3. <a href="#16" class="mim-tip-reference" title="Grumati, P., Coletto, L., Sabatelli, P., Cescon, M., Angelin, A., Bertaggia, E., Blaauw, B., Urciuolo, A., Tiepolo, T., Merlini, L., Maraldi, N. M., Bernardi, P., Sandri, M., Bonaldo, P. <strong>Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration.</strong> Nature Med. 16: 1313-1320, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21037586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21037586</a>] [<a href="https://doi.org/10.1038/nm.2247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21037586">Grumati et al. (2010)</a> concluded that defective activation of the autophagic machinery is pathogenic in some congenital muscular dystrophies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21037586" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#40" class="mim-tip-reference" title="Telfer, W. R., Busta, A. S., Bonnemann, C. G., Feldman, E. L., Dowling, J. J. <strong>Zebrafish models of collagen VI-related myopathies.</strong> Hum. Molec. Genet. 19: 2433-2444, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20338942/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20338942</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20338942[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq126" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20338942">Telfer et al. (2010)</a> generated zebrafish models of the collagen VI myopathies. Morpholinos designed to exon 9 of col6a1 produced a severe muscle disease reminiscent of UCMD, while ones to exon 13 produced a milder phenotype similar to Bethlem myopathy. UCMD-like zebrafish had increased cell death and abnormal mitochondria, which could be attenuated by treatment with cyclosporin A (CsA). CsA improved the motor deficits in UCMD-like zebrafish, but failed to reverse the sarcolemmal membrane damage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20338942" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#30" class="mim-tip-reference" title="Murata, K., Motoyama, T., Suka, M., Ohno, M., Kuboki, Y. <strong>High production of type VI collagen in multiple fibromatosis with multiple articular dysplasia.</strong> Biochem. Biophys. Res. Commun. 147: 275-281, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3632670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3632670</a>] [<a href="https://doi.org/10.1016/s0006-291x(87)80117-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3632670">Murata et al. (1987)</a> found predominant production of type VI collagen by the tumors in a patient with 'multiple fibromatosis occurring at the sites of multiple cartilaginous dysplasia.' They stated that the patient had 'a hereditary disease, with regions of multiple articular dysplasia surrounded by numerous protuberant tumors. Elastic globe-shaped tumors, weighed (sic) about 100 g., were removed from his cervical regions at operation.' The age of the patient was not given, and the nature of the ailment was unclear. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3632670" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0001 BETHLEM MYOPATHY 1A</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> rs121912934 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912934;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/rs121912934?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=rs121912934" 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=rs121912934" 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=RCV000018709" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018709" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018709</a>
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<p>In affected members of a Dutch kindred (family 2, originally reported by <a href="#3" 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>) with Bethlem myopathy (BTHLM1A; <a href="/entry/158810">158810</a>), <a href="#21" 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 a heterozygous 962G-T transversion in the COL6A1 gene, resulting in a gly286-to-val (G286V) substitution in the triple-helical domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8782832+963533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 BETHLEM MYOPATHY 1A</strong>
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COL6A1, IVS11AS, G-A, -1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs886042354 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886042354;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=rs886042354" 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=rs886042354" 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=RCV000018710 OR RCV000725055" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018710, RCV000725055" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018710...</a>
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<p>In a patient with Bethlem myopathy (BTHLM1A; <a href="/entry/158810">158810</a>), <a href="#25" class="mim-tip-reference" title="Lamande, S. R., Bateman, J. F., Hutchison, W., Gardner, R. J. M., Bower, S. P., Byrne, E., Dahl, H.-H. M. <strong>Reduced collagen VI causes Bethlem myopathy: a heterozygous COL6A1 nonsense mutation results in mRNA decay and functional haploinsufficiency.</strong> Hum. Molec. Genet. 7: 981-989, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9580662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9580662</a>] [<a href="https://doi.org/10.1093/hmg/7.6.981" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9580662">Lamande et al. (1998)</a> found an approximately 50% reduction in the level of COL6A1 mRNA relative to COL6A2 and COL6A3 mRNAs. Since nonsense-mediated mRNA decay results in decreased steady-state mRNA levels and is a common but often overlooked consequence of mutations that introduce an in-frame premature stop codon, they used the protein truncation test (<a href="#37" class="mim-tip-reference" title="Roest, P. A. M., Roberts, R. G., Sugino, S., van Ommen, G.-J. B., den Dunnen, J. T. <strong>Protein truncation test (PTT) for rapid detection of translation-terminating mutations.</strong> Hum. Molec. Genet. 2: 1719-1721, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8268929/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8268929</a>] [<a href="https://doi.org/10.1093/hmg/2.10.1719" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8268929">Roest et al., 1993</a>) to find a COL6A1 transcription termination mutation. Because protein synthesis inhibitors had been shown to reverse the decay of mRNAs containing premature stop codons, they treated the Bethlem myopathy fibroblasts with cycloheximide before RNA extraction in an attempt to stabilize any mRNAs that might have contained a mutation of this class. With these steps they detected a heterozygous deletion of a G residue from a group of 3 that are interrupted in the COL6A1 gene by intron 11. To determine the precise nature of the gene mutation, genomic DNA from 10 normal and 9 affected family members was PCR amplified using primers within exons 10 and 13, and directly sequenced. The analysis demonstrated that the mutation was a heterozygous G-to-A transition at the -1 position of the consensus acceptor splice site of intron 11. The effect of the mutation was not to remove the splice site but to move it 3-prime by 1 base, resulting in the deletion of a G from the mRNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9580662+8268929" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0003" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0003 BETHLEM MYOPATHY 1A</strong>
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COL6A1, IVS14DS, T-C, +2
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs797044456 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797044456;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=rs797044456" 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=rs797044456" 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=RCV000018711" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018711" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018711</a>
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<p><a href="#34" class="mim-tip-reference" title="Pepe, G., Giusti, B., Bertini, E., Brunelli, T., Saitta, B., Comeglio, P., Bolognese, A., Merlini, L., Federici, G., Abbate, R., Chu, M.-L. <strong>A heterozygous splice site mutation in COL6A1 leading to an in-frame deletion of the alpha-1(VI) collagen chain in an Italian family affected by Bethlem myopathy.</strong> Biochem. Biophys. Res. Commun. 258: 802-807, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10329467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10329467</a>] [<a href="https://doi.org/10.1006/bbrc.1999.0680" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10329467">Pepe et al. (1999)</a> identified heterozygosity for a T-to-C transition at the +2 position of intron 14 of the COL6A1 gene in affected members of a family with Bethlem myopathy (BTHLM1A; <a href="/entry/158810">158810</a>). The nucleotide substitution caused an in-frame deletion of 18 amino acids in the triple-helical domain of the COL6A1 chain. The deletion included a cysteine residue believed to be involved in the assembly of type VI collagen dimers intracellularly, prior to secretion of the protein. Analysis of affected fibroblasts showed that the shortened COL6A1 chains were synthesized but not secreted by the cells and that the amount of type VI collagen microfibrils deposited by the cells was reduced. The results suggested that the clinical phenotype was due to a reduction in the level of type VI collagen in the extracellular matrix. The proband was evaluated at age 4 years for limb girdle weakness. At age 2 years, he had shown disability in climbing stairs and standing up from a sitting position. At 4 years, he showed a Gowers sign, weakness of lower limb girdle muscles, particularly of the quadriceps femoris and glutei muscles. There were no joint contractures. Creatine kinase (CK) was 4 times higher than normal. Bilateral tenotomy of Achilles tendons was required at age 7 years. At age 9 years, the boy was able to walk but could not climb stairs or stand up from a sitting position. There was distal joint hyperlaxity, together with shortening of the tendons of the finger flexors. He had generalized muscle weakness sparing flexors of the knees and fingers as well as ankle extensors. The mother showed severe congenital torticollis at birth and flexion contractures of the elbows since the age of 3 years. She had been operated on for tightness of the heel cord at age 13 years. At age 35 years, neurologic examination showed generalized reduced muscle bulk, marked lumbar lordosis, limb girdle and distal weakness, and flexion contractures of elbows, ankles, and interphalangeal joints. CK was increased 2-fold. She showed marked disability in climbing stairs and in standing up from a sitting position. The maternal grandfather had severe motor disability and lost the ability to walk at age 35 years. Although he died of cancer at age 65 years, relatives reported that he had severe multiple joint contractures with shortening of Achilles tendons, flexion contractures of elbows and knees, and severe flexion contractures of the interphalangeal joints. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10329467" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 BETHLEM MYOPATHY 1A</strong>
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COL6A1, GLY341ASP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121912935 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912935;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=rs121912935" 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=rs121912935" 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=RCV000018712 OR RCV002274883" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018712, RCV002274883" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018712...</a>
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<p>In 1 of 3 families with an autosomal dominant limb-girdle muscular dystrophy phenotype, <a href="#38" 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 G-to-A transition at nucleotide 1070 of the COL6A1 gene, resulting in a gly341-to-asp (G341D) mutation. Twelve of 22 individuals in a Caucasian family from Mississippi were affected. An infantile onset with delay in motor milestones was noted in 6 individuals in this family; motor difficulties began in childhood, i.e., under 10 years of age, in 5 members. Onset began in adult life in 1 patient. Two patients (12 and 48 years old) were wheelchair-bound. Many affected members had muscle cramps, pain, and weakness. Clinical examination showed diffuse muscle weakness, both proximal and distal muscles being weak in all 12 affected individuals. Proximal accentuation of weakness was noted in 4 patients with severe leg weakness, and 3 had severe arm weakness. At the outset, none had contractures of shoulders, hips, spine, or neck. In 5 patients, no contractures were found at ages ranging from 8 to 76 years. Four of 12 patients had contractures of interphalangeal joints, 3 had contractures of the ankles, and 2 of the elbows. In many patients, interphalangeal contractures could be discovered only by the inability to extend fingers passively once the wrist was extended. <a href="#38" 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 (BTHLM1A; <a href="/entry/158810">158810</a>) 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/?cmd=link&linkname=pubmed_pubmed&from_uid=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>.0005 BETHLEM MYOPATHY 1A</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">rs121912936 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912936;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=rs121912936" 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=rs121912936" 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=RCV000018713 OR RCV000177135" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018713, RCV000177135" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018713...</a>
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<p>In a large Caucasian family from Ohio with an autosomal dominant limb-girdle muscular dystrophy phenotype, <a href="#38" 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> found that affected members had a heterozygous lys121-to-arg (K121R) missense mutation in exon 3 of the COL6A1 gene. The clinical presentation was similar to that reported in the Mississippi family with the gln341-to-asp mutation (<a href="#0004">120220.0004</a>). <a href="#38" 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 (BTHLM1A; <a href="/entry/158810">158810</a>) 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/?cmd=link&linkname=pubmed_pubmed&from_uid=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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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398123631 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398123631;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=rs398123631" 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=rs398123631" 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=RCV000018714 OR RCV000079739 OR RCV000626814 OR RCV001813996" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018714, RCV000079739, RCV000626814, RCV001813996" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018714...</a>
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<p>In a 32-year-old man with Bethlem myopathy (BTHLM1A; <a href="/entry/158810">158810</a>), <a href="#26" class="mim-tip-reference" title="Lamande, S. R., Shields, K. A., Kornberg, A. J., Shield, L. K., Bateman, J. F. <strong>Bethlem myopathy and engineered collagen VI triple helical deletions prevent intracellular multimer assembly and protein secretion.</strong> J. Biol. Chem. 274: 21817-21822, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10419498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10419498</a>] [<a href="https://doi.org/10.1074/jbc.274.31.21817" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10419498">Lamande et al. (1999)</a> identified a heterozygous G-to-A transition at the +1 position of intron 14 of the COL6A1 gene, which resulted in skipping of exon 14 and deletion of 18 amino acids from the triple-helical domain of the COL6A1 chain. The mutant COL6A1 chains associated intracellularly with COL6A2 (<a href="/entry/120240">120240</a>) and COL6A3 (<a href="/entry/120250">120250</a>) to form disulfide-bonded monomers, but further assembly into dimers and tetramers was prevented, and molecules containing the mutant chain were not secreted. This triple-helical deletion thus resulted in production of half the normal amount of collagen VI. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10419498" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Pan, T.-C., Zhang, R.-Z., Sudano, D. G., Marie, S. K., Bonnemann, C. G., Chu, M.-L. <strong>New molecular mechanism for Ullrich congenital muscular dystrophy: a heterozygous in-frame deletion in the COL6A1 gene causes a severe phenotype.</strong> Am. J. Hum. Genet. 73: 355-369, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12840783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12840783</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12840783[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/377107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12840783">Pan et al. (2003)</a> identified the IVS14+1G-A transition in a 6-year-old boy with a relatively mild congenital muscular dystrophy phenotype with distal joint hyperlaxity but no joint contractures characteristic Bethlem myopathy. Because the patient was young and could still develop contractures, <a href="#33" class="mim-tip-reference" title="Pan, T.-C., Zhang, R.-Z., Sudano, D. G., Marie, S. K., Bonnemann, C. G., Chu, M.-L. <strong>New molecular mechanism for Ullrich congenital muscular dystrophy: a heterozygous in-frame deletion in the COL6A1 gene causes a severe phenotype.</strong> Am. J. Hum. Genet. 73: 355-369, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12840783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12840783</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12840783[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/377107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12840783">Pan et al. (2003)</a> concluded that his phenotype could be compatible with sporadic Bethlem myopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12840783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Lucioli, S., Giusti, B., Mercuri, E., Vanegas, O. C., Lucarini, L., Pietroni, V., Urtizberea, A., Ben Yaou, R., de Visser, M., van der Kooi, A. J., Bonnemann, C., Iannaccone, S. T., Merlini, L., Bushby, K., Muntoni, F., Bertini, E., Chu, M.-L., Pepe, G. <strong>Detection of common and private mutations in the COL6A1 gene of patients with Bethlem myopathy.</strong> Neurology 64: 1931-1937, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15955946/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15955946</a>] [<a href="https://doi.org/10.1212/01.WNL.0000163990.00057.66" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15955946">Lucioli et al. (2005)</a> identified the IVS14+1G-A mutation in 6 of 16 unrelated patients with Bethlem myopathy and mutations in the COL6A1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15955946" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#2" 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 the IVS14+1G-A mutation in 2 additional patients with Bethlem myopathy. Studies showed undisulfide-bonded collagen VI in cell culture medium, suggesting that some structurally abnormal protein was secreted. <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>.0007 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1A, AUTOSOMAL DOMINANT</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003764605" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003764605" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003764605</a>
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<p>In a 12-year-old boy with classic severe Ullrich congenital muscular dystrophy (UCMD1A; <a href="/entry/254090">254090</a>), <a href="#33" class="mim-tip-reference" title="Pan, T.-C., Zhang, R.-Z., Sudano, D. G., Marie, S. K., Bonnemann, C. G., Chu, M.-L. <strong>New molecular mechanism for Ullrich congenital muscular dystrophy: a heterozygous in-frame deletion in the COL6A1 gene causes a severe phenotype.</strong> Am. J. Hum. Genet. 73: 355-369, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12840783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12840783</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12840783[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/377107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12840783">Pan et al. (2003)</a> identified a de novo heterozygous deletion near a minisatellite DNA sequence in intron 8 of the COL6A1 gene, which removed 1.1 kb of genomic DNA encompassing exons 9 and 10. The deletion included 33 amino acids near the N terminus of the triple-helical domain but preserved a unique cysteine within this domain that is important for dimer formation prior to secretion. Thus, dimer formation and secretion of abnormal tetramers could occur and exert a strong dominant-negative effect on microfibrillar assembly, leading to a loss of normal localization of collagen VI in the basement membrane surrounding muscle fibers. Consistent with this mechanism, <a href="#33" class="mim-tip-reference" title="Pan, T.-C., Zhang, R.-Z., Sudano, D. G., Marie, S. K., Bonnemann, C. G., Chu, M.-L. <strong>New molecular mechanism for Ullrich congenital muscular dystrophy: a heterozygous in-frame deletion in the COL6A1 gene causes a severe phenotype.</strong> Am. J. Hum. Genet. 73: 355-369, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12840783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12840783</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12840783[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/377107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12840783">Pan et al. (2003)</a> described a 6-year-old boy with a much milder phenotype who had a previously identified mutation in the COL6A1 gene resulting in Bethlem myopathy (<a href="/entry/158810">158810</a>). This heterozygous in-frame deletion of 18 amino acids occurred somewhat downstream in the triple-helical domain, a result of exon 14 skipping in the COL6A1 gene (<a href="#0006">120220.0006</a>). The deletion removed the crucial cysteine, so that dimer formation could not occur and the abnormal molecule was not secreted, preventing the strong dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12840783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs1569517717 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1569517717;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=rs1569517717" 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=rs1569517717" 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=RCV000018716 OR RCV004795926" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018716, RCV004795926" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018716...</a>
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<p>In affected members of an Italian family with Bethlem myopathy (BTHLM1A; <a href="/entry/158810">158810</a>) previously reported by <a href="#29" class="mim-tip-reference" title="Merlini, L., Morandi, L., Granata, C., Ballestrazzi, A. <strong>Bethlem myopathy: early-onset benign autosomal dominant myopathy with contractures: description of two new families.</strong> Neuromusc. Disord. 4: 503-511, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7881296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7881296</a>] [<a href="https://doi.org/10.1016/0960-8966(94)90091-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7881296">Merlini et al. (1994)</a>, <a href="#42" class="mim-tip-reference" title="Vanegas, O. C., Zhang, R.-Z., Sabatelli, P., Lattanzi, G., Bencivenga, P., Giusti, B., Columbaro, M., Chu, M.-L., Merlini, L., Pepe, G. <strong>Novel COL6A1 splicing mutation in a family affected by mild Bethlem myopathy.</strong> Muscle Nerve 25: 513-519, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11932968/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11932968</a>] [<a href="https://doi.org/10.1002/mus.10100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11932968">Vanegas et al. (2002)</a> identified a heterozygous G-to-A transition at the +1 position of intron 3 of the COL6A1 gene. The mutation results in the activation of a cryptic splice donor site at the 3-prime end of exon 3, leading to an in-frame deletion of 22 amino acids from codon 122 to 143 within the NH2-globular domain. Fibroblast studies showed that the mutated mRNA was stable, but the mutated protein could not be detected, suggesting that it was highly unstable and rapidly degraded. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7881296+11932968" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a Turkish patient with Ullrich congenital muscular dystrophy (UCMD1A; <a href="/entry/254090">254090</a>), <a href="#15" class="mim-tip-reference" title="Giusti, B., Lucarini, L., Pietroni, V., Lucioli, S., Bandinelli, B., Sabatelli, P., Squarzoni, S., Petrini, S., Gartioux, C., Talim, B., Roelens, F., Merlini, L., Topaloglu, H., Bertini, E., Guicheney, P., Pepe, G. <strong>Dominant and recessive COL6A1 mutations in Ullrich scleroatonic muscular dystrophy.</strong> Ann. Neurol. 58: 400-410, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16130093/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16130093</a>] [<a href="https://doi.org/10.1002/ana.20586" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16130093">Giusti et al. (2005)</a> identified a homozygous 1-bp deletion (856/857delC) in exon 9 of the COL6A1 gene, resulting in a frameshift and premature termination of the protein within the triple-helical domain. The patient was born of consanguineous parents, both of whom were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16130093" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1A, 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">rs797044458 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797044458;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=rs797044458" 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=rs797044458" 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 patient with Ullrich congenital muscular dystrophy (UCMD1A; <a href="/entry/254090">254090</a>), <a href="#15" class="mim-tip-reference" title="Giusti, B., Lucarini, L., Pietroni, V., Lucioli, S., Bandinelli, B., Sabatelli, P., Squarzoni, S., Petrini, S., Gartioux, C., Talim, B., Roelens, F., Merlini, L., Topaloglu, H., Bertini, E., Guicheney, P., Pepe, G. <strong>Dominant and recessive COL6A1 mutations in Ullrich scleroatonic muscular dystrophy.</strong> Ann. Neurol. 58: 400-410, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16130093/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16130093</a>] [<a href="https://doi.org/10.1002/ana.20586" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16130093">Giusti et al. (2005)</a> identified a homozygous 1-bp deletion (1465delG) in exon 22 of the COL6A1 gene, resulting in a frameshift and premature termination of the protein within the triple-helical domain. The patient was born of consanguineous parents, both of whom were heterozygous for the mutation. (In the article by <a href="#15" class="mim-tip-reference" title="Giusti, B., Lucarini, L., Pietroni, V., Lucioli, S., Bandinelli, B., Sabatelli, P., Squarzoni, S., Petrini, S., Gartioux, C., Talim, B., Roelens, F., Merlini, L., Topaloglu, H., Bertini, E., Guicheney, P., Pepe, G. <strong>Dominant and recessive COL6A1 mutations in Ullrich scleroatonic muscular dystrophy.</strong> Ann. Neurol. 58: 400-410, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16130093/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16130093</a>] [<a href="https://doi.org/10.1002/ana.20586" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16130093">Giusti et al. (2005)</a>, the nucleotide for this mutation was given as 1456 in Table 1 but as 1465 in the text.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16130093" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs121912937 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912937;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/rs121912937?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=rs121912937" 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=rs121912937" 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=RCV000018719" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018719" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018719</a>
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<p>In a Turkish patient with Ullrich congenital muscular dystrophy (UCMD1A; <a href="/entry/254090">254090</a>), <a href="#15" class="mim-tip-reference" title="Giusti, B., Lucarini, L., Pietroni, V., Lucioli, S., Bandinelli, B., Sabatelli, P., Squarzoni, S., Petrini, S., Gartioux, C., Talim, B., Roelens, F., Merlini, L., Topaloglu, H., Bertini, E., Guicheney, P., Pepe, G. <strong>Dominant and recessive COL6A1 mutations in Ullrich scleroatonic muscular dystrophy.</strong> Ann. Neurol. 58: 400-410, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16130093/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16130093</a>] [<a href="https://doi.org/10.1002/ana.20586" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16130093">Giusti et al. (2005)</a> identified a homozygous 1977C-G transversion in exon 31 of the COL6A1 gene, resulting in a tyr659-to-ter (Y659X) substitution. Detailed analysis of the RNA species showed that the mutation resulted in 2 truncated proteins: Y659X and a distinct protein that showed exon 31 skipping and termination at amino acids 728-729. <a href="#15" class="mim-tip-reference" title="Giusti, B., Lucarini, L., Pietroni, V., Lucioli, S., Bandinelli, B., Sabatelli, P., Squarzoni, S., Petrini, S., Gartioux, C., Talim, B., Roelens, F., Merlini, L., Topaloglu, H., Bertini, E., Guicheney, P., Pepe, G. <strong>Dominant and recessive COL6A1 mutations in Ullrich scleroatonic muscular dystrophy.</strong> Ann. Neurol. 58: 400-410, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16130093/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16130093</a>] [<a href="https://doi.org/10.1002/ana.20586" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16130093">Giusti et al. (2005)</a> emphasized the unique molecular mechanism. The patient was born of consanguineous parents, both of whom were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16130093" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 1A, 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"><span class="text-primary">●</span> rs121912938 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912938;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/rs121912938?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=rs121912938" 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=rs121912938" 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=RCV000079828 OR RCV000180573 OR RCV000180574 OR RCV003314554 OR RCV003764606" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000079828, RCV000180573, RCV000180574, RCV003314554, RCV003764606" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000079828...</a>
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<p>In a patient with Ullrich congenital muscular dystrophy (UCMD1A; <a href="/entry/254090">254090</a>), <a href="#15" class="mim-tip-reference" title="Giusti, B., Lucarini, L., Pietroni, V., Lucioli, S., Bandinelli, B., Sabatelli, P., Squarzoni, S., Petrini, S., Gartioux, C., Talim, B., Roelens, F., Merlini, L., Topaloglu, H., Bertini, E., Guicheney, P., Pepe, G. <strong>Dominant and recessive COL6A1 mutations in Ullrich scleroatonic muscular dystrophy.</strong> Ann. Neurol. 58: 400-410, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16130093/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16130093</a>] [<a href="https://doi.org/10.1002/ana.20586" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16130093">Giusti et al. (2005)</a> identified a de novo heterozygous 850G-A transition in exon 9 of the COL6A1 gene, resulting in a gly284-to-arg (G284R) substitution in the triple-helical domain. Northern and Western blot analyses detected normal amounts of COL6A1 mRNA and protein. However, immunohistochemistry and electron microscopy showed reduction of COL6A1 in the extracellular space as well as filamentous aggregates of COL6A1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16130093" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Kawahara, G., Okada, M., Morone, N., Ibarra, C. A., Nonaka, I., Noguchi, S., Hayashi, Y. K., Nishino, I. <strong>Reduced cell anchorage may cause sarcolemma-specific collagen VI deficiency in Ullrich disease.</strong> Neurology 69: 1043-1049, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17785674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17785674</a>] [<a href="https://doi.org/10.1212/01.wnl.0000271386.89878.22" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17785674">Kawahara et al. (2007)</a> observed sarcolemmal-specific collagen VI deficiency in muscle biopsies from patients with a heterozygous G284R mutation in the N-terminal region in the triple-helical domain. Collagen VI was present in the interstitium but was barely detectable in the sarcolemma; patients with compound heterozygous COL6A1 mutations had complete absence of the protein. Electron microscopy showed that collagen VI microfibrils did not bind to the basement membrane. Further studies showed that fibroblasts with the mutation assembled and secreted normal collagen VI microfibrils. However, cell adhesion of heterozygous G284R fibroblasts was markedly decreased, similar to that of collagen VI-deficient cells, but could be rescued by the addition of normal collagen VI. <a href="#23" class="mim-tip-reference" title="Kawahara, G., Okada, M., Morone, N., Ibarra, C. A., Nonaka, I., Noguchi, S., Hayashi, Y. K., Nishino, I. <strong>Reduced cell anchorage may cause sarcolemma-specific collagen VI deficiency in Ullrich disease.</strong> Neurology 69: 1043-1049, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17785674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17785674</a>] [<a href="https://doi.org/10.1212/01.wnl.0000271386.89878.22" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17785674">Kawahara et al. (2007)</a> concluded that heterozygous mutations in the COL6A1 gene result in decreased binding of collagen VI to the extracellular matrix. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17785674" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#31" 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> reported 17-year-old twin sisters with UCMD resulting from a heterozygous de novo G284R mutation. Both had onset at age 3 years of delayed motor milestones and proximal, axial, and facial muscle weakness. They learned to walk independently, but had rigid spine, scoliosis, contractures, and required nocturnal ventilation in late childhood. Both had chewing difficulties and low weight necessitating gastrostomy at age 11.8 years. Intelligence was normal and there was no cardiac involvement. <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 1A, 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">rs121912939 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912939;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=rs121912939" 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=rs121912939" 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=RCV001851922 OR RCV003764607" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001851922, RCV003764607" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001851922...</a>
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<p>In a patient with Ullrich congenital muscular dystrophy (UCMD1A; <a href="/entry/254090">254090</a>), <a href="#15" class="mim-tip-reference" title="Giusti, B., Lucarini, L., Pietroni, V., Lucioli, S., Bandinelli, B., Sabatelli, P., Squarzoni, S., Petrini, S., Gartioux, C., Talim, B., Roelens, F., Merlini, L., Topaloglu, H., Bertini, E., Guicheney, P., Pepe, G. <strong>Dominant and recessive COL6A1 mutations in Ullrich scleroatonic muscular dystrophy.</strong> Ann. Neurol. 58: 400-410, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16130093/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16130093</a>] [<a href="https://doi.org/10.1002/ana.20586" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16130093">Giusti et al. (2005)</a> identified a de novo heterozygous 868G-C transversion in exon 10 of the COL6A1 gene, resulting in a gly290-to-arg (G290R) substitution in the triple-helical domain. Northern and Western blot analyses detected normal amounts of COL6A1 mRNA and protein. However, immunohistochemistry and electron microscopy showed reduction of COL6A1 in the extracellular space as well as filamentous aggregates of COL6A1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16130093" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#31" 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> reported 2 unrelated patients with UCMD due to a heterozygous G290R substitution. One 18-year-old patient had onset at birth with torticollis, contractures, and delayed motor development. Independent walking was achieved at age 3.5 years, and the patient had contractures, rigid spine, scoliosis, and follicular hyperkeratosis and keloid formation. The other patient had onset at birth of hypotonia, contractures, and delayed motor development. Independent walking was never achieved, and the patient became wheelchair-bound at age 10.7 years. Other features included rigid spine, scoliosis, kyphosis, contractures, and follicular hyperkeratosis. The second patient died suddenly at age 15 years after a fracture of the long bone. <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 1A, DIGENIC, COL6A1/COL6A2</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">rs267606746 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606746;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=rs267606746" 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=rs267606746" 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=RCV000018722 OR RCV000497629 OR RCV001216604" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018722, RCV000497629, RCV001216604" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018722...</a>
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<p>In a 25-year-old patient with Ullrich congenital muscular dystrophy (UCMD1A; <a href="/entry/254090">254090</a>), <a href="#31" 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 heterozygous mutations in 2 different genes: an 841G-A transition in exon 9 of the COL6A1 gene, resulting in a gly281-to-arg (G281R) substitution, and a substitution in the COL6A2 gene (R498H; <a href="/entry/120240#0014">120240.0014</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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<a href="#Duff1990" class="mim-tip-reference" title="Duff, K., Williamson, R., Richards, S. J. <strong>Expression of genes encoding two chains of the collagen type VI molecule during fetal heart development.</strong> Int. J. Cardiol. 27: 128-129, 1990.">Duff et al. (1990)</a>; <a href="#Hessle1984" class="mim-tip-reference" title="Hessle, H., Engvall, E. <strong>Type VI collagen: studies on its localization, structure, and biosynthetic form with monoclonal antibodies.</strong> J. Biol. Chem. 259: 3955-3961, 1984.">Hessle and Engvall (1984)</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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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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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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Bonaldo, P., Braghetta, P., Zanetti, M., Piccolo, S., Volpin, D., Bressan, G. M.
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<strong>Collagen VI deficiency induces early onset myopathy in the mouse: an animal model for Bethlem myopathy.</strong>
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Hum. Molec. Genet. 7: 2135-2140, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9817932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9817932</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9817932" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Chu, M.-L., Mann, K., Deutzmann, R., Pribula-Conway, D., Hsu-Chen, C.-C., Bernard, M. P., Timpl, R.
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<strong>Characterization of three constituent chains of collagen type VI by peptide sequences and cDNA clones.</strong>
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Europ. J. Biochem. 168: 309-317, 1987.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3665927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3665927</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3665927" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1432-1033.1987.tb13422.x" target="_blank">Full Text</a>]
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Chung, E., Rhodes, R. K., Miller, E. J.
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<strong>Isolation of three collagenous components of probable basement membrane origin from several tissues.</strong>
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Biochem. Biophys. Res. Commun. 71: 1167-1174, 1976.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/971306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">971306</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=971306" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Cutting, G., Francomano, C. A., Chu, M. L., Timpl, R., McCormick, M. K., Warren, A. C., Hong, H. K., Pyeritz, R. E., Antonarakis, S. E.
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<strong>Genetic linkage analysis and macrorestriction mapping of COL6A1 and COL6A2, structural genes of type VI collagen. (Abstract)</strong>
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Am. J. Hum. Genet. 43: A141 only, 1988.
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Davies, G. E., Howard, C. M., Farrer, M. J., Coleman, M. M., Bennett, L. B., Cullen, L. M., Wyse, R. K. H., Burn, J., Williamson, R., Kessling, A. M.
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<strong>Genetic variation in the COL6A1 region is associated with congenital heart defects in trisomy 21 (Down's syndrome).</strong>
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Ann. Hum. Genet. 59: 253-269, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7486833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7486833</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7486833" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1469-1809.1995.tb00746.x" target="_blank">Full Text</a>]
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Delabar, J.-M., Chettouh, Z., Rahmani, Z., Theophile, D., Blouin, J.-L., Bono, R., Kraus, J., Barton, J., Patterson, D., Sinet, P.-M.
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<strong>Gene-dosage mapping of 30 DNA markers on chromosome 21.</strong>
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[<a href="https://doi.org/10.1007/BF00204174" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1021/bi00509a035" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M709540200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.20586" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/genetics/125.4.855" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000271386.89878.22" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11932968/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11932968</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11932968" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/mus.10100" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="43" 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>
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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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<a id="contributors" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 10/23/2015
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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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George E. Tiller - updated : 8/5/2013<br>Ada Hamosh - updated : 2/14/2013<br>Paul J. Converse - updated : 4/20/2011<br>George E. Tiller - updated : 2/24/2010<br>Cassandra L. Kniffin - updated : 12/15/2009<br>Cassandra L. Kniffin - updated : 5/23/2008<br>Cassandra L. Kniffin - updated : 12/17/2007<br>Cassandra L. Kniffin - updated : 4/13/2006<br>Cassandra L. Kniffin - updated : 11/29/2005<br>Cassandra L. Kniffin - updated : 11/1/2005<br>Marla J. F. O'Neill - updated : 3/1/2005<br>Victor A. McKusick - updated : 12/2/2003<br>Victor A. McKusick - updated : 10/7/2003<br>Victor A. McKusick - updated : 8/11/2003<br>Victor A. McKusick - updated : 4/8/2002<br>Victor A. McKusick - updated : 8/4/1999<br>Victor A. McKusick - updated : 1/7/1999<br>Victor A. McKusick - updated : 6/15/1998<br>Paul Brennan - updated : 5/14/1998
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</span>
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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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<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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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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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 : 06/06/2024
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<div class="row collapse" id="mimCollapseEditHistory">
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<span class="mim-text-font">
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ckniffin : 06/05/2024<br>carol : 02/21/2024<br>carol : 09/20/2022<br>carol : 09/19/2022<br>carol : 08/15/2016<br>carol : 06/23/2016<br>mgross : 10/23/2015<br>carol : 10/6/2015<br>carol : 9/15/2015<br>carol : 7/22/2015<br>carol : 7/20/2015<br>mcolton : 3/3/2015<br>alopez : 8/5/2013<br>alopez : 2/14/2013<br>carol : 8/2/2011<br>mgross : 5/10/2011<br>terry : 4/20/2011<br>wwang : 2/26/2010<br>terry : 2/24/2010<br>carol : 12/23/2009<br>ckniffin : 12/15/2009<br>wwang : 9/23/2009<br>wwang : 7/8/2008<br>ckniffin : 5/23/2008<br>wwang : 1/7/2008<br>ckniffin : 12/17/2007<br>alopez : 7/5/2007<br>alopez : 5/31/2007<br>alopez : 5/31/2007<br>carol : 5/15/2007<br>wwang : 4/18/2006<br>ckniffin : 4/13/2006<br>carol : 12/29/2005<br>wwang : 12/28/2005<br>terry : 12/20/2005<br>wwang : 12/5/2005<br>ckniffin : 11/29/2005<br>wwang : 11/21/2005<br>wwang : 11/16/2005<br>ckniffin : 11/1/2005<br>wwang : 3/14/2005<br>wwang : 3/8/2005<br>terry : 3/1/2005<br>tkritzer : 1/7/2004<br>alopez : 12/2/2003<br>terry : 12/2/2003<br>tkritzer : 10/10/2003<br>terry : 10/7/2003<br>carol : 8/18/2003<br>tkritzer : 8/15/2003<br>tkritzer : 8/15/2003<br>terry : 8/11/2003<br>cwells : 4/19/2002<br>cwells : 4/17/2002<br>cwells : 4/17/2002<br>terry : 4/8/2002<br>terry : 1/25/2001<br>jlewis : 8/16/1999<br>terry : 8/4/1999<br>carol : 1/18/1999<br>terry : 1/7/1999<br>dkim : 12/15/1998<br>dkim : 12/10/1998<br>dkim : 12/9/1998<br>alopez : 6/18/1998<br>terry : 6/15/1998<br>carol : 5/14/1998<br>terry : 9/5/1996<br>terry : 9/3/1996<br>terry : 11/7/1995<br>mark : 10/19/1995<br>carol : 3/1/1993<br>carol : 12/23/1992<br>carol : 7/21/1992<br>carol : 6/17/1992
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<span class="mim-font">
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<strong>*</strong> 120220
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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-1; COL6A1
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</div>
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<div>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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COLLAGEN, INTIMAL<br />
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SHORT-CHAIN COLLAGEN
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: COL6A1</em></strong>
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</span>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 718572004;
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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> : 21:45,981,770-46,005,048 </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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<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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Location
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Phenotype
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Phenotype <br /> MIM number
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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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<td rowspan="2">
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<span class="mim-font">
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21q22.3
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<td>
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<span class="mim-font">
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Bethlem myopathy 1A
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</td>
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<td>
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<span class="mim-font">
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158810
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<td>
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<span class="mim-font">
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Autosomal dominant
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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Ullrich congenital muscular dystrophy 1A
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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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254090
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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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</tbody>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</div>
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<span class="mim-text-font">
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<p>Collagens play important roles in maintaining extracellular matrix structure and function. Members of the collagen VI family, like COL6A1, form distinct networks of microfibrils in connective tissue and interact with other extracellular matrix components (summary by Gara et al., 2008). </p>
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</span>
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<div>
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<br />
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</h4>
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<span class="mim-text-font">
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<p>Chung et al. (1976) isolated a collagen from the intima of human aorta that differed from types IV and V collagen. Seemingly, the same collagen was isolated from bovine placenta by Jander et al. (1981) and from human placenta by Furuto and Miller (1981). It is cysteine-rich and appears to have 3 peptides: a single relatively acidic peptide plus 2 more basic peptides. Type VI collagen appears to be unusual among collagens in the small size of its collagenous domains and in its supramolecular structure. It has been called 'short-chain collagen.' It is relatively resistant to bacterial collagenase and has a glycine content less than one-third of the protein, suggesting interrupted helical regions. Electron microscopy shows additional unique features. Collagen VI is a component of microfibrillar structures in many tissues (Engel et al., 1985). These microfibrils localize close to cells, nerves, blood vessels, and large collagen fibrils and are considered to have an anchoring function. Consistent with such a function are the biochemical findings that type VI collagen binds cells and that its fusion protein binds type I collagen. The binding activity also implies that, in addition to a structural role, type VI collagen may be involved in cell migration and differentiation and embryonic development. </p><p>Trueb and Winterhalter (1986) showed that type VI collagen consists of 2 different 140-kD subunits (alpha-1 and alpha-2) and a 200-kD subunit (alpha-3). The alpha-3(VI) chain is synthesized by cells in culture as a precursor of 260 kD, while no precursor forms of the other 2 chains could be detected. Working with pepsin-solubilized collagen VI from human placenta, Chu et al. (1987) characterized the 3 constituent chains by peptide-sequences and cDNA clones. </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 analysis and in situ hybridization, Weil et al. (1988) localized the alpha-1 and alpha-2 (COL6A2) collagen VI genes to chromosome 21q22.3 and the alpha-3(VI) gene (COL6A3; 120250) to chromosome 2q37. By Southern hybridization analysis of DNA from Chinese hamster-human somatic cell hybrids segregating different portions of human chromosome 21, Cutting et al. (1988) showed that COL6A1 and COL6A2 map distal to the locus D21S3. Linkage analysis in 40 CEPH families showed 12.5% recombination between COL6A1 and ETS2 (164740). No recombinants were observed between COL6A1 and COL6A2. Recombinants between the Marfan phenotype (154700) and COL6A1 markers in 3 families excluded mutation of COL6A1 and COL6A2 as the cause of the Marfan syndrome. By pulsed field gel electrophoresis (PFGE), Cutting et al. (1988) showed that COL6A1 and COL6A2 hybridized to the same size restriction fragments, the smallest of which was 205 kb. </p><p>Petersen et al. (1991) presented a genetic linkage map of chromosome 21 involving 27 markers (10 genes and 17 anonymous sequences). The length of the male map was 132 cM and of the female map 161 cM. In both sexes, approximately one-half of the crossovers occurred distally in terminal band 21q22.3, which also contained 16 of the markers studied, including 8 of the 10 genes. Band 21q22.3 spans about 75 cM in the female map. The Petersen map illustrated the homogeneity in the distribution of genes in the genome, with a concentration of genes in Giemsa-light bands and near the ends of chromosomes. Francomano et al. (1991) used PFGE and somatic cell hybrids to demonstrate that COL6A1 and COL6A2 form a gene cluster on the most distal part of chromosome 21. They detected several DNA polymorphisms (both restriction site and VNTRs) associated with these loci. Using a slot-blot method for the dosage of single-copy sequences, </p><p>Delabar et al. (1992) assessed the copy number of 30 chromosome 21 markers in the blood DNA of 11 patients with partial trisomy or monosomy 21. The physical order of the markers on chromosome 21 was thereby determined. The results showed that COL6A1 and S100B (176990) were in the most terminal region, with CD18 (600065) in the penultimate segment of 21q and PFKL (171860) in the next segment toward the centromere. Using a single interspecific backcross, Justice et al. (1990) mapped the homologous gene to mouse chromosome 10 and determined its location relative to 17 other markers. </p><p>By high-resolution fluorescence in situ hybridization (FISH) techniques, Heiskanen et al. (1995) determined the distance separating the COL6A1 and COL6A2 genes (150 kb), the size of the COL6A1 gene (29 kb), and the 5-prime/3-prime orientation of these genes. By fiber-FISH, they showed that the orientation is 5-prime COL6A1 3-prime/5-prime COL6A2 3-prime. This appeared to be the first collagen gene pair found to be in a head-to-tail configuration. Other closely located collagen gene pairs are either in a head-to-head configuration (type IV collagen genes) with a common promoter region or in a tail-to-tail configuration (COL3A1 and COL5A2) on chromosome 2q. </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>By immunohistochemical analysis, Gara et al. (2008) detected expression of Col6a5 (611916) and Col6a6 (616613) in quadriceps femoris and diaphragm of wildtype mice, but not in Col6a1-deficient mice, suggesting that the alpha-1 chain is a prerequisite for trimeric assembly of collagens containing Col6a5 and Col6a6. </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 1 and Ullrich Congenital Muscular Dystrophy 1</em></strong></p><p>
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In affected members of a family with autosomal dominant Bethlem myopathy-1 (BTHLM1A; 158810), Jobsis et al. (1996) identified a heterozygous missense mutation in the COL6A1 gene (G286V; 120220.0001). The mutation 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 to the authors a similar mechanism in Bethlem myopathy. </p><p>Lamande et al. (1998) found that functional haploinsufficiency of collagen VI causes Bethlem myopathy. They identified a heterozygous COL6A1 mutation (120220.0002) resulting in a 1-bp deletion from the mRNA and a premature stop codon. Mutant mRNA was unstable, subject to nonsense-mediated mRNA decay and was almost completely absent both from patient fibroblasts and skeletal muscle. They stated that Bethlem myopathy is the first example of a muscular dystrophy caused by haploinsufficiency of a structural protein or member of the dystrophin-glycoprotein complex, and identifies collagen VI as a critical contributor to cell-matrix adhesion in skeletal muscle. </p><p>In 3 large families with an autosomal dominant limb-girdle muscular dystrophy phenotype, Scacheri et al. (2002) studied the COL6A1 and COL6A2 (120240) genes and found 2 novel missense mutations (120220.0004; 120220.0005) in the former and 1 (120240.0005) in the latter; 2 of these mutations were in regions of the proteins not previously associated with disease. To address the question of why symptoms in limb-girdle muscular dystrophy and Bethlem myopathy are restricted to skeletal muscle although collagen VI is ubiquitously expressed in connective tissue, the authors studied protein expression in 3 patient muscle biopsies. A marked reduction of laminin beta-1 protein (LAMB1; 150240) was found in the myofiber basal lamina in all biopsies, although this protein was expressed normally in the neighboring capillary basal laminae. 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. They hypothesized that collagen VI mutations lead to muscle-specific defects of the basal lamina, thus explaining the muscle-specific symptoms of Bethlem and limb-girdle muscular dystrophy in patients with collagen VI mutations. </p><p>Pan et al. (2003) reported a 12-year-old boy with a de novo heterozygous deletion near a minisatellite DNA sequence in intron 8 of the COL6A1 gene that removed 1.1 kb of genomic DNA encompassing exons 9 and 10 (120220.0007), resulting in a severe phenotype of classic Ullrich congenital muscular dystrophy (UCMD1A; 254090). UCMD had previously been shown to be caused by recessive mutations in COL6A2 and COL6A3. Pan et al. (2003) stated that heterozygous skipping of exon 14 in the COL6A1 transcript is a recurring mutation, as it had been identified in 2 unrelated patients with Bethlem myopathy resulting from mutations in either the first (120220.0006) or second (120220.0003) nucleotide of the splice donor site in intron 14. </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) using 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>Lucioli et al. (2005) identified 8 different mutations in the COL6A1 gene in 16 unrelated patients with Bethlem myopathy. The most common mutation was a splice site mutation (120220.0006), which was found in 6 unrelated patients. All the mutations were localized between exons 3 and 14, corresponding to the COOH end of the NH2-globular domain and the NH2-end of the triple-helical domain. </p><p>In 3 unrelated patients with Ullrich congenital muscular dystrophy, Giusti et al. (2005) identified 3 different homozygous mutations in the COL6A1 gene (120220.0009-120220.0011). Two additional patients with a relatively milder form of UCMD had de novo heterozygous missense mutations (G284R; 120220.0012 and G290R; 120220.0013). </p><p>Pepe et al. (2006) reported 2 unrelated patients with a mild form of UCMD and Bethlem myopathy, respectively, who had similar heterozygous deletions in the COL6A1 gene spanning from intron 8 to exon 13 or intron 13. The 5-prime breakpoints of both deletions were located within a minisatellite in intron 8. Coimmunoprecipitation studies of fibroblasts derived from the 2 patients showed that mutant proteins were inefficiently secreted, thus preventing a strong dominant effect. Pepe et al. (2006) concluded that the minisatellite region in intron 8 predisposes that area of the COL6A1 gene to multiexon deletions and noted that this type of mutation is often not detectable by standard DNA analysis. </p><p>Nadeau et al. (2009) reported heterozygous mutations in the COL6A1 gene (G284R, 120220.0012; G290R, 120220.0013) in 2 twin sisters and 2 unrelated patients, respectively, with UCMD. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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Davies et al. (1995) studied genetic variation in the COL6A1/COL6A2 gene cluster on chromosome 21 in 113 controls and 58 European families (including control and family subgroups of British/Irish origin) having a child with trisomy 21. They found statistically significant differences among subgroups of trisomy children with and without congenital heart defects in distributions of definitive, 3-RFLP haplotype classes received from their nondisjoining and disjoining parents. The haplotypes received by trisomy children with congenital heart defects from the disjoining parents were not a random sample of controls' haplotypes. Analysis of parental single-RFLP genotypes and linkage disequilibrium patterns confirmed this parent subgroup differed from a random sample of controls. There was no significant difference in parent subgroup genotype distribution at any of 9 control loci distributed along chromosome 21q. The study by Davies et al. (1995) showed an association between genetic variation in the COL6A1 region and congenital heart defects in trisomy 21. </p><p>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 (120240), 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><p>Ossification of the posterior longitudinal ligament of the spine (OPLL; 602475) is a subset of 'bone-forming' diseases, characterized by ectopic ossification in the spinal ligaments. OPLL is a common disorder among elderly populations in eastern Asia and is a leading cause of spinal myelopathy in Japan. Tanaka et al. (2003) performed a genomewide linkage study of 142 affected sib pairs to identify genetic loci related to OPLL. The best evidence of linkage was detected near marker D21S1903 on 21q22.3; the linkage region was therefore extensively investigated for linkage disequilibrium with SNPs covering 20 Mb. Haplotype analysis with 3 SNPs in the COL6A1 gene gave a single-point P value of 0.0000007. </p>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Using in situ hybridization to sectioned embryonic mouse hearts, Klewer et al. (1998) delineated the developmental expression pattern of the COL6A1, COL6A2, and COL6A3 genes. COL6A1 mRNA was first detected at embryonic day 11-11.5 in endothelial cells overlying the atrioventricular endocardial cushions. Expression was seen throughout the atrioventricular endocardial cushions following epithelial-mesenchymal transition. High expression levels were seen after embryonic day 13 in the remodeling atrioventricular endocardial cushions as they contributed to the developing atrioventricular valves and atrioventricular septum. The authors noted that type VI collagen is present in higher amounts than usual in the extracellular matrix of skin from individuals with trisomy 21, but commented that it is uncertain whether overexpression of COL6A1 and COL6A2 is sufficient to disrupt normal atrioventricular valvuloseptal morphogenesis and lead to the congenital heart malformations typical of trisomy 21. </p><p>To gain insight into the function of type VI collagen, Bonaldo et al. (1998) inactivated the Col6a1 gene by targeted gene disruption in the mouse. The homozygous mutants lacked collagen VI in the tissues and showed histologic features of myopathy such as fiber necrosis and phagocytosis and a pronounced variation in muscle fiber diameter. Muscles also showed signs of stimulated regeneration of fibers. Necrotic fibers were particularly frequent in the diaphragm at all ages examined. Similar, although milder, alterations were detected in heterozygous mutant mice, indicating haploinsufficiency of the Col6a1 gene function. The authors concluded that collagen VI is necessary for maintenance of the integrity of muscle fibers and that the Col6a1-deficient mouse can be considered an animal model of Bethlem myopathy. </p><p>Irwin et al. (2003) showed that muscles of the Col6a1 -/- mice have a loss of contractile strength associated with ultrastructural alterations of sarcoplasmic reticulum (SR) and mitochondria and spontaneous apoptosis. They found a latent mitochondrial dysfunction in myofibers of Col6a1 -/- mice on incubation with oligomycin, which caused mitochondrial depolarization, Ca(2+) deregulation, and increased apoptosis. These defects were reversible, as they could be normalized by plating Col6a1 -/- myofibers on collagen VI or by addition of cyclosporin A, the inhibitor of mitochondrial permeability transition pore. Treatment of Col6a1 -/- mice with cyclosporin A rescued the muscle ultrastructural defects and markedly decreased the number of apoptotic nuclei in vivo. These findings indicated that collagen VI myopathies have an unexpected mitochondrial pathogenesis that could be exploited for therapeutic intervention. </p><p>Palma et al. (2009) showed that inactivation of the Ppid gene (601753), which encodes cyclophilin D (CypD), rescued the disease phenotype of Col6a1 deficiency. In the absence of CypD, Col6a1-null mice showed negligible myofiber degeneration, rescue from mitochondrial dysfunction and ultrastructural defects, and normalized incidence of apoptosis. Palma et al. (2009) concluded that lack of CypD is equivalent to its inhibition with cyclosporin A at curing the mouse dystrophic phenotype and that there is a cause and effect relationship between CypD-dependent permeability transition pore (PTP) regulation and pathogenesis of Bethlem myopathy and UCMD, suggesting CypD and PTP as a pharmacologic target for therapy. </p><p>Grumati et al. (2010) found that Col6a1 -/- mice showed impaired autophagic flux that matched the lower induction of Becn1 (604378) and Bnip3 (603293) and lack of autophagosomes after starvation. Forced activation of autophagy by genetic, dietary, and pharmacologic approaches restored myofiber survival and ameliorated the dystrophic phenotype of Col6a1 -/- mice. Western blot analysis showed that muscle biopsies from 4 individuals with Bethlem myopathy and 5 individuals with UMCD had reduced protein expression of BECN1 and BNIP3. Grumati et al. (2010) concluded that defective activation of the autophagic machinery is pathogenic in some congenital muscular dystrophies. </p><p>Telfer et al. (2010) generated zebrafish models of the collagen VI myopathies. Morpholinos designed to exon 9 of col6a1 produced a severe muscle disease reminiscent of UCMD, while ones to exon 13 produced a milder phenotype similar to Bethlem myopathy. UCMD-like zebrafish had increased cell death and abnormal mitochondria, which could be attenuated by treatment with cyclosporin A (CsA). CsA improved the motor deficits in UCMD-like zebrafish, but failed to reverse the sarcolemmal membrane damage. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>History</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>Murata et al. (1987) found predominant production of type VI collagen by the tumors in a patient with 'multiple fibromatosis occurring at the sites of multiple cartilaginous dysplasia.' They stated that the patient had 'a hereditary disease, with regions of multiple articular dysplasia surrounded by numerous protuberant tumors. Elastic globe-shaped tumors, weighed (sic) about 100 g., were removed from his cervical regions at operation.' The age of the patient was not given, and the nature of the ailment was unclear. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>14 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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<h4>
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<span class="mim-font">
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<strong>.0001 BETHLEM MYOPATHY 1A</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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COL6A1, GLY286VAL
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<br />
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SNP: rs121912934,
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gnomAD: rs121912934,
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ClinVar: RCV000018709
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a Dutch kindred (family 2, originally reported by Bethlem and van Wijngaarden, 1976) with Bethlem myopathy (BTHLM1A; 158810), Jobsis et al. (1996) demonstrated a heterozygous 962G-T transversion in the COL6A1 gene, resulting in a gly286-to-val (G286V) substitution in the triple-helical domain. </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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<h4>
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<span class="mim-font">
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<strong>.0002 BETHLEM MYOPATHY 1A</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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COL6A1, IVS11AS, G-A, -1
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<br />
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SNP: rs886042354,
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ClinVar: RCV000018710, RCV000725055
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</span>
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<div>
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<span class="mim-text-font">
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<p>In a patient with Bethlem myopathy (BTHLM1A; 158810), Lamande et al. (1998) found an approximately 50% reduction in the level of COL6A1 mRNA relative to COL6A2 and COL6A3 mRNAs. Since nonsense-mediated mRNA decay results in decreased steady-state mRNA levels and is a common but often overlooked consequence of mutations that introduce an in-frame premature stop codon, they used the protein truncation test (Roest et al., 1993) to find a COL6A1 transcription termination mutation. Because protein synthesis inhibitors had been shown to reverse the decay of mRNAs containing premature stop codons, they treated the Bethlem myopathy fibroblasts with cycloheximide before RNA extraction in an attempt to stabilize any mRNAs that might have contained a mutation of this class. With these steps they detected a heterozygous deletion of a G residue from a group of 3 that are interrupted in the COL6A1 gene by intron 11. To determine the precise nature of the gene mutation, genomic DNA from 10 normal and 9 affected family members was PCR amplified using primers within exons 10 and 13, and directly sequenced. The analysis demonstrated that the mutation was a heterozygous G-to-A transition at the -1 position of the consensus acceptor splice site of intron 11. The effect of the mutation was not to remove the splice site but to move it 3-prime by 1 base, resulting in the deletion of a G from the mRNA. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 BETHLEM MYOPATHY 1A</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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COL6A1, IVS14DS, T-C, +2
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<br />
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SNP: rs797044456,
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ClinVar: RCV000018711
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</span>
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<div>
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<span class="mim-text-font">
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<p>Pepe et al. (1999) identified heterozygosity for a T-to-C transition at the +2 position of intron 14 of the COL6A1 gene in affected members of a family with Bethlem myopathy (BTHLM1A; 158810). The nucleotide substitution caused an in-frame deletion of 18 amino acids in the triple-helical domain of the COL6A1 chain. The deletion included a cysteine residue believed to be involved in the assembly of type VI collagen dimers intracellularly, prior to secretion of the protein. Analysis of affected fibroblasts showed that the shortened COL6A1 chains were synthesized but not secreted by the cells and that the amount of type VI collagen microfibrils deposited by the cells was reduced. The results suggested that the clinical phenotype was due to a reduction in the level of type VI collagen in the extracellular matrix. The proband was evaluated at age 4 years for limb girdle weakness. At age 2 years, he had shown disability in climbing stairs and standing up from a sitting position. At 4 years, he showed a Gowers sign, weakness of lower limb girdle muscles, particularly of the quadriceps femoris and glutei muscles. There were no joint contractures. Creatine kinase (CK) was 4 times higher than normal. Bilateral tenotomy of Achilles tendons was required at age 7 years. At age 9 years, the boy was able to walk but could not climb stairs or stand up from a sitting position. There was distal joint hyperlaxity, together with shortening of the tendons of the finger flexors. He had generalized muscle weakness sparing flexors of the knees and fingers as well as ankle extensors. The mother showed severe congenital torticollis at birth and flexion contractures of the elbows since the age of 3 years. She had been operated on for tightness of the heel cord at age 13 years. At age 35 years, neurologic examination showed generalized reduced muscle bulk, marked lumbar lordosis, limb girdle and distal weakness, and flexion contractures of elbows, ankles, and interphalangeal joints. CK was increased 2-fold. She showed marked disability in climbing stairs and in standing up from a sitting position. The maternal grandfather had severe motor disability and lost the ability to walk at age 35 years. Although he died of cancer at age 65 years, relatives reported that he had severe multiple joint contractures with shortening of Achilles tendons, flexion contractures of elbows and knees, and severe flexion contractures of the interphalangeal joints. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 BETHLEM MYOPATHY 1A</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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COL6A1, GLY341ASP
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<br />
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SNP: rs121912935,
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ClinVar: RCV000018712, RCV002274883
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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 1 of 3 families with an autosomal dominant limb-girdle muscular dystrophy phenotype, Scacheri et al. (2002) identified a heterozygous G-to-A transition at nucleotide 1070 of the COL6A1 gene, resulting in a gly341-to-asp (G341D) mutation. Twelve of 22 individuals in a Caucasian family from Mississippi were affected. An infantile onset with delay in motor milestones was noted in 6 individuals in this family; motor difficulties began in childhood, i.e., under 10 years of age, in 5 members. Onset began in adult life in 1 patient. Two patients (12 and 48 years old) were wheelchair-bound. Many affected members had muscle cramps, pain, and weakness. Clinical examination showed diffuse muscle weakness, both proximal and distal muscles being weak in all 12 affected individuals. Proximal accentuation of weakness was noted in 4 patients with severe leg weakness, and 3 had severe arm weakness. At the outset, none had contractures of shoulders, hips, spine, or neck. In 5 patients, no contractures were found at ages ranging from 8 to 76 years. Four of 12 patients had contractures of interphalangeal joints, 3 had contractures of the ankles, and 2 of the elbows. In many patients, interphalangeal contractures could be discovered only by the inability to extend fingers passively once the wrist was extended. Scacheri et al. (2002) suggested that their studies widen the clinical spectrum of Bethlem myopathy (BTHLM1A; 158810) 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>.0005 BETHLEM MYOPATHY 1A</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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COL6A1, LYS121ARG
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<br />
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SNP: rs121912936,
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ClinVar: RCV000018713, RCV000177135
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a large Caucasian family from Ohio with an autosomal dominant limb-girdle muscular dystrophy phenotype, Scacheri et al. (2002) found that affected members had a heterozygous lys121-to-arg (K121R) missense mutation in exon 3 of the COL6A1 gene. The clinical presentation was similar to that reported in the Mississippi family with the gln341-to-asp mutation (120220.0004). Scacheri et al. (2002) suggested that their studies widen the clinical spectrum of Bethlem myopathy (BTHLM1A; 158810) 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 BETHLEM MYOPATHY 1A</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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COL6A1, IVS14DS, G-A, +1
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<br />
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SNP: rs398123631,
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ClinVar: RCV000018714, RCV000079739, RCV000626814, RCV001813996
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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 32-year-old man with Bethlem myopathy (BTHLM1A; 158810), Lamande et al. (1999) identified a heterozygous G-to-A transition at the +1 position of intron 14 of the COL6A1 gene, which resulted in skipping of exon 14 and deletion of 18 amino acids from the triple-helical domain of the COL6A1 chain. The mutant COL6A1 chains associated intracellularly with COL6A2 (120240) and COL6A3 (120250) to form disulfide-bonded monomers, but further assembly into dimers and tetramers was prevented, and molecules containing the mutant chain were not secreted. This triple-helical deletion thus resulted in production of half the normal amount of collagen VI. </p><p>Pan et al. (2003) identified the IVS14+1G-A transition in a 6-year-old boy with a relatively mild congenital muscular dystrophy phenotype with distal joint hyperlaxity but no joint contractures characteristic Bethlem myopathy. Because the patient was young and could still develop contractures, Pan et al. (2003) concluded that his phenotype could be compatible with sporadic Bethlem myopathy. </p><p>Lucioli et al. (2005) identified the IVS14+1G-A mutation in 6 of 16 unrelated patients with Bethlem myopathy and mutations in the COL6A1 gene. </p><p>Baker et al. (2007) identified the IVS14+1G-A mutation in 2 additional patients with Bethlem myopathy. Studies showed undisulfide-bonded collagen VI in cell culture medium, suggesting that some structurally abnormal protein was secreted. </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 1A, 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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COL6A1, EX9-10DEL
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<br />
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ClinVar: RCV003764605
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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 12-year-old boy with classic severe Ullrich congenital muscular dystrophy (UCMD1A; 254090), Pan et al. (2003) identified a de novo heterozygous deletion near a minisatellite DNA sequence in intron 8 of the COL6A1 gene, which removed 1.1 kb of genomic DNA encompassing exons 9 and 10. The deletion included 33 amino acids near the N terminus of the triple-helical domain but preserved a unique cysteine within this domain that is important for dimer formation prior to secretion. Thus, dimer formation and secretion of abnormal tetramers could occur and exert a strong dominant-negative effect on microfibrillar assembly, leading to a loss of normal localization of collagen VI in the basement membrane surrounding muscle fibers. Consistent with this mechanism, Pan et al. (2003) described a 6-year-old boy with a much milder phenotype who had a previously identified mutation in the COL6A1 gene resulting in Bethlem myopathy (158810). This heterozygous in-frame deletion of 18 amino acids occurred somewhat downstream in the triple-helical domain, a result of exon 14 skipping in the COL6A1 gene (120220.0006). The deletion removed the crucial cysteine, so that dimer formation could not occur and the abnormal molecule was not secreted, preventing the strong dominant-negative effect. </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 BETHLEM MYOPATHY 1A</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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COL6A1, IVS3DS, G-A, +1
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<br />
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SNP: rs1569517717,
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ClinVar: RCV000018716, RCV004795926
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of an Italian family with Bethlem myopathy (BTHLM1A; 158810) previously reported by Merlini et al. (1994), Vanegas et al. (2002) identified a heterozygous G-to-A transition at the +1 position of intron 3 of the COL6A1 gene. The mutation results in the activation of a cryptic splice donor site at the 3-prime end of exon 3, leading to an in-frame deletion of 22 amino acids from codon 122 to 143 within the NH2-globular domain. Fibroblast studies showed that the mutated mRNA was stable, but the mutated protein could not be detected, suggesting that it was highly unstable and rapidly degraded. </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 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1A, 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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COL6A1, 1-BP DEL, 856C
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<br />
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SNP: rs797044457,
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ClinVar: RCV000018717
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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 Turkish patient with Ullrich congenital muscular dystrophy (UCMD1A; 254090), Giusti et al. (2005) identified a homozygous 1-bp deletion (856/857delC) in exon 9 of the COL6A1 gene, resulting in a frameshift and premature termination of the protein within the triple-helical domain. The patient was born of consanguineous parents, both of whom were heterozygous for the mutation. </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 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1A, 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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COL6A1, 1-BP DEL, 1465G
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<br />
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SNP: rs797044458,
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ClinVar: RCV000018718
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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 patient with Ullrich congenital muscular dystrophy (UCMD1A; 254090), Giusti et al. (2005) identified a homozygous 1-bp deletion (1465delG) in exon 22 of the COL6A1 gene, resulting in a frameshift and premature termination of the protein within the triple-helical domain. The patient was born of consanguineous parents, both of whom were heterozygous for the mutation. (In the article by Giusti et al. (2005), the nucleotide for this mutation was given as 1456 in Table 1 but as 1465 in the text.) </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 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1A, 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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COL6A1, TYR659TER
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<br />
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SNP: rs121912937,
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gnomAD: rs121912937,
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ClinVar: RCV000018719
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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 Turkish patient with Ullrich congenital muscular dystrophy (UCMD1A; 254090), Giusti et al. (2005) identified a homozygous 1977C-G transversion in exon 31 of the COL6A1 gene, resulting in a tyr659-to-ter (Y659X) substitution. Detailed analysis of the RNA species showed that the mutation resulted in 2 truncated proteins: Y659X and a distinct protein that showed exon 31 skipping and termination at amino acids 728-729. Giusti et al. (2005) emphasized the unique molecular mechanism. The patient was born of consanguineous parents, both of whom were heterozygous for the mutation. </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 1A, 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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COL6A1, GLY284ARG
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<br />
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SNP: rs121912938,
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gnomAD: rs121912938,
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|
|
ClinVar: RCV000079828, RCV000180573, RCV000180574, RCV003314554, RCV003764606
|
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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 (UCMD1A; 254090), Giusti et al. (2005) identified a de novo heterozygous 850G-A transition in exon 9 of the COL6A1 gene, resulting in a gly284-to-arg (G284R) substitution in the triple-helical domain. Northern and Western blot analyses detected normal amounts of COL6A1 mRNA and protein. However, immunohistochemistry and electron microscopy showed reduction of COL6A1 in the extracellular space as well as filamentous aggregates of COL6A1. </p><p>Kawahara et al. (2007) observed sarcolemmal-specific collagen VI deficiency in muscle biopsies from patients with a heterozygous G284R mutation in the N-terminal region in the triple-helical domain. Collagen VI was present in the interstitium but was barely detectable in the sarcolemma; patients with compound heterozygous COL6A1 mutations had complete absence of the protein. Electron microscopy showed that collagen VI microfibrils did not bind to the basement membrane. Further studies showed that fibroblasts with the mutation assembled and secreted normal collagen VI microfibrils. However, cell adhesion of heterozygous G284R fibroblasts was markedly decreased, similar to that of collagen VI-deficient cells, but could be rescued by the addition of normal collagen VI. Kawahara et al. (2007) concluded that heterozygous mutations in the COL6A1 gene result in decreased binding of collagen VI to the extracellular matrix. </p><p>Nadeau et al. (2009) reported 17-year-old twin sisters with UCMD resulting from a heterozygous de novo G284R mutation. Both had onset at age 3 years of delayed motor milestones and proximal, axial, and facial muscle weakness. They learned to walk independently, but had rigid spine, scoliosis, contractures, and required nocturnal ventilation in late childhood. Both had chewing difficulties and low weight necessitating gastrostomy at age 11.8 years. Intelligence was normal and there was no cardiac involvement. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1A, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
COL6A1, GLY290ARG
|
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|
|
|
<br />
|
|
|
|
SNP: rs121912939,
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|
|
|
|
|
|
|
ClinVar: RCV001851922, RCV003764607
|
|
|
|
|
|
</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Ullrich congenital muscular dystrophy (UCMD1A; 254090), Giusti et al. (2005) identified a de novo heterozygous 868G-C transversion in exon 10 of the COL6A1 gene, resulting in a gly290-to-arg (G290R) substitution in the triple-helical domain. Northern and Western blot analyses detected normal amounts of COL6A1 mRNA and protein. However, immunohistochemistry and electron microscopy showed reduction of COL6A1 in the extracellular space as well as filamentous aggregates of COL6A1. </p><p>Nadeau et al. (2009) reported 2 unrelated patients with UCMD due to a heterozygous G290R substitution. One 18-year-old patient had onset at birth with torticollis, contractures, and delayed motor development. Independent walking was achieved at age 3.5 years, and the patient had contractures, rigid spine, scoliosis, and follicular hyperkeratosis and keloid formation. The other patient had onset at birth of hypotonia, contractures, and delayed motor development. Independent walking was never achieved, and the patient became wheelchair-bound at age 10.7 years. Other features included rigid spine, scoliosis, kyphosis, contractures, and follicular hyperkeratosis. The second patient died suddenly at age 15 years after a fracture of the long bone. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1A, DIGENIC, COL6A1/COL6A2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
|
|
COL6A1, GLY281ARG
|
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|
|
|
|
<br />
|
|
|
|
SNP: rs267606746,
|
|
|
|
|
|
|
|
ClinVar: RCV000018722, RCV000497629, RCV001216604
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 25-year-old patient with Ullrich congenital muscular dystrophy (UCMD1A; 254090), Nadeau et al. (2009) identified heterozygous mutations in 2 different genes: an 841G-A transition in exon 9 of the COL6A1 gene, resulting in a gly281-to-arg (G281R) substitution, and a substitution in the COL6A2 gene (R498H; 120240.0014). 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>
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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>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Duff et al. (1990); Hessle and Engvall (1984)
|
|
</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>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
|
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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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: 23040494]
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[Full Text: https://doi.org/10.1016/j.ajhg.2012.08.017]
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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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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.
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[PubMed: 17886299]
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[Full Text: https://doi.org/10.1002/ana.21213]
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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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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: 963533]
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[Full Text: https://doi.org/10.1093/brain/99.1.91]
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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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Bonaldo, P., Braghetta, P., Zanetti, M., Piccolo, S., Volpin, D., Bressan, G. M.
|
|
<strong>Collagen VI deficiency induces early onset myopathy in the mouse: an animal model for Bethlem myopathy.</strong>
|
|
Hum. Molec. Genet. 7: 2135-2140, 1998.
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[PubMed: 9817932]
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[Full Text: https://doi.org/10.1093/hmg/7.13.2135]
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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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Chu, M.-L., Mann, K., Deutzmann, R., Pribula-Conway, D., Hsu-Chen, C.-C., Bernard, M. P., Timpl, R.
|
|
<strong>Characterization of three constituent chains of collagen type VI by peptide sequences and cDNA clones.</strong>
|
|
Europ. J. Biochem. 168: 309-317, 1987.
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[PubMed: 3665927]
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[Full Text: https://doi.org/10.1111/j.1432-1033.1987.tb13422.x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Chung, E., Rhodes, R. K., Miller, E. J.
|
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<strong>Isolation of three collagenous components of probable basement membrane origin from several tissues.</strong>
|
|
Biochem. Biophys. Res. Commun. 71: 1167-1174, 1976.
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[PubMed: 971306]
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[Full Text: https://doi.org/10.1016/0006-291x(76)90776-2]
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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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Cutting, G., Francomano, C. A., Chu, M. L., Timpl, R., McCormick, M. K., Warren, A. C., Hong, H. K., Pyeritz, R. E., Antonarakis, S. E.
|
|
<strong>Genetic linkage analysis and macrorestriction mapping of COL6A1 and COL6A2, structural genes of type VI collagen. (Abstract)</strong>
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Trueb, B., Winterhalter, K. H.
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<strong>Type VI collagen is composed of a 200 kD subunit and two 140 kD subunits.</strong>
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EMBO J. 5: 2815-2819, 1986.
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Vanegas, O. C., Zhang, R.-Z., Sabatelli, P., Lattanzi, G., Bencivenga, P., Giusti, B., Columbaro, M., Chu, M.-L., Merlini, L., Pepe, G.
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<strong>Novel COL6A1 splicing mutation in a family affected by mild Bethlem myopathy.</strong>
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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>
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Patricia A. Hartz - updated : 10/23/2015<br>George E. Tiller - updated : 8/5/2013<br>Ada Hamosh - updated : 2/14/2013<br>Paul J. Converse - updated : 4/20/2011<br>George E. Tiller - updated : 2/24/2010<br>Cassandra L. Kniffin - updated : 12/15/2009<br>Cassandra L. Kniffin - updated : 5/23/2008<br>Cassandra L. Kniffin - updated : 12/17/2007<br>Cassandra L. Kniffin - updated : 4/13/2006<br>Cassandra L. Kniffin - updated : 11/29/2005<br>Cassandra L. Kniffin - updated : 11/1/2005<br>Marla J. F. O'Neill - updated : 3/1/2005<br>Victor A. McKusick - updated : 12/2/2003<br>Victor A. McKusick - updated : 10/7/2003<br>Victor A. McKusick - updated : 8/11/2003<br>Victor A. McKusick - updated : 4/8/2002<br>Victor A. McKusick - updated : 8/4/1999<br>Victor A. McKusick - updated : 1/7/1999<br>Victor A. McKusick - updated : 6/15/1998<br>Paul Brennan - updated : 5/14/1998
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Victor A. McKusick : 6/4/1986
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