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Entry
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- *128239 - DYSTROGLYCAN 1; DAG1
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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">*128239</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/128239">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000173402;t=ENST00000308775" 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=1605" 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=128239" 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=ENSG00000173402;t=ENST00000308775" 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_001165928,NM_001177634,NM_001177635,NM_001177636,NM_001177637,NM_001177638,NM_001177639,NM_001177640,NM_001177641,NM_001177642,NM_001177643,NM_001177644,NM_004393,XM_047447539,XM_047447540,XM_047447541,XM_047447542,XM_047447543,XM_047447544,XM_047447545,XM_047447546,XM_047447547,XM_047447548,XM_047447549,XM_047447550,XM_047447551,XM_047447552,XM_047447553,XM_047447554,XM_047447555,XM_047447556,XM_047447557,XM_047447558,XM_047447559,XM_047447560,XM_047447561,XM_047447562,XM_047447563,XM_047447564,XM_047447565,XM_047447566,XM_047447567,XM_047447568,XM_047447569,XM_047447570,XM_047447571,XM_047447572,XM_047447573,XM_047447574,XM_047447575,XM_047447576,XM_047447577,XM_047447578,XM_047447579" 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_004393" 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=128239" 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=00546&isoform_id=00546_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/DAG1" 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/398026,15215308,15779100,119585393,119585394,158256816,194387552,229462879,1702811201,1961331497,2198916611,2198916613,2198916627,2198916639,2198916651,2198916657,2198916663,2198916674,2198916678,2198916681,2198916683,2217342150,2217342152,2217342154,2217342156,2217342158,2217342160,2217342162,2217342164,2217342166,2217342168,2217342170,2217342172,2217342174,2217342176,2217342178,2217342180,2217342182,2217342184,2217342186,2217342188,2217342190,2217342192,2217342194,2217342196,2217342198,2217342200,2217342202,2217342204,2217342206,2217342208,2217342210,2217342212,2217342214,2217342216,2217342218,2217342220,2217342222,2217342224,2217342226,2217342228,2217342230,2462587523,2462587525,2462587527,2462587529,2462587531,2462587533,2462587535,2462587537,2462587539,2462587541,2462587543,2462587545,2462587547,2462587549,2462587551,2462587553,2462587555,2462587557,2462587559,2462587561,2462587563,2462587565,2462587567,2462587569,2462587571,2462587573,2462587575,2462587577,2462587579,2462587581,2462587583,2462587585,2462587588,2462587590,2462587592,2462587594,2462587596,2462587598,2462587600,2462587602,2462587604" 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/Q14118" 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=1605" 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=ENSG00000173402;t=ENST00000308775" 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=DAG1" 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=DAG1" 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+1605" 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/DAG1" 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:1605" 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/1605" 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=chr3&hgg_gene=ENST00000308775.7&hgg_start=49468948&hgg_end=49535615&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:2666" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=128239[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=128239[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000173402" 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=DAG1" 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=DAG1" 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=DAG1" 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/DAG1" 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=DAG1&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/PA27138" 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:2666" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0034072.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:101864" 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/DAG1#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:101864" 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/1605/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=1605" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
|
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<div id="mimWormbaseGeneFold" class="collapse">
|
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00000961;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00000961 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00018943;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00018943 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-021223-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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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:1605" 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=DAG1&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> 726614009<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>
|
|
128239
|
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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>
|
|
<span class="mim-font">
|
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DYSTROGLYCAN 1; DAG1
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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">
|
|
DYSTROPHIN-ASSOCIATED GLYCOPROTEIN 1<br />
|
|
DAG
|
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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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<a id="includedTitles" class="mim-anchor"></a>
|
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<div>
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<p>
|
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<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
DYSTROGLYCAN, ALPHA, INCLUDED
|
|
</span>
|
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</div>
|
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|
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<div>
|
|
<span class="h4 mim-font">
|
|
|
|
DYSTROGLYCAN, BETA, INCLUDED<br />
|
|
AGRIN RECEPTOR, INCLUDED; AGRNR, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=DAG1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">DAG1</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/3/313?start=-3&limit=10&highlight=313">3p21.31</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:49468948-49535615&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'})">3:49,468,948-49,535,615</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
|
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|
|
</span>
|
|
</p>
|
|
</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">
|
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<th>
|
|
Location
|
|
</th>
|
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<th>
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Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 9
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Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 9
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PheneGene Graphics <span class="caret"></span>
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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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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>Dystroglycan is a high-affinity receptor for several extracellular matrix components, including laminin (see <a href="/entry/150320">150320</a>) and perlecan (HSPG2; <a href="/entry/142461">142461</a>). The alpha and beta subunits of dystroglycan arise from posttranslational cleavage of a single dystroglycan propeptide encoded by the DAG1 gene. Alpha-dystroglycan is a peripheral membrane protein that interacts with laminin in the basal lamina and beta-dystroglycan. Beta-dystroglycan crosses the membrane bilayer, associates with dystrophin (DMD; <a href="/entry/300377">300377</a>), and is thereby connected to the alpha cytoskeleton. Dystroglycan is also a component of the dystrophin-glycoprotein complex (DGC), which stabilizes muscle fiber sarcolemma against contraction forces by linking the extracellular matrix and actin cytoskeleton (summary by <a href="#16" class="mim-tip-reference" title="Holt, K. H., Crosbie, R. H., Venzke, D. P., Campbell, K. P. <strong>Biosynthesis of dystroglycan: processing of a precursor propeptide.</strong> FEBS Lett. 468: 79-83, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10683445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10683445</a>] [<a href="https://doi.org/10.1016/s0014-5793(00)01195-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10683445">Holt et al., 2000</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10683445" 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="#18" class="mim-tip-reference" title="Ibraghimov-Beskrovnaya, O., Ervasti, J. M., Leveille, C. J., Slaughter, C. A., Sernett, S. W., Campbell, K. P. <strong>Primary structure of dystrophin-associated glycoproteins linking dystrophin to the extracellular matrix.</strong> Nature 355: 696-702, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1741056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1741056</a>] [<a href="https://doi.org/10.1038/355696a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1741056">Ibraghimov-Beskrovnaya et al. (1992)</a> demonstrated that the transmembrane 43-kD and extracellular 156-kD DAG proteins are encoded by a single 5.8-kb mRNA in rabbit. The deduced 895-residue precursor protein has a molecular mass of 96 kD and undergoes posttranslational processing to generate a 43-kD transmembrane protein and a 156-kD extracellular protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1741056" 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="Ibraghimov-Beskrovnaya, O., Milatovich, A., Ozcelik, T., Yang, B., Koepnick, K., Francke, U., Campbell, K. P. <strong>Human dystroglycan: skeletal muscle cDNA, genomic structure, origin of tissue specific isoforms and chromosomal localization.</strong> Hum. Molec. Genet. 2: 1651-1657, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8268918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8268918</a>] [<a href="https://doi.org/10.1093/hmg/2.10.1651" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8268918">Ibraghimov-Beskrovnaya et al. (1993)</a> cloned full-length human DAG1 from a skeletal muscle cDNA library. The predicted 895-amino acid human protein shares 93% amino acid identity with the rabbit protein, with conservation of predicted glycosylation sites. Like the rabbit protein, the 97-kD human precursor protein is posttranslationally processed into 156-kD alpha-dystroglycan and 43-kD beta-dystroglycan. Northern blot analysis detected a 5.8-kb DAG1 transcript in all adult and fetal human tissues examined, with highest expression in skeletal muscle and heart and lower expression in nonmuscle tissues. Further analysis suggested that the muscle and nonmuscle isoforms of dystroglycan differ by carbohydrate moieties, but not by protein sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8268918" 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="#19" class="mim-tip-reference" title="Ibraghimov-Beskrovnaya, O., Milatovich, A., Ozcelik, T., Yang, B., Koepnick, K., Francke, U., Campbell, K. P. <strong>Human dystroglycan: skeletal muscle cDNA, genomic structure, origin of tissue specific isoforms and chromosomal localization.</strong> Hum. Molec. Genet. 2: 1651-1657, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8268918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8268918</a>] [<a href="https://doi.org/10.1093/hmg/2.10.1651" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8268918">Ibraghimov-Beskrovnaya et al. (1993)</a> determined that the DAG1 gene contains 2 coding exons separated by a large intron. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8268918" 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>Ibraghimov-Beskrovnaya et al. (<a href="#18" class="mim-tip-reference" title="Ibraghimov-Beskrovnaya, O., Ervasti, J. M., Leveille, C. J., Slaughter, C. A., Sernett, S. W., Campbell, K. P. <strong>Primary structure of dystrophin-associated glycoproteins linking dystrophin to the extracellular matrix.</strong> Nature 355: 696-702, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1741056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1741056</a>] [<a href="https://doi.org/10.1038/355696a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1741056">1992</a>, <a href="#19" class="mim-tip-reference" title="Ibraghimov-Beskrovnaya, O., Milatovich, A., Ozcelik, T., Yang, B., Koepnick, K., Francke, U., Campbell, K. P. <strong>Human dystroglycan: skeletal muscle cDNA, genomic structure, origin of tissue specific isoforms and chromosomal localization.</strong> Hum. Molec. Genet. 2: 1651-1657, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8268918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8268918</a>] [<a href="https://doi.org/10.1093/hmg/2.10.1651" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8268918">1993</a>) mapped the DAG1 gene to chromosome 3 by Southern blot analysis of human/Chinese hamster somatic cell hybrid DNAs. The regional assignment to 3p21 was confirmed and further refined by fluorescence in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1741056+8268918" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Gorecki, D. C., Derry, J. M. J., Barnard, E. A. <strong>Dystroglycan: brain localisation and chromosome mapping in the mouse.</strong> Hum. Molec. Genet. 3: 1589-1597, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7833916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7833916</a>] [<a href="https://doi.org/10.1093/hmg/3.9.1589" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7833916">Gorecki et al. (1994)</a> demonstrated that the Dag1 gene is located on mouse chromosome 9 in a region of conserved synteny with human 3p. The location was consistent with a possibility that dystroglycan mutations are involved in either of 2 mouse neurologic mutations, 'ducky' (du) or 'tippy' (tip). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7833916" 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="#18" class="mim-tip-reference" title="Ibraghimov-Beskrovnaya, O., Ervasti, J. M., Leveille, C. J., Slaughter, C. A., Sernett, S. W., Campbell, K. P. <strong>Primary structure of dystrophin-associated glycoproteins linking dystrophin to the extracellular matrix.</strong> Nature 355: 696-702, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1741056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1741056</a>] [<a href="https://doi.org/10.1038/355696a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1741056">Ibraghimov-Beskrovnaya et al. (1992)</a> demonstrated that the extracellular 156-kD DAG binds laminin, and thus may provide linkage between the sarcolemma and extracellular matrix. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1741056" 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>Using a heterologous mammalian expression system, <a href="#16" class="mim-tip-reference" title="Holt, K. H., Crosbie, R. H., Venzke, D. P., Campbell, K. P. <strong>Biosynthesis of dystroglycan: processing of a precursor propeptide.</strong> FEBS Lett. 468: 79-83, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10683445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10683445</a>] [<a href="https://doi.org/10.1016/s0014-5793(00)01195-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10683445">Holt et al. (2000)</a> confirmed processing of the rabbit Dag1 precursor propeptide into alpha- and beta-dystroglycan. The precursor propeptide was glycosylated, but blockade of N-linked glycosylation did not prevent cleavage into alpha- and beta-dystroglycan. However, inhibition of N-linked glycosylation resulted in aberrant trafficking of alpha- and beta-dystroglycan to the plasma membrane. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10683445" 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>Agrin (<a href="/entry/103320">103320</a>) is a component of the synaptic basal lamina that induces the aggregation of acetylcholine receptors and other elements of the postsynaptic membrane. <a href="#22" class="mim-tip-reference" title="Ma, J., Nastuk, M. A., McKechnie, B. A., Fallon, J. R. <strong>The agrin receptor: localization in the postsynaptic membrane, interaction with agrin, and relationship to the acetylcholine receptor.</strong> J. Biol. Chem. 268: 25108-25117, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8227074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8227074</a>]" pmid="8227074">Ma et al. (1993)</a> determined the localization, binding characteristics, and biochemical profile of agrin receptor in Torpedo electric organ membranes and defined domains of agrin that bind this receptor. <a href="#2" class="mim-tip-reference" title="Campanelli, J. T., Roberds, S. L., Campbell, K. P., Scheller, R. H. <strong>A role for dystrophin-associated glycoproteins and utrophin in agrin-induced AChR clustering.</strong> Cell 77: 663-674, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8205616/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8205616</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90051-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8205616">Campanelli et al. (1994)</a> and <a href="#9" class="mim-tip-reference" title="Gee, S. H., Montanaro, F., Lindenbaum, M. H., Carbonetto, S. <strong>Dystroglycan-alpha, a dystrophin-associated glycoprotein, is a functional agrin receptor.</strong> Cell 77: 675-686, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8205617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8205617</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90052-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8205617">Gee et al. (1994)</a> presented evidence that the alpha-dystrophin-associated glycoprotein functions as an agrin receptor. Utrophin (<a href="/entry/128240">128240</a>) colocalizes with agrin-induced acetylcholine receptor clusters. Agrin may function by initiating or stabilizing a synapse-specific membrane cytoskeleton that in turn serves as a scaffold upon which synaptic molecules are concentrated. <a href="#31" class="mim-tip-reference" title="Sealock, R., Froehner, S. C. <strong>Dystrophin-associated proteins and synapse formation: is alpha-dystroglycan the agrin receptor?</strong> Cell 77: 617-619, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8205610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8205610</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90045-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8205610">Sealock and Froehner (1994)</a> reviewed the evidence that alpha-dystroglycan is an agrin-binding protein and the functional implications of this. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8205617+8205616+8205610+8227074" 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="#37" class="mim-tip-reference" title="Yamada, H., Denzer, A. J., Hori, H., Tanaka, T., Anderson, L. V. B., Fujita, S., Fukuta-Ohi, H., Shimizu, T., Ruegg, M. A., Matsumura, K. <strong>Dystroglycan is a dual receptor for agrin and laminin-2 in Schwann cell membrane.</strong> J. Biol. Chem. 271: 23418-23423, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8798547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8798547</a>] [<a href="https://doi.org/10.1074/jbc.271.38.23418" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8798547">Yamada et al. (1996)</a> showed that dystroglycan is a dual receptor for agrin and laminin-2 in the Schwann cell membrane. Laminin-2 is composed of the alpha-2 (LAMA2; <a href="/entry/156225">156225</a>), beta-1 (LAMB1; <a href="/entry/150240">150240</a>), and gamma-1 (LAMC1; <a href="/entry/150290">150290</a>) laminin chains. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8798547" 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="Rambukkana, A., Yamada, H., Zanazzi, G., Mathus, T., Salzer, J. L., Yurchenco, P. D., Campbell, K. P., Fischetti, V. A. <strong>Role of alpha-dystroglycan as a Schwann cell receptor for Mycobacterium leprae.</strong> Science 282: 2076-2078, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9851927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9851927</a>] [<a href="https://doi.org/10.1126/science.282.5396.2076" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9851927">Rambukkana et al. (1998)</a> showed that alpha-DG serves as a Schwann cell receptor for Mycobacterium leprae, the causative organism of leprosy. They found that M. leprae specifically binds to alpha-DG only in the presence of the G domain of the alpha-2 chain of laminin-2. Native alpha-DG competitively inhibited the laminin-2-mediated M. leprae binding to primary Schwann cells. Thus, M. leprae may use linkage between the extracellular matrix and the cytoskeleton through laminin-2 and alpha-DG for its interaction with Schwann cells. The neuropathy of leprosy is caused, in part, by invasion of peripheral nerves by M. leprae. The Schwann cell is an important target for bacterial invasion. In the endoneurium of peripheral nerves, Schwann cells are covered by basal lamina, composed of laminin, type IV collagen, entactin/nidogen, and heparan sulfate proteoglycans. Similarly, <a href="#3" class="mim-tip-reference" title="Cao, W., Henry, M. D., Borrow, P., Yamada, H., Elder, J. H., Ravkov, E. V., Nichol, S. T., Compans, R. W., Campbell, K. P., Oldstone, M. B. A. <strong>Identification of alpha-dystroglycan as a receptor for lymphocytic choriomeningitis virus and Lassa fever virus.</strong> Science 282: 2079-2081, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9851928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9851928</a>] [<a href="https://doi.org/10.1126/science.282.5396.2079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9851928">Cao et al. (1998)</a> found that alpha-DG serves as a receptor for lymphocytic choriomeningitis virus (LCMV) and for Lassa fever virus (LFV). They purified a peripheral membrane protein that interacts with LCMV from cells permissive to infection by this virus. Tryptic peptides from this protein were determined to be alpha-DG. Several strains of LCMV and other arenaviruses, including LFV, Oliveros, and Mobala, bound to purified alpha-DG protein. Soluble alpha-DG blocked both LCMV and LFV infection. Cells bearing a null mutation of the gene encoding DG were resistant to LCMV infection, and reconstitution of DG expression in null mutant cells restored susceptibility to LCMV infection. Thus, alpha-DG is a cellular receptor for both LCMV and LFV. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9851927+9851928" 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="Spence, H. J., Chen, Y.-J., Batchelor, C. L., Higginson, J. R., Suila, H., Carpen, O., Winder, S. J. <strong>Ezrin-dependent regulation of the actin cytoskeleton by beta-dystroglycan.</strong> Hum. Molec. Genet. 13: 1657-1668, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15175275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15175275</a>] [<a href="https://doi.org/10.1093/hmg/ddh170" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15175275">Spence et al. (2004)</a> localized beta-dystroglycan to microvilli structures in a number of cell types where it associated with the cytoskeletal adaptor ezrin (VIL2; <a href="/entry/123900">123900</a>), through which it was able to modulate the actin cytoskeleton and induced peripheral filopodia and microvilli. Ezrin was able to interact with dystroglycan through a cluster of basic residues in the juxtamembrane region of dystroglycan, and mutation of these residues both prevented ezrin binding and the induction of actin-rich surface protrusions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15175275" 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="Wright, K. M., Lyon, K. A., Leung, H., Leahy, D. J., Ma, L., Ginty, D. D. <strong>Dystroglycan organizes axon guidance cue localization and axonal pathfinding.</strong> Neuron 76: 931-944, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23217742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23217742</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23217742[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2012.10.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23217742">Wright et al. (2012)</a> found that mouse dystroglycan bound directly to the laminin G domain of the axonal guidance molecule Slit (see SLIT1, <a href="/entry/603742">603742</a>) in a calcium-dependent manner. Binding to dystroglycan was required for proper Slit localization within the basement membrane and floor plate, and for development of normal commissural axon guidance tracts. Mutations in mouse Ispd (Crppa; <a href="/entry/614631">614631</a>) or B3gnt1 (<a href="/entry/605517">605517</a>) that disrupted dystroglycan glycosylation resulted in similar abnormalities in axonal pathfinding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23217742" 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>Lassa virus, which spreads from rodents to humans, can cause lethal hemorrhagic fever. Despite the broad tropism of the virus, chicken cells were reported 30 years ago to resist infection. <a href="#20" class="mim-tip-reference" title="Jae, L. T., Raaben, M., Herbert, A. S., Kuehne, A. I., Wirchnianski, A. S., Soh, T. K., Stubbs, S. H., Janssen, H., Damme, M., Saftig, P., Whelan, S. P., Dye, J. M., Brummelkamp, T. R. <strong>Lassa virus entry requires a trigger-induced receptor switch.</strong> Science 344: 1506-1510, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24970085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24970085</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24970085[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/10.1126/science.1252480" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24970085">Jae et al. (2014)</a> found that Lassa virus readily engaged its cell-surface receptor alpha-dystroglycan in avian cells, but virus entry in susceptible species involved a pH-dependent switch to an intracellular receptor, LAMP1 (<a href="/entry/153330">153330</a>). Iterative haploid screens revealed that ST3GAL4 (<a href="/entry/104240">104240</a>) was required for the interaction of the virus glycoprotein with LAMP1. A single glycosylated residue in LAMP1, present in susceptible species but absent in birds, was essential for interaction with the Lassa virus envelope protein and subsequent infection. Lamp1-deficient mice had cleared intraperitoneally-injected wildtype Lassa virus 6 days after injection, whereas infection was manifest in all organ samples taken from wildtype or heterozygous animals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24970085" 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 mice, <a href="#27" class="mim-tip-reference" title="Morikawa, Y., Heallen, T., Leach, J., Xiao, Y., Martin, J. F. <strong>Dystrophin-glycoprotein complex sequesters Yap to inhibit cardiomyocyte proliferation.</strong> Nature 547: 227-231, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28581498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28581498</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28581498[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature22979" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28581498">Morikawa et al. (2017)</a> demonstrated that Dag1 directly binds to the Hippo pathway effector Yap (<a href="/entry/606608">606608</a>) to inhibit cardiomyocyte proliferation. The Yap-Dag1 interaction was enhanced by Hippo-induced Yap phosphorylation, revealing a connection between Hippo pathway function and the dystrophin-glycoprotein complex. After injury, Hippo-deficient postnatal mouse hearts maintained organ size control by repairing the defect with correct dimensions, whereas postnatal hearts deficient in both Hippo and the dystrophin-glycoprotein complex showed cardiomyocyte overproliferation at the injury site. In the hearts of mature Mdx mice (which have a point mutation in the Dmd gene , <a href="/entry/300377">300377</a>), Hippo deficiency protected against overload-induced heart failure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28581498" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Role in Muscular Dystrophy</em></strong></p><p>
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Abnormal glycosylation of DAG1 results in several forms of congenital muscular dystrophy that range phenotypically from severe forms with brain and eye anomalies (see, e.g., MDDGA1; <a href="/entry/236670">236670</a>) to milder limb-girdle types (see, e.g., MDDGC1; <a href="/entry/609308">609308</a>). Mutations in 6 different genes involved in glycosylation of DAG1 have been identified; these genes include POMT1 (<a href="/entry/607423">607423</a>), POMT2 (<a href="/entry/607439">607439</a>), POMGNT1 (<a href="/entry/606822">606822</a>), FKTN (<a href="/entry/607440">607440</a>), FKRP (<a href="/entry/606596">606596</a>), and LARGE (<a href="/entry/603590">603590</a>). These disorders are collectively known as 'dystroglycanopathies' (<a href="#11" class="mim-tip-reference" title="Godfrey, C., Clement, E., Mein, R., Brockington, M., Smith, J., Talim, B., Straub, V., Robb, S., Quinlivan, R., Feng, L., Jimenez-Mallebrer a, C., Mercuri, E., and 10 others. <strong>Refining genotype-phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan.</strong> Brain 130: 2725-2735, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17878207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17878207</a>] [<a href="https://doi.org/10.1093/brain/awm212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17878207">Godfrey et al., 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17878207" 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="Matsumura, K., Nonaka, I., Campbell, K. P. <strong>Abnormal expression of dystrophin-associated proteins in Fukuyama-type congenital muscular dystrophy.</strong> Lancet 341: 521-522, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8094772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8094772</a>] [<a href="https://doi.org/10.1016/0140-6736(93)90279-p" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8094772">Matsumura et al. (1993)</a> demonstrated deficient expression of multiple dystrophin-associated glycoproteins in a form of congenital muscular dystrophy due to mutation in the FKTN gene (<a href="/entry/607440">607440</a>). This form of congenital muscular dystrophy, also known as Fukuyama-type congenital muscular dystrophy (FCMD) or muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A4; MDDGA4; <a href="/entry/253800">253800</a>) is characterized by defective glycosylation of DAG1. <a href="#23" class="mim-tip-reference" title="Matsumura, K., Nonaka, I., Campbell, K. P. <strong>Abnormal expression of dystrophin-associated proteins in Fukuyama-type congenital muscular dystrophy.</strong> Lancet 341: 521-522, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8094772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8094772</a>] [<a href="https://doi.org/10.1016/0140-6736(93)90279-p" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8094772">Matsumura et al. (1993)</a> noted that the 156DAG/43DAG proteins are expressed in both muscle and brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8094772" 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="Arahata, K., Hayashi, Y. K., Mizuno, Y., Yoshida, M., Ozawa, E. <strong>Dystrophin-associated glycoprotein and dystrophin co-localisation at sarcolemma in Fukuyama congenital muscular dystrophy. (Letter)</strong> Lancet 342: 623-624, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8102757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8102757</a>] [<a href="https://doi.org/10.1016/0140-6736(93)91454-t" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8102757">Arahata et al. (1993)</a> found preservation of immunostaining for 43DAG in FCMD at the plasma membrane of the muscle fibers. On the other hand, they found reduced merosin (see LAMA2, <a href="/entry/156225">156225</a>)-- a striated muscle-specific basal-lamina-associated protein--in most muscle fibers of FCMD, suggesting that it may have an early or primary role in the pathogenesis of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8102757" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Matsumura, K., Tome, F. M. S., Ionasescu, V., Ervasti, J. M., Anderson, R. D., Romero, N. B., Simon, D., Recan, D., Kaplan, J.-C., Fardeau, M., Campbell, K. P. <strong>Deficiency of dystrophin-associated proteins in Duchenne muscular dystrophy patients lacking COOH-terminal domains of dystrophin.</strong> J. Clin. Invest. 92: 866-871, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8349821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8349821</a>] [<a href="https://doi.org/10.1172/JCI116661" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8349821">Matsumura et al. (1993)</a> showed that truncation of the dystrophin molecule with loss of the C-terminal domains can lead to severe muscular dystrophy, even when truncated dystrophin is demonstrable in the subsarcolemmal cytoskeleton. This is because the C-terminal domains are involved in the interaction with the large oligomeric complex of sarcolemmal glycoproteins, including dystroglycan. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8349821" 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="#34" class="mim-tip-reference" title="Tinsley, J. M., Blake, D. J., Zuellig, R. A., Davies, K. E. <strong>Increasing complexity of the dystrophin-associated protein complex.</strong> Proc. Nat. Acad. Sci. 91: 8307-8313, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8078878/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8078878</a>] [<a href="https://doi.org/10.1073/pnas.91.18.8307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8078878">Tinsley et al. (1994)</a> reviewed the 'increasing complexity of the dystrophin-associated protein complex.' Although the exact function of dystrophin remained to be determined, analysis of its interaction with this large oligomeric protein complex at the sarcolemma and the identification of a structurally related protein, utrophin (<a href="/entry/128240">128240</a>), were leading to the identification of candidate genes for various neuromuscular disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8078878" 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>As reviewed by <a href="#32" class="mim-tip-reference" title="Spear, P. G. <strong>A welcome mat for leprosy and Lassa fever.</strong> Science 282: 1999-2000, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9874652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9874652</a>] [<a href="https://doi.org/10.1126/science.282.5396.1999" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9874652">Spear (1998)</a>, structural integrity of the sarcolemma in skeletal and cardiac muscle appears to depend in part on binding of the cytoplasmic protein dystrophin to both actin and the cytoplasmic tail of beta-dystroglycan, and binding of alpha-dystroglycan to laminin-2 in the basal lamina. Laminins are composed of 3 polypeptide chains designated alpha, beta, and gamma. The multiple isoforms of laminin differ in their constituent chains. Laminin-2 is composed of alpha-2, beta-1, and gamma-1. Homozygous deletion of the gene encoding dystroglycan is lethal at the embryonic stage in mice (<a href="#35" class="mim-tip-reference" title="Williamson, R. A., Henry, M. D., Daniels, K. J., Hrstka, R. F., Lee, J. C., Sunada, Y., Ibraghimov-Beskrovnaya, O., Campbell, K. P. <strong>Dystroglycan is essential for early embryonic development: disruption of Reichert's membrane in Dag1-null mice.</strong> Hum. Molec. Genet. 6: 831-841, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9175728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9175728</a>] [<a href="https://doi.org/10.1093/hmg/6.6.831" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9175728">Williamson et al., 1997</a>) and would presumably also be lethal in humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9874652+9175728" 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="#38" class="mim-tip-reference" title="Yamada, H., Saito, F., Fukuta-Ohi, H., Zhong, D., Hase, A., Arai, K., Okuyama, A., Maekawa, R., Shimizu, T., Matsumura, K. <strong>Processing of beta-dystroglycan by matrix metalloproteinase disrupts the link between the extracellular matrix and cell membrane via the dystroglycan complex.</strong> Hum. Molec. Genet. 10: 1563-1569, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11468274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11468274</a>] [<a href="https://doi.org/10.1093/hmg/10.15.1563" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11468274">Yamada et al. (2001)</a> demonstrated that a 30-kD fragment of beta-dystroglycan is the product of proteolytic processing of the extracellular domain of beta-dystroglycan by the membrane-associated matrix metalloproteinase (MMP2; <a href="/entry/120360">120360</a>). This processing disintegrates the dystroglycan complex and disrupts this particular link between the extracellular matrix and cell membrane. The authors proposed that this processing of beta-dystroglycan may play a crucial role in the molecular pathogenesis of sarcoglycanopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11468274" 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>Using PCR, immunohistochemistry, and immunoblotting to analyze samples from patients with Fukuyama congenital muscular dystrophy (MDDGA4; <a href="/entry/253800">253800</a>), <a href="#14" class="mim-tip-reference" title="Hayashi, Y. K., Ogawa, M., Tagawa, K., Noguchi, S., Ishihara, T., Nonaka, I., Arahata, K. <strong>Selective deficiency of alpha-dystroglycan in Fukuyama-type congenital muscular dystrophy.</strong> Neurology 57: 115-121, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11445638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11445638</a>] [<a href="https://doi.org/10.1212/wnl.57.1.115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11445638">Hayashi et al. (2001)</a> confirmed a deficiency of fukutin (FKTN; <a href="/entry/607440">607440</a>) and found marked deficiency of highly glycosylated DAG1 in skeletal and cardiac muscle and reduced amounts of DAG1 in brain tissue. Beta-dystroglycan was normal in all tissues examined. These findings supported the suggestion that fukutin deficiency affects the modification of glycosylation of DAG1, which then cannot localize or function properly and may be degraded or eluted from the extracellular surface membrane of the muscle fiber. <a href="#14" class="mim-tip-reference" title="Hayashi, Y. K., Ogawa, M., Tagawa, K., Noguchi, S., Ishihara, T., Nonaka, I., Arahata, K. <strong>Selective deficiency of alpha-dystroglycan in Fukuyama-type congenital muscular dystrophy.</strong> Neurology 57: 115-121, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11445638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11445638</a>] [<a href="https://doi.org/10.1212/wnl.57.1.115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11445638">Hayashi et al. (2001)</a> concluded that this disruption underlies the developmental, structural, and functional damage to muscles in patients with FCMD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11445638" 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>Using transfection experiments, <a href="#8" class="mim-tip-reference" title="Esapa, C. T., Benson, M. A., Schroder, J. E., Martin-Rendon, E., Brockington, M., Brown, S. C., Muntoni, F., Kroger, S., Blake, D. J. <strong>Functional requirements for fukutin-related protein in the Golgi apparatus.</strong> Hum. Molec. Genet. 11: 3319-3331, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12471058/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12471058</a>] [<a href="https://doi.org/10.1093/hmg/11.26.3319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12471058">Esapa et al. (2002)</a> determined that fukutin and fukutin-related protein (FKRP; <a href="/entry/606596">606596</a>) are targeted to the medial Golgi apparatus through their N termini and transmembrane domains. Overexpression of FKRP in CHO cells altered the posttranslational processing of alpha- and beta-dystroglycan, thus inhibiting maturation of the 2 isoforms. Mutations in the DxD motif or in the Golgi-targeting sequence, which cause inefficient trafficking of FKRP to the Golgi apparatus, did not alter dystroglycan processing in vitro. The P448L mutation in FKRP (<a href="/entry/606596#0003">606596.0003</a>) resulted in mislocalization of the mutant protein and disruption in dystroglycan processing. <a href="#8" class="mim-tip-reference" title="Esapa, C. T., Benson, M. A., Schroder, J. E., Martin-Rendon, E., Brockington, M., Brown, S. C., Muntoni, F., Kroger, S., Blake, D. J. <strong>Functional requirements for fukutin-related protein in the Golgi apparatus.</strong> Hum. Molec. Genet. 11: 3319-3331, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12471058/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12471058</a>] [<a href="https://doi.org/10.1093/hmg/11.26.3319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12471058">Esapa et al. (2002)</a> concluded that FKRP is required for the posttranslational modification of dystroglycan. They suggested that aberrant processing of dystroglycan caused by a mislocalized FKRP mutant could be a novel mechanism that causes congenital muscular dystrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12471058" 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="#21" class="mim-tip-reference" title="Kanagawa, M., Saito, F., Kunz, S., Yoshida-Moriguchi, T., Barresi, R., Kobayashi, Y. M., Muschler, J., Dumanski, J. P., Michele, D. E., Oldstone, M. B. A., Campbell, K. P. <strong>Molecular recognition by LARGE is essential for expression of functional dystroglycan.</strong> Cell 117: 953-964, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15210115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15210115</a>] [<a href="https://doi.org/10.1016/j.cell.2004.06.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15210115">Kanagawa et al. (2004)</a> showed that both the N-terminal domain and a portion of the mucin-like domain of alpha-dystroglycan are essential for high affinity laminin receptor function. They found that posttranslational modification of alpha-dystroglycan by LARGE (<a href="/entry/603590">603590</a>) occurs within the mucin-like domain, but the N-terminal domain interacts with LARGE, defining an intracellular enzyme-substrate recognition motif necessary to initiate functional glycosylation. Gene replacement in dystroglycan-deficient muscle demonstrated that the dystroglycan C-terminal domain is sufficient only for dystrophin-glycoprotein complex assembly. To prevent muscle degeneration, expression of a functional dystroglycan through LARGE recognition and glycosylation was required. The authors concluded that molecular recognition of dystroglycan by LARGE is a key determinant in the biosynthetic pathway to produce mature and functional dystroglycan. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15210115" 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>The ribbon synapse is a specialized structure where photoreceptors transfer information to bipolar and horizontal cells. By immunofluorescence analysis of mouse retina, <a href="#30" class="mim-tip-reference" title="Sato, S., Omori, Y., Katoh, K., Kondo, M., Kanagawa, M., Miyata, K., Funabiki, K., Koyasu, T., Kajimura, N., Miyoshi, T., Sawai, H., Kobayashi, K., Tani, A., Toda, T., Usukura, J., Tano, Y., Fujikado, T., Furukawa, T. <strong>Pikachurin, a dystroglycan ligand, is essential for photoreceptor ribbon synapse formation.</strong> Nature Neurosci. 11: 923-931, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18641643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18641643</a>] [<a href="https://doi.org/10.1038/nn.2160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18641643">Sato et al. (2008)</a> found that expression of pikachurin (EGFLAM; <a href="/entry/617683">617683</a>) at the ribbon synapse overlapped with that of dystrophin and beta-dystroglycan. Pull-down and coimmunoprecipitation assays using eye extracts demonstrated that pikachurin bound alpha-dystroglycan. Inhibition studies suggested that binding of pikachurin to alpha-dystroglycan was dependent on glycosylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18641643" 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>Using protein overlay assays, <a href="#17" class="mim-tip-reference" title="Hu, H., Li, J., Zhang, Z., Yu, M. <strong>Pikachurin interaction with dystroglycan is diminished by defective O-mannosyl glycosylation in congenital muscular dystrophy models and rescued by LARGE overexpression.</strong> Neurosci. Lett. 489: 10-15, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21129441/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21129441</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21129441[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neulet.2010.11.056" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21129441">Hu et al. (2011)</a> observed impaired binding of pikachurin to alpha-dystroglycan in brains from Pomgnt1 (<a href="/entry/606822">606822</a>)-knockout or Large-deficient mice and in neural stem cells from Pomt2 (<a href="/entry/607439">607439</a>)-knockout mice, suggesting that O-mannosylglycosylation of alpha-dystroglycan is required for its interaction with pikachurin. Overexpression of human LARGE rescued interaction of pikachurin with alpha-dystroglycan in Pomgnt1-knockout cells. Immunofluorescence analysis revealed that localization of pikachurin to the photoreceptor synapse in the outer plexiform layer was lost or diminished in retinas of Pomgnt1-knockout, Large-deficient, or Dag1 conditional-knockout mice. <a href="#17" class="mim-tip-reference" title="Hu, H., Li, J., Zhang, Z., Yu, M. <strong>Pikachurin interaction with dystroglycan is diminished by defective O-mannosyl glycosylation in congenital muscular dystrophy models and rescued by LARGE overexpression.</strong> Neurosci. Lett. 489: 10-15, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21129441/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21129441</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21129441[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neulet.2010.11.056" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21129441">Hu et al. (2011)</a> concluded that proper glycosylation of alpha-dystroglycan is required for its interaction with pikachurin and for localization of pikachurin to the photoreceptor ribbon synapse. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21129441" 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>Using mass spectrometry- and nuclear magnetic resonance-based structural analyses, <a href="#39" class="mim-tip-reference" title="Yoshida-Moriguchi, T., Yu, L., Stalnaker, S. H., Davis, S., Kunz, S., Madson, M., Oldstone, M. B. A., Schachter, H., Wells, L., Campbell, K. P. <strong>O-Mannosyl phosphorylation of alpha-dystroglycan is required for laminin binding.</strong> Science 327: 88-92, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20044576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20044576</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20044576[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/10.1126/science.1180512" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20044576">Yoshida-Moriguchi et al. (2010)</a> identified a phosphorylated O-mannosyl glycan on the mucin-like domain of recombinant alpha-DG, which was required for laminin binding. <a href="#39" class="mim-tip-reference" title="Yoshida-Moriguchi, T., Yu, L., Stalnaker, S. H., Davis, S., Kunz, S., Madson, M., Oldstone, M. B. A., Schachter, H., Wells, L., Campbell, K. P. <strong>O-Mannosyl phosphorylation of alpha-dystroglycan is required for laminin binding.</strong> Science 327: 88-92, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20044576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20044576</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20044576[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/10.1126/science.1180512" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20044576">Yoshida-Moriguchi et al. (2010)</a> demonstrated that patients with muscle-eye-brain disease (MDDGA3; <a href="/entry/253280">253280</a>) and Fukuyama congenital muscular dystrophy (MDDGA4; <a href="/entry/253800">253800</a>), as well as mice with myodystrophy, commonly have defects in a postphosphoryl modification of this phosphorylated O-linked mannose, and that this modification is mediated by the LARGE protein. <a href="#39" class="mim-tip-reference" title="Yoshida-Moriguchi, T., Yu, L., Stalnaker, S. H., Davis, S., Kunz, S., Madson, M., Oldstone, M. B. A., Schachter, H., Wells, L., Campbell, K. P. <strong>O-Mannosyl phosphorylation of alpha-dystroglycan is required for laminin binding.</strong> Science 327: 88-92, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20044576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20044576</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20044576[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/10.1126/science.1180512" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20044576">Yoshida-Moriguchi et al. (2010)</a> concluded that their findings expand knowledge of the mechanisms that underlie congenital muscular dystrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20044576" 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>Muscular Dystrophy-Dystroglycanopathy (Limb-Girdle), Type C9</em></strong></p><p>
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In a Turkish woman with limb-girdle muscular dystrophy-dystroglycanopathy type C9 (MDDGC9; <a href="/entry/613818">613818</a>) and severe cognitive impairment, also symbolized LGMDR16 and LGMD2P, reported by <a href="#6" class="mim-tip-reference" title="Dincer, P., Balci, B., Yuva, Y., Talim, B., Brockington, M., Dincel, D., Torelli, S., Brown, S., Kale, G., Haliloglu, G., Gerceker, F. O., Atalay, R. C., Yakicier, C., Longman, C., Muntoni, F., Topaloglu, H. <strong>A novel form of recessive limb girdle muscular dystrophy with mental retardation and abnormal expression of alpha-dystroglycan.</strong> Neuromusc. Disord. 13: 771-778, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14678799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14678799</a>] [<a href="https://doi.org/10.1016/s0960-8966(03)00161-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14678799">Dincer et al. (2003)</a>, <a href="#13" class="mim-tip-reference" title="Hara, Y., Balci-Hayta, B., Yoshida-Moriguchi, T., Kanagawa, M., Beltran-Valero de Bernabe, D., Gundesli, H., Willer, T., Satz, J. S., Crawford, R. W., Burden, S. J., Kunz, S., Oldstone, M. B. A., Accardi, A., Talim, B., Muntoni, F., Topaloglu, H., Dincer, P., Campbell, K. P. <strong>A dystroglycan mutation associated with limb-girdle muscular dystrophy.</strong> New Eng. J. Med. 364: 939-946, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21388311/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21388311</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21388311[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/10.1056/NEJMoa1006939" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21388311">Hara et al. (2011)</a> identified a homozygous mutation in the DAG1 gene (T192M; <a href="#0001">128239.0001</a>). Functional expression analysis in vitro and in mice indicated that the mutation decreased LARGE (<a href="/entry/603590">603590</a>)-mediated posttranslational O-mannosyl glycosylation of DAG1, interfering with its receptor function and laminin binding in skeletal muscle and brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21388311+14678799" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 7-year-old Japanese boy with a very mild form of MDDGC9 presenting only as asymptomatic increased serum creatine kinase, <a href="#7" class="mim-tip-reference" title="Dong, M., Noguchi, S., Endo, Y., Hayashi, Y. K., Yoshida, S., Nonaka, I., Nishino, I. <strong>DAG1 mutations associated with asymptomatic hyperCKemia and hypoglycosylation of alpha-dystroglycan.</strong> Neurology 84: 273-279, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25503980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25503980</a>] [<a href="https://doi.org/10.1212/WNL.0000000000001162" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25503980">Dong et al. (2015)</a> identified compound heterozygous missense mutations in the DAG1 gene (V74I, <a href="#0002">128239.0002</a> and D111N, <a href="#0003">128239.0003</a>). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were found at a low frequency in the dbSNP, 1000 Genomes Project, and HapMap databases. In vitro functional expression studies indicated that the mutations did not influence expression of dystroglycan, but did cause a defect in posttranslational modification. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25503980" 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>Muscular Dystrophy-Dystroglycanopathy (Congenital with Brain and Eye Anomalies), Type A9</em></strong></p><p>
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In 2 sisters, born of presumably unrelated Libyan parents, with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type A9 (MDDGA9; <a href="/entry/616538">616538</a>), <a href="#10" class="mim-tip-reference" title="Geis, T., Marquard, K., Rodl, T., Reihle, C., Schirmer, S., von Kalle, T., Bornemann, A., Hehr, U., Blankenburg, M. <strong>Homozygous dystroglycan mutation associated with a novel muscle-eye-brain disease-like phenotype with multicystic leucodystrophy.</strong> Neurogenetics 14: 205-213, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24052401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24052401</a>] [<a href="https://doi.org/10.1007/s10048-013-0374-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24052401">Geis et al. (2013)</a> identified a homozygous missense mutation in the DAG1 gene (C669F; <a href="#0004">128239.0004</a>). The mutation was found by whole-exome sequencing and confirmed by direct sequencing. The unaffected mother was heterozygous for the mutation. The cys669 residue, postulated to form a covalent disulfide bond with cys713 of beta-dystroglycan, is important for the structure of beta-dystroglycan and thus most likely also for the function of the alpha- and beta-dystroglycan complex. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24052401" 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 5 female infants from a consanguineous Israeli-Arab family with MDDGA9 resulting in death soon after birth, <a href="#29" class="mim-tip-reference" title="Riemersma, M., Mandel, H., van Beusekom, E., Gazzoli, I., Roscioli, T., Eran, A., Gershoni-Baruch, R., Gershoni, M., Pietrokovski, S., Vissers, L. E., Lefeber, D. J., Willemsen, M. A., Wevers, R. A., van Bokhoven, H. <strong>Absence of alpha- and beta-dystroglycan is associated with Walker-Warburg syndrome.</strong> Neurology 84: 2177-2182, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25934851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25934851</a>] [<a href="https://doi.org/10.1212/WNL.0000000000001615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25934851">Riemersma et al. (2015)</a> identified a homozygous truncating mutation in the DAG1 gene (<a href="#0005">128239.0005</a>). The mutation was found by a combination of homozygosity mapping and whole-exome sequencing. Patient fibroblasts that were transformed to myoblasts showed no detectable properly glycosylated alpha-dystroglycan and no detectable alpha- or beta-dystroglycan protein, consistent with complete absence of both protein isoforms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25934851" 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="#35" class="mim-tip-reference" title="Williamson, R. A., Henry, M. D., Daniels, K. J., Hrstka, R. F., Lee, J. C., Sunada, Y., Ibraghimov-Beskrovnaya, O., Campbell, K. P. <strong>Dystroglycan is essential for early embryonic development: disruption of Reichert's membrane in Dag1-null mice.</strong> Hum. Molec. Genet. 6: 831-841, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9175728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9175728</a>] [<a href="https://doi.org/10.1093/hmg/6.6.831" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9175728">Williamson et al. (1997)</a> found that heterozygous Dag1-null mice were viable and fertile. In contrast, homozygous embryos exhibited gross developmental abnormalities beginning around 6.5 days' gestation. They found that an early defect in the development of homozygous embryos was a disruption of the Reichert membrane, an extra-embryonic basement membrane. Consistent with the functional defects observed in Reichert membrane, dystroglycan protein was localized in apposition to this structure in normal egg cylinder-stage embryos. They also showed that the localization of 2 critical structural elements of Reichert membrane, laminin and collagen IV, were specifically disrupted in the homozygous Dag1 embryos. The data indicated that dystroglycan is required for the development of Reichert membrane and that disruption of basement membrane organization is a common feature of muscular dystrophies linked to the dystrophin-glycoprotein complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9175728" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Henry, M. D., Campbell, K. P. <strong>A role for dystroglycan in basement membrane assembly.</strong> Cell 95: 859-970, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9865703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9865703</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81708-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9865703">Henry and Campbell (1998)</a> found that Dag1-null murine embryonic stem cells had defective formation of basement membranes in embryoid bodies. These results further indicated that dystroglycan-laminin interactions are prerequisites for the deposition of other basement membrane proteins. Dystroglycan may exert its influence on basement membrane assembly by binding soluble laminin and organizing it on the cell surface. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9865703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Cote, P. D., Moukhles, H., Lindenbaum, M., Carbonetto, S. <strong>Chimaeric mice deficient in dystroglycans develop muscular dystrophy and have disrupted myoneural synapses.</strong> Nature Genet. 23: 338-342, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10610181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10610181</a>] [<a href="https://doi.org/10.1038/15519" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10610181">Cote et al. (1999)</a> reported that chimeric mice generated with ES cells targeted for both dystroglycan alleles have skeletal muscles essentially devoid of dystroglycans and develop a progressive muscle pathology with changes emblematic of muscular dystrophies in humans. In addition, many neuromuscular junctions are disrupted in these mice. The ultrastructure of basement membranes and the deposition of laminin within them, however, appears unaffected in dystroglycan-deficient muscles. <a href="#5" class="mim-tip-reference" title="Cote, P. D., Moukhles, H., Lindenbaum, M., Carbonetto, S. <strong>Chimaeric mice deficient in dystroglycans develop muscular dystrophy and have disrupted myoneural synapses.</strong> Nature Genet. 23: 338-342, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10610181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10610181</a>] [<a href="https://doi.org/10.1038/15519" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10610181">Cote et al. (1999)</a> concluded that dystroglycans are necessary for myofiber survival and synapse differentiation or stability, but not for the formation of the muscle basement membrane, and that dystroglycans may have more than a purely structural function in maintaining muscle integrity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10610181" 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="#26" class="mim-tip-reference" title="Moore, S. A., Saito, F., Chen, J., Michele, D. E., Henry, M. D., Messing, A., Cohn, R. D., Ross-Barta, S. E., Westra, S., Williamson, R. A., Hoshi, T., Campbell, K. P. <strong>Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy.</strong> Nature 418: 422-425, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12140559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12140559</a>] [<a href="https://doi.org/10.1038/nature00838" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12140559">Moore et al. (2002)</a> showed that brain-selective deletion of dystroglycan in mice is sufficient to cause congenital muscular dystrophy-like brain malformations, including disarray of cerebral cortical layering, fusion of cerebral hemispheres and cerebellar folia, and aberrant migration of granule cells. Dystroglycan-null brain loses its high affinity binding to the extracellular matrix protein laminin (see <a href="/entry/150240">150240</a>) and shows discontinuities in the pial surface basal lamina (glia limitans) that probably underlie the neuronal migration errors. Furthermore, mutant mice have severely blunted hippocampal long-term potentiation with electrophysiologic characterization, indicating that dystroglycan might have a postsynaptic role in learning and memory. <a href="#26" class="mim-tip-reference" title="Moore, S. A., Saito, F., Chen, J., Michele, D. E., Henry, M. D., Messing, A., Cohn, R. D., Ross-Barta, S. E., Westra, S., Williamson, R. A., Hoshi, T., Campbell, K. P. <strong>Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy.</strong> Nature 418: 422-425, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12140559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12140559</a>] [<a href="https://doi.org/10.1038/nature00838" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12140559">Moore et al. (2002)</a> concluded that these data strongly supported the hypothesis that defects in dystroglycan are central to the pathogenesis of structural and functional brain abnormalities seen in congenital muscular dystrophies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12140559" 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="Michele, D. E., Barresi, R., Kanagawa, M., Saito, F., Cohn, R. D., Satz, J. S., Dollar, J., Nishino, I., Kelley, R. I., Somer, H., Straub, V., Mathews, K. D., Moore, S. A., Campbell, K. P. <strong>Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies.</strong> Nature 418: 417-422, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12140558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12140558</a>] [<a href="https://doi.org/10.1038/nature00837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12140558">Michele et al. (2002)</a> demonstrated in both muscle-eye-brain disease (MDDGA3; <a href="/entry/253280">253280</a>) and Fukuyama congenital muscular dystrophy (MDDGA4; <a href="/entry/253800">253800</a>) patients that alpha-dystroglycan is expressed at the muscle membrane, but similar hypoglycosylation in the diseases directly abolishes binding activity of dystroglycan for the ligands laminin, neurexin (see <a href="/entry/600565">600565</a>), and agrin (<a href="/entry/103320">103320</a>). <a href="#25" class="mim-tip-reference" title="Michele, D. E., Barresi, R., Kanagawa, M., Saito, F., Cohn, R. D., Satz, J. S., Dollar, J., Nishino, I., Kelley, R. I., Somer, H., Straub, V., Mathews, K. D., Moore, S. A., Campbell, K. P. <strong>Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies.</strong> Nature 418: 417-422, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12140558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12140558</a>] [<a href="https://doi.org/10.1038/nature00837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12140558">Michele et al. (2002)</a> showed that this posttranslational biochemical and functional disruption of alpha-dystroglycan is recapitulated in the muscle and central nervous system of mutant myodystrophy (myd) mice, who have a mutation in the LARGE gene. <a href="#25" class="mim-tip-reference" title="Michele, D. E., Barresi, R., Kanagawa, M., Saito, F., Cohn, R. D., Satz, J. S., Dollar, J., Nishino, I., Kelley, R. I., Somer, H., Straub, V., Mathews, K. D., Moore, S. A., Campbell, K. P. <strong>Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies.</strong> Nature 418: 417-422, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12140558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12140558</a>] [<a href="https://doi.org/10.1038/nature00837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12140558">Michele et al. (2002)</a> demonstrated that myd mice have abnormal neuronal migration in the cerebral cortex, cerebellum, and hippocampus, and show disruption of the basal lamina. In addition, myd mice reveal that dystroglycan targets proteins to functional sites in brain through its interactions with extracellular matrix proteins. <a href="#25" class="mim-tip-reference" title="Michele, D. E., Barresi, R., Kanagawa, M., Saito, F., Cohn, R. D., Satz, J. S., Dollar, J., Nishino, I., Kelley, R. I., Somer, H., Straub, V., Mathews, K. D., Moore, S. A., Campbell, K. P. <strong>Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies.</strong> Nature 418: 417-422, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12140558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12140558</a>] [<a href="https://doi.org/10.1038/nature00837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12140558">Michele et al. (2002)</a> suggested that at least 3 mammalian genes function within a convergent posttranslational processing pathway during the biosynthesis of dystroglycan and that abnormal dystroglycan-ligand interactions underlie the pathogenic mechanism of muscular dystrophy with brain abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12140558" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Cohn, R. D., Henry, M. D., Michele, D. E., Barresi, R., Saito, F., Moore, S. A., Flanagan, J. D., Skwarchuk, M. W., Robbins, M. E., Mendell, J. R., Williamson, R. A., Campbell, K. P. <strong>Disruption of Dag1 in differentiated skeletal muscle reveals a role for dystroglycan in muscle regeneration.</strong> Cell 110: 639-648, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12230980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12230980</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)00907-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12230980">Cohn et al. (2002)</a> found that striated muscle-specific disruption of the Dag1 gene in mice resulted in loss of the dystrophin-glycoprotein complex in differentiated muscle and a remarkably mild muscular dystrophy with hypertrophy and without tissue fibrosis. They found that satellite cells, expressing dystroglycan, supported continued efficient regeneration of skeletal muscle along with transient expression of dystroglycan in regenerating muscle fibers. <a href="#4" class="mim-tip-reference" title="Cohn, R. D., Henry, M. D., Michele, D. E., Barresi, R., Saito, F., Moore, S. A., Flanagan, J. D., Skwarchuk, M. W., Robbins, M. E., Mendell, J. R., Williamson, R. A., Campbell, K. P. <strong>Disruption of Dag1 in differentiated skeletal muscle reveals a role for dystroglycan in muscle regeneration.</strong> Cell 110: 639-648, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12230980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12230980</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)00907-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12230980">Cohn et al. (2002)</a> demonstrated a similar phenomenon of reexpression of functional dystroglycan in regenerating muscle fibers in a mild form of human muscular dystrophy caused by disruption of posttranslational dystroglycan processing. They concluded that maintenance of regenerative capacity by satellite cells expressing dystroglycan is likely responsible for mild disease progression in mice and possibly humans. <a href="#4" class="mim-tip-reference" title="Cohn, R. D., Henry, M. D., Michele, D. E., Barresi, R., Saito, F., Moore, S. A., Flanagan, J. D., Skwarchuk, M. W., Robbins, M. E., Mendell, J. R., Williamson, R. A., Campbell, K. P. <strong>Disruption of Dag1 in differentiated skeletal muscle reveals a role for dystroglycan in muscle regeneration.</strong> Cell 110: 639-648, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12230980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12230980</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)00907-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12230980">Cohn et al. (2002)</a> suggested that inadequate repair of skeletal muscle by satellite cells represents an important mechanism affecting the pathogenesis of muscular dystrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12230980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Hara, Y., Balci-Hayta, B., Yoshida-Moriguchi, T., Kanagawa, M., Beltran-Valero de Bernabe, D., Gundesli, H., Willer, T., Satz, J. S., Crawford, R. W., Burden, S. J., Kunz, S., Oldstone, M. B. A., Accardi, A., Talim, B., Muntoni, F., Topaloglu, H., Dincer, P., Campbell, K. P. <strong>A dystroglycan mutation associated with limb-girdle muscular dystrophy.</strong> New Eng. J. Med. 364: 939-946, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21388311/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21388311</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21388311[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/10.1056/NEJMoa1006939" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21388311">Hara et al. (2011)</a> demonstrated that mice with a homozygous T190M mutation in the Dag1 gene, which corresponds to the human T192M mutation (<a href="#0001">128239.0001</a>), developed muscular dystrophy and neurologic motor impairment. The mutation decreased LARGE (<a href="/entry/603590">603590</a>)-mediated posttranslational O-mannosyl glycosylation of Dag1, interfering with its receptor function and laminin binding in skeletal muscle and brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21388311" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=128239[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 9</strong>
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DAG1, THR192MET (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs193922955;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs193922955</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs193922955 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs193922955;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=rs193922955" 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=rs193922955" 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=RCV000022532 OR RCV000024453 OR RCV001044548" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022532, RCV000024453, RCV001044548" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022532...</a>
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<p>In a Turkish woman with limb-girdle muscular dystrophy-dystroglycanopathy (MDDGC9; <a href="/entry/613818">613818</a>) and cognitive impairment, who was previously reported by <a href="#6" class="mim-tip-reference" title="Dincer, P., Balci, B., Yuva, Y., Talim, B., Brockington, M., Dincel, D., Torelli, S., Brown, S., Kale, G., Haliloglu, G., Gerceker, F. O., Atalay, R. C., Yakicier, C., Longman, C., Muntoni, F., Topaloglu, H. <strong>A novel form of recessive limb girdle muscular dystrophy with mental retardation and abnormal expression of alpha-dystroglycan.</strong> Neuromusc. Disord. 13: 771-778, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14678799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14678799</a>] [<a href="https://doi.org/10.1016/s0960-8966(03)00161-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14678799">Dincer et al. (2003)</a>, <a href="#13" class="mim-tip-reference" title="Hara, Y., Balci-Hayta, B., Yoshida-Moriguchi, T., Kanagawa, M., Beltran-Valero de Bernabe, D., Gundesli, H., Willer, T., Satz, J. S., Crawford, R. W., Burden, S. J., Kunz, S., Oldstone, M. B. A., Accardi, A., Talim, B., Muntoni, F., Topaloglu, H., Dincer, P., Campbell, K. P. <strong>A dystroglycan mutation associated with limb-girdle muscular dystrophy.</strong> New Eng. J. Med. 364: 939-946, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21388311/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21388311</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21388311[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/10.1056/NEJMoa1006939" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21388311">Hara et al. (2011)</a> identified a homozygous 575C-T transition in the DAG1 gene, resulting in a thr192-to-met (T192M) substitution in a highly conserved residue in the N terminus of the protein. Each unaffected parent was heterozygous for the mutation, which was not found in 200 control chromosomes. Functional expression analysis in vitro and in mice indicated that the mutation decreased LARGE (<a href="/entry/603590">603590</a>)-mediated posttranslational O-mannosyl glycosylation of DAG1, interfering with its receptor function and laminin binding in skeletal muscle and brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21388311+14678799" 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 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 9</strong>
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DAG1, VAL74ILE (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs189360006;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs189360006</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs189360006 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs189360006;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/rs189360006?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=rs189360006" 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=rs189360006" 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=RCV000190545 OR RCV001857671 OR RCV003144154" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000190545, RCV001857671, RCV003144154" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000190545...</a>
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<p>In a 7-year-old Japanese boy with a very mild form of limb-girdle muscular dystrophy-dystroglycanopathy type C9 (MDDGC9; <a href="/entry/613818">613818</a>) presenting only as asymptomatic increased serum creatine kinase, <a href="#7" class="mim-tip-reference" title="Dong, M., Noguchi, S., Endo, Y., Hayashi, Y. K., Yoshida, S., Nonaka, I., Nishino, I. <strong>DAG1 mutations associated with asymptomatic hyperCKemia and hypoglycosylation of alpha-dystroglycan.</strong> Neurology 84: 273-279, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25503980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25503980</a>] [<a href="https://doi.org/10.1212/WNL.0000000000001162" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25503980">Dong et al. (2015)</a> identified compound heterozygous mutations in the DAG1 gene: a c.220G-A transition, resulting in a val74-to-ile (V74I) substitution, and a c.331G-A transition, resulting in an asp111-to-asn (D111N; <a href="#0003">128239.0003</a>) substitution. Both mutations occurred at highly conserved residues in the N terminal domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were annotated in the dbSNP, 1000 Genomes Project, and HapMap databases: c.331G-A has a frequency of 0.005 in all populations in the 1000 Genomes Project database and a higher frequency (0.028) in the Japanese population in the Human Genetic Variation Database. Patient skeletal muscle biopsy stained negatively with an antibody for the glycoepitope of DAG1, and Western blot analysis showed decreased glycosylation of alpha-dystroglycan compared to controls. Transfection of either mutation into DAG1-null cells did not restore alpha-dystroglycan immunoreactivity. Beta-dystroglycan was unaffected, indicating that the mutations did not influence expression of dystroglycan, but did cause a defect in posttranslational modification. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25503980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 9</strong>
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DAG1, ASP111ASN (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs117209107;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs117209107</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs117209107 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs117209107;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/rs117209107?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=rs117209107" 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=rs117209107" 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=RCV000190546 OR RCV000335532 OR RCV000556875 OR RCV001723761 OR RCV003907668" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000190546, RCV000335532, RCV000556875, RCV001723761, RCV003907668" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000190546...</a>
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<p>For discussion of the asp111-to-asn (D111N) mutation in the DAG1 gene that was found in compound heterozygous state in a patient with a very mild form of limb-girdle muscular dystrophy-dystroglycanopathy type C9 (MDDGC9; <a href="/entry/613818">613818</a>) by <a href="#7" class="mim-tip-reference" title="Dong, M., Noguchi, S., Endo, Y., Hayashi, Y. K., Yoshida, S., Nonaka, I., Nishino, I. <strong>DAG1 mutations associated with asymptomatic hyperCKemia and hypoglycosylation of alpha-dystroglycan.</strong> Neurology 84: 273-279, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25503980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25503980</a>] [<a href="https://doi.org/10.1212/WNL.0000000000001162" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25503980">Dong et al. (2015)</a>, see <a href="#0002">128239.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25503980" 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 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 9</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">rs797045023 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797045023;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=rs797045023" 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=rs797045023" 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=RCV000190547 OR RCV001224389 OR RCV001781562" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000190547, RCV001224389, RCV001781562" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000190547...</a>
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<p>In 2 sisters, born of presumably unrelated Libyan parents, with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type A9 (MDDGA9; <a href="/entry/616538">616538</a>), <a href="#10" class="mim-tip-reference" title="Geis, T., Marquard, K., Rodl, T., Reihle, C., Schirmer, S., von Kalle, T., Bornemann, A., Hehr, U., Blankenburg, M. <strong>Homozygous dystroglycan mutation associated with a novel muscle-eye-brain disease-like phenotype with multicystic leucodystrophy.</strong> Neurogenetics 14: 205-213, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24052401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24052401</a>] [<a href="https://doi.org/10.1007/s10048-013-0374-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24052401">Geis et al. (2013)</a> identified a homozygous c.2006G-T transversion in exon 2 of the DAG1 gene (c.2006G-T, NM_004393.4), resulting in a cys669-to-phe (C669F) substitution at a highly conserved residue in the extracellular portion of the beta-dystroglycan domain. The mutation, which was found by whole-exome sequencing and confirmed by direct sequencing, was not found in publicly available databases, including dbSNP, or in 52 control individuals. The unaffected mother was heterozygous for the mutation. The cys669 residue is postulated to form a covalent disulfide bond with cys713 of beta-dystroglycan and is important for the structure of beta-dystroglycan. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24052401" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 9</strong>
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DAG1, 1-BP DEL, 743C
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs869320680 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869320680;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=rs869320680" 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=rs869320680" 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=RCV000190548" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000190548" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000190548</a>
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<p>In 5 female infants from a consanguineous Israeli-Arab family with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type A9 (MDDGA9; <a href="/entry/616538">616538</a>) resulting in death soon after birth, <a href="#29" class="mim-tip-reference" title="Riemersma, M., Mandel, H., van Beusekom, E., Gazzoli, I., Roscioli, T., Eran, A., Gershoni-Baruch, R., Gershoni, M., Pietrokovski, S., Vissers, L. E., Lefeber, D. J., Willemsen, M. A., Wevers, R. A., van Bokhoven, H. <strong>Absence of alpha- and beta-dystroglycan is associated with Walker-Warburg syndrome.</strong> Neurology 84: 2177-2182, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25934851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25934851</a>] [<a href="https://doi.org/10.1212/WNL.0000000000001615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25934851">Riemersma et al. (2015)</a> identified a homozygous 1-bp deletion (c.743delC, NM_004393.4) in exon 3 of the DAG1 gene, resulting in a frameshift and premature termination (Ala248GlufsTer19). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was filtered against the dbSNP (build 132) database and an in-house database of 1,142 exomes. Analysis of patient cells showed the presence of the mutant transcript, indicating that it is not completely degraded by nonsense-mediated mRNA decay. Patient fibroblasts that were transformed to myoblasts showed no detectable properly glycosylated alpha-dystroglycan and no detectable alpha- or beta-dystroglycan protein, consistent with complete absence of both protein isoforms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25934851" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Arahata1993" class="mim-anchor"></a>
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Arahata, K., Hayashi, Y. K., Mizuno, Y., Yoshida, M., Ozawa, E.
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[<a href="https://doi.org/10.1016/0140-6736(93)91454-t" target="_blank">Full Text</a>]
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Campanelli, J. T., Roberds, S. L., Campbell, K. P., Scheller, R. H.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8205616/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8205616</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8205616" 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/10.1016/0092-8674(94)90051-5" target="_blank">Full Text</a>]
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Cao, W., Henry, M. D., Borrow, P., Yamada, H., Elder, J. H., Ravkov, E. V., Nichol, S. T., Compans, R. W., Campbell, K. P., Oldstone, M. B. A.
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<strong>Identification of alpha-dystroglycan as a receptor for lymphocytic choriomeningitis virus and Lassa fever virus.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9851928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9851928</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9851928" 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/10.1126/science.282.5396.2079" target="_blank">Full Text</a>]
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Cohn, R. D., Henry, M. D., Michele, D. E., Barresi, R., Saito, F., Moore, S. A., Flanagan, J. D., Skwarchuk, M. W., Robbins, M. E., Mendell, J. R., Williamson, R. A., Campbell, K. P.
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<strong>Disruption of Dag1 in differentiated skeletal muscle reveals a role for dystroglycan in muscle regeneration.</strong>
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Cell 110: 639-648, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12230980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12230980</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12230980" 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/s0092-8674(02)00907-8" target="_blank">Full Text</a>]
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Cote, P. D., Moukhles, H., Lindenbaum, M., Carbonetto, S.
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<strong>Chimaeric mice deficient in dystroglycans develop muscular dystrophy and have disrupted myoneural synapses.</strong>
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Nature Genet. 23: 338-342, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10610181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10610181</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10610181" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/15519" target="_blank">Full Text</a>]
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Dincer, P., Balci, B., Yuva, Y., Talim, B., Brockington, M., Dincel, D., Torelli, S., Brown, S., Kale, G., Haliloglu, G., Gerceker, F. O., Atalay, R. C., Yakicier, C., Longman, C., Muntoni, F., Topaloglu, H.
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<strong>A novel form of recessive limb girdle muscular dystrophy with mental retardation and abnormal expression of alpha-dystroglycan.</strong>
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Neuromusc. Disord. 13: 771-778, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14678799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14678799</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14678799" 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/s0960-8966(03)00161-5" target="_blank">Full Text</a>]
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Dong, M., Noguchi, S., Endo, Y., Hayashi, Y. K., Yoshida, S., Nonaka, I., Nishino, I.
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<strong>DAG1 mutations associated with asymptomatic hyperCKemia and hypoglycosylation of alpha-dystroglycan.</strong>
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Neurology 84: 273-279, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25503980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25503980</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25503980" 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/10.1212/WNL.0000000000001162" target="_blank">Full Text</a>]
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Esapa, C. T., Benson, M. A., Schroder, J. E., Martin-Rendon, E., Brockington, M., Brown, S. C., Muntoni, F., Kroger, S., Blake, D. J.
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<strong>Functional requirements for fukutin-related protein in the Golgi apparatus.</strong>
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Hum. Molec. Genet. 11: 3319-3331, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12471058/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12471058</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12471058" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/11.26.3319" target="_blank">Full Text</a>]
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Gee, S. H., Montanaro, F., Lindenbaum, M. H., Carbonetto, S.
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<strong>Dystroglycan-alpha, a dystrophin-associated glycoprotein, is a functional agrin receptor.</strong>
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Cell 77: 675-686, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8205617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8205617</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8205617" 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/10.1016/0092-8674(94)90052-3" target="_blank">Full Text</a>]
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Geis, T., Marquard, K., Rodl, T., Reihle, C., Schirmer, S., von Kalle, T., Bornemann, A., Hehr, U., Blankenburg, M.
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<strong>Homozygous dystroglycan mutation associated with a novel muscle-eye-brain disease-like phenotype with multicystic leucodystrophy.</strong>
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Neurogenetics 14: 205-213, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24052401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24052401</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24052401" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s10048-013-0374-9" target="_blank">Full Text</a>]
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Godfrey, C., Clement, E., Mein, R., Brockington, M., Smith, J., Talim, B., Straub, V., Robb, S., Quinlivan, R., Feng, L., Jimenez-Mallebrer a, C., Mercuri, E., and 10 others.
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<strong>Refining genotype-phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan.</strong>
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Brain 130: 2725-2735, 2007.
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[<a href="https://doi.org/10.1038/nature22979" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.91.18.8307" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/6.6.831" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.neuron.2012.10.009" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.271.38.23418" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20044576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20044576</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20044576[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20044576" 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/10.1126/science.1180512" target="_blank">Full Text</a>]
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Matthew B. Gross - updated : 01/25/2022
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Ada Hamosh - updated : 01/26/2018<br>Jane A. Welch - updated : 09/20/2017<br>Cassandra L. Kniffin - updated : 8/31/2015<br>Ada Hamosh - updated : 8/6/2014<br>Patricia A. Hartz - updated : 8/1/2013<br>Cassandra L. Kniffin - updated : 1/29/2013<br>Cassandra L. Kniffin - updated : 3/21/2011<br>Cassandra L. Kniffin - updated : 11/15/2010<br>Ada Hamosh - updated : 1/26/2010<br>George E. Tiller - updated : 1/16/2007<br>George E. Tiller - updated : 9/13/2004<br>Stylianos E. Antonarakis - updated : 8/4/2004<br>Cassandra L. Kniffin - updated : 10/15/2002<br>Stylianos E. Antonarakis - updated : 9/13/2002<br>Ada Hamosh - updated : 9/13/2002<br>Ada Hamosh - updated : 9/11/2002<br>George E. Tiller - updated : 12/17/2001<br>Ada Hamosh - updated : 11/1/1999<br>Stylianos E. Antonarakis - updated : 12/22/1998<br>Victor A. McKusick - updated : 12/9/1998<br>Victor A. McKusick - updated : 6/23/1997<br>Mark H. Paalman - updated : 10/14/1996
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Victor A. McKusick : 9/27/1994
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mgross : 01/25/2022<br>mgross : 01/25/2022<br>carol : 12/14/2020<br>carol : 10/01/2018<br>carol : 09/25/2018<br>alopez : 01/26/2018<br>mgross : 09/20/2017<br>carol : 05/09/2017<br>alopez : 09/04/2015<br>alopez : 9/4/2015<br>ckniffin : 8/31/2015<br>carol : 10/20/2014<br>mcolton : 10/16/2014<br>alopez : 8/6/2014<br>alopez : 8/1/2013<br>ckniffin : 7/31/2013<br>carol : 1/30/2013<br>ckniffin : 1/29/2013<br>terry : 9/28/2011<br>carol : 3/21/2011<br>ckniffin : 3/21/2011<br>ckniffin : 11/15/2010<br>alopez : 2/1/2010<br>terry : 1/26/2010<br>ckniffin : 5/29/2008<br>wwang : 11/26/2007<br>wwang : 1/22/2007<br>terry : 1/16/2007<br>tkritzer : 9/20/2004<br>tkritzer : 9/13/2004<br>mgross : 8/4/2004<br>carol : 10/18/2002<br>carol : 10/18/2002<br>ckniffin : 10/15/2002<br>mgross : 9/13/2002<br>alopez : 9/13/2002<br>carol : 9/11/2002<br>alopez : 3/13/2002<br>alopez : 3/13/2002<br>cwells : 12/28/2001<br>cwells : 12/17/2001<br>alopez : 11/3/1999<br>terry : 11/1/1999<br>psherman : 9/2/1999<br>terry : 4/30/1999<br>carol : 4/16/1999<br>mgross : 3/17/1999<br>carol : 12/22/1998<br>alopez : 12/10/1998<br>terry : 12/9/1998<br>terry : 8/13/1998<br>jenny : 6/23/1997<br>terry : 6/19/1997<br>mark : 10/15/1996<br>terry : 10/14/1996<br>mark : 10/14/1996<br>terry : 11/16/1994<br>carol : 9/27/1994
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<span class="mim-font">
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<strong>*</strong> 128239
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</h3>
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<h3>
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<span class="mim-font">
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DYSTROGLYCAN 1; DAG1
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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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DYSTROPHIN-ASSOCIATED GLYCOPROTEIN 1<br />
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DAG
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</h4>
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Other entities represented in this entry:
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<span class="h3 mim-font">
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DYSTROGLYCAN, ALPHA, INCLUDED
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<span class="h4 mim-font">
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DYSTROGLYCAN, BETA, INCLUDED<br />
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AGRIN RECEPTOR, INCLUDED; AGRNR, INCLUDED
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: DAG1</em></strong>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 726614009;
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Cytogenetic location: 3p21.31
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Genomic coordinates <span class="small">(GRCh38)</span> : 3:49,468,948-49,535,615 </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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<strong>Gene-Phenotype Relationships</strong>
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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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Phenotype <br /> mapping key
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<span class="mim-font">
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3p21.31
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Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 9
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<span class="mim-font">
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616538
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Autosomal recessive
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<span class="mim-font">
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3
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Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 9
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<span class="mim-font">
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613818
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<span class="mim-font">
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Autosomal recessive
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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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<strong>TEXT</strong>
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<span class="mim-font">
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<strong>Description</strong>
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<p>Dystroglycan is a high-affinity receptor for several extracellular matrix components, including laminin (see 150320) and perlecan (HSPG2; 142461). The alpha and beta subunits of dystroglycan arise from posttranslational cleavage of a single dystroglycan propeptide encoded by the DAG1 gene. Alpha-dystroglycan is a peripheral membrane protein that interacts with laminin in the basal lamina and beta-dystroglycan. Beta-dystroglycan crosses the membrane bilayer, associates with dystrophin (DMD; 300377), and is thereby connected to the alpha cytoskeleton. Dystroglycan is also a component of the dystrophin-glycoprotein complex (DGC), which stabilizes muscle fiber sarcolemma against contraction forces by linking the extracellular matrix and actin cytoskeleton (summary by Holt et al., 2000). </p>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</h4>
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<span class="mim-text-font">
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<p>Ibraghimov-Beskrovnaya et al. (1992) demonstrated that the transmembrane 43-kD and extracellular 156-kD DAG proteins are encoded by a single 5.8-kb mRNA in rabbit. The deduced 895-residue precursor protein has a molecular mass of 96 kD and undergoes posttranslational processing to generate a 43-kD transmembrane protein and a 156-kD extracellular protein. </p><p>Ibraghimov-Beskrovnaya et al. (1993) cloned full-length human DAG1 from a skeletal muscle cDNA library. The predicted 895-amino acid human protein shares 93% amino acid identity with the rabbit protein, with conservation of predicted glycosylation sites. Like the rabbit protein, the 97-kD human precursor protein is posttranslationally processed into 156-kD alpha-dystroglycan and 43-kD beta-dystroglycan. Northern blot analysis detected a 5.8-kb DAG1 transcript in all adult and fetal human tissues examined, with highest expression in skeletal muscle and heart and lower expression in nonmuscle tissues. Further analysis suggested that the muscle and nonmuscle isoforms of dystroglycan differ by carbohydrate moieties, but not by protein sequence. </p>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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<span class="mim-text-font">
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<p>Ibraghimov-Beskrovnaya et al. (1993) determined that the DAG1 gene contains 2 coding exons separated by a large intron. </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p>Ibraghimov-Beskrovnaya et al. (1992, 1993) mapped the DAG1 gene to chromosome 3 by Southern blot analysis of human/Chinese hamster somatic cell hybrid DNAs. The regional assignment to 3p21 was confirmed and further refined by fluorescence in situ hybridization. </p><p>Gorecki et al. (1994) demonstrated that the Dag1 gene is located on mouse chromosome 9 in a region of conserved synteny with human 3p. The location was consistent with a possibility that dystroglycan mutations are involved in either of 2 mouse neurologic mutations, 'ducky' (du) or 'tippy' (tip). </p>
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<span class="mim-font">
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<strong>Gene Function</strong>
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<span class="mim-text-font">
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<p>Ibraghimov-Beskrovnaya et al. (1992) demonstrated that the extracellular 156-kD DAG binds laminin, and thus may provide linkage between the sarcolemma and extracellular matrix. </p><p>Using a heterologous mammalian expression system, Holt et al. (2000) confirmed processing of the rabbit Dag1 precursor propeptide into alpha- and beta-dystroglycan. The precursor propeptide was glycosylated, but blockade of N-linked glycosylation did not prevent cleavage into alpha- and beta-dystroglycan. However, inhibition of N-linked glycosylation resulted in aberrant trafficking of alpha- and beta-dystroglycan to the plasma membrane. </p><p>Agrin (103320) is a component of the synaptic basal lamina that induces the aggregation of acetylcholine receptors and other elements of the postsynaptic membrane. Ma et al. (1993) determined the localization, binding characteristics, and biochemical profile of agrin receptor in Torpedo electric organ membranes and defined domains of agrin that bind this receptor. Campanelli et al. (1994) and Gee et al. (1994) presented evidence that the alpha-dystrophin-associated glycoprotein functions as an agrin receptor. Utrophin (128240) colocalizes with agrin-induced acetylcholine receptor clusters. Agrin may function by initiating or stabilizing a synapse-specific membrane cytoskeleton that in turn serves as a scaffold upon which synaptic molecules are concentrated. Sealock and Froehner (1994) reviewed the evidence that alpha-dystroglycan is an agrin-binding protein and the functional implications of this. </p><p>Yamada et al. (1996) showed that dystroglycan is a dual receptor for agrin and laminin-2 in the Schwann cell membrane. Laminin-2 is composed of the alpha-2 (LAMA2; 156225), beta-1 (LAMB1; 150240), and gamma-1 (LAMC1; 150290) laminin chains. </p><p>Rambukkana et al. (1998) showed that alpha-DG serves as a Schwann cell receptor for Mycobacterium leprae, the causative organism of leprosy. They found that M. leprae specifically binds to alpha-DG only in the presence of the G domain of the alpha-2 chain of laminin-2. Native alpha-DG competitively inhibited the laminin-2-mediated M. leprae binding to primary Schwann cells. Thus, M. leprae may use linkage between the extracellular matrix and the cytoskeleton through laminin-2 and alpha-DG for its interaction with Schwann cells. The neuropathy of leprosy is caused, in part, by invasion of peripheral nerves by M. leprae. The Schwann cell is an important target for bacterial invasion. In the endoneurium of peripheral nerves, Schwann cells are covered by basal lamina, composed of laminin, type IV collagen, entactin/nidogen, and heparan sulfate proteoglycans. Similarly, Cao et al. (1998) found that alpha-DG serves as a receptor for lymphocytic choriomeningitis virus (LCMV) and for Lassa fever virus (LFV). They purified a peripheral membrane protein that interacts with LCMV from cells permissive to infection by this virus. Tryptic peptides from this protein were determined to be alpha-DG. Several strains of LCMV and other arenaviruses, including LFV, Oliveros, and Mobala, bound to purified alpha-DG protein. Soluble alpha-DG blocked both LCMV and LFV infection. Cells bearing a null mutation of the gene encoding DG were resistant to LCMV infection, and reconstitution of DG expression in null mutant cells restored susceptibility to LCMV infection. Thus, alpha-DG is a cellular receptor for both LCMV and LFV. </p><p>Spence et al. (2004) localized beta-dystroglycan to microvilli structures in a number of cell types where it associated with the cytoskeletal adaptor ezrin (VIL2; 123900), through which it was able to modulate the actin cytoskeleton and induced peripheral filopodia and microvilli. Ezrin was able to interact with dystroglycan through a cluster of basic residues in the juxtamembrane region of dystroglycan, and mutation of these residues both prevented ezrin binding and the induction of actin-rich surface protrusions. </p><p>Wright et al. (2012) found that mouse dystroglycan bound directly to the laminin G domain of the axonal guidance molecule Slit (see SLIT1, 603742) in a calcium-dependent manner. Binding to dystroglycan was required for proper Slit localization within the basement membrane and floor plate, and for development of normal commissural axon guidance tracts. Mutations in mouse Ispd (Crppa; 614631) or B3gnt1 (605517) that disrupted dystroglycan glycosylation resulted in similar abnormalities in axonal pathfinding. </p><p>Lassa virus, which spreads from rodents to humans, can cause lethal hemorrhagic fever. Despite the broad tropism of the virus, chicken cells were reported 30 years ago to resist infection. Jae et al. (2014) found that Lassa virus readily engaged its cell-surface receptor alpha-dystroglycan in avian cells, but virus entry in susceptible species involved a pH-dependent switch to an intracellular receptor, LAMP1 (153330). Iterative haploid screens revealed that ST3GAL4 (104240) was required for the interaction of the virus glycoprotein with LAMP1. A single glycosylated residue in LAMP1, present in susceptible species but absent in birds, was essential for interaction with the Lassa virus envelope protein and subsequent infection. Lamp1-deficient mice had cleared intraperitoneally-injected wildtype Lassa virus 6 days after injection, whereas infection was manifest in all organ samples taken from wildtype or heterozygous animals. </p><p>In mice, Morikawa et al. (2017) demonstrated that Dag1 directly binds to the Hippo pathway effector Yap (606608) to inhibit cardiomyocyte proliferation. The Yap-Dag1 interaction was enhanced by Hippo-induced Yap phosphorylation, revealing a connection between Hippo pathway function and the dystrophin-glycoprotein complex. After injury, Hippo-deficient postnatal mouse hearts maintained organ size control by repairing the defect with correct dimensions, whereas postnatal hearts deficient in both Hippo and the dystrophin-glycoprotein complex showed cardiomyocyte overproliferation at the injury site. In the hearts of mature Mdx mice (which have a point mutation in the Dmd gene , 300377), Hippo deficiency protected against overload-induced heart failure. </p><p><strong><em>Role in Muscular Dystrophy</em></strong></p><p>
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Abnormal glycosylation of DAG1 results in several forms of congenital muscular dystrophy that range phenotypically from severe forms with brain and eye anomalies (see, e.g., MDDGA1; 236670) to milder limb-girdle types (see, e.g., MDDGC1; 609308). Mutations in 6 different genes involved in glycosylation of DAG1 have been identified; these genes include POMT1 (607423), POMT2 (607439), POMGNT1 (606822), FKTN (607440), FKRP (606596), and LARGE (603590). These disorders are collectively known as 'dystroglycanopathies' (Godfrey et al., 2007). </p><p>Matsumura et al. (1993) demonstrated deficient expression of multiple dystrophin-associated glycoproteins in a form of congenital muscular dystrophy due to mutation in the FKTN gene (607440). This form of congenital muscular dystrophy, also known as Fukuyama-type congenital muscular dystrophy (FCMD) or muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A4; MDDGA4; 253800) is characterized by defective glycosylation of DAG1. Matsumura et al. (1993) noted that the 156DAG/43DAG proteins are expressed in both muscle and brain. </p><p>Arahata et al. (1993) found preservation of immunostaining for 43DAG in FCMD at the plasma membrane of the muscle fibers. On the other hand, they found reduced merosin (see LAMA2, 156225)-- a striated muscle-specific basal-lamina-associated protein--in most muscle fibers of FCMD, suggesting that it may have an early or primary role in the pathogenesis of the disorder. </p><p>Matsumura et al. (1993) showed that truncation of the dystrophin molecule with loss of the C-terminal domains can lead to severe muscular dystrophy, even when truncated dystrophin is demonstrable in the subsarcolemmal cytoskeleton. This is because the C-terminal domains are involved in the interaction with the large oligomeric complex of sarcolemmal glycoproteins, including dystroglycan. </p><p>Tinsley et al. (1994) reviewed the 'increasing complexity of the dystrophin-associated protein complex.' Although the exact function of dystrophin remained to be determined, analysis of its interaction with this large oligomeric protein complex at the sarcolemma and the identification of a structurally related protein, utrophin (128240), were leading to the identification of candidate genes for various neuromuscular disorders. </p><p>As reviewed by Spear (1998), structural integrity of the sarcolemma in skeletal and cardiac muscle appears to depend in part on binding of the cytoplasmic protein dystrophin to both actin and the cytoplasmic tail of beta-dystroglycan, and binding of alpha-dystroglycan to laminin-2 in the basal lamina. Laminins are composed of 3 polypeptide chains designated alpha, beta, and gamma. The multiple isoforms of laminin differ in their constituent chains. Laminin-2 is composed of alpha-2, beta-1, and gamma-1. Homozygous deletion of the gene encoding dystroglycan is lethal at the embryonic stage in mice (Williamson et al., 1997) and would presumably also be lethal in humans. </p><p>Yamada et al. (2001) demonstrated that a 30-kD fragment of beta-dystroglycan is the product of proteolytic processing of the extracellular domain of beta-dystroglycan by the membrane-associated matrix metalloproteinase (MMP2; 120360). This processing disintegrates the dystroglycan complex and disrupts this particular link between the extracellular matrix and cell membrane. The authors proposed that this processing of beta-dystroglycan may play a crucial role in the molecular pathogenesis of sarcoglycanopathy. </p><p>Using PCR, immunohistochemistry, and immunoblotting to analyze samples from patients with Fukuyama congenital muscular dystrophy (MDDGA4; 253800), Hayashi et al. (2001) confirmed a deficiency of fukutin (FKTN; 607440) and found marked deficiency of highly glycosylated DAG1 in skeletal and cardiac muscle and reduced amounts of DAG1 in brain tissue. Beta-dystroglycan was normal in all tissues examined. These findings supported the suggestion that fukutin deficiency affects the modification of glycosylation of DAG1, which then cannot localize or function properly and may be degraded or eluted from the extracellular surface membrane of the muscle fiber. Hayashi et al. (2001) concluded that this disruption underlies the developmental, structural, and functional damage to muscles in patients with FCMD. </p><p>Using transfection experiments, Esapa et al. (2002) determined that fukutin and fukutin-related protein (FKRP; 606596) are targeted to the medial Golgi apparatus through their N termini and transmembrane domains. Overexpression of FKRP in CHO cells altered the posttranslational processing of alpha- and beta-dystroglycan, thus inhibiting maturation of the 2 isoforms. Mutations in the DxD motif or in the Golgi-targeting sequence, which cause inefficient trafficking of FKRP to the Golgi apparatus, did not alter dystroglycan processing in vitro. The P448L mutation in FKRP (606596.0003) resulted in mislocalization of the mutant protein and disruption in dystroglycan processing. Esapa et al. (2002) concluded that FKRP is required for the posttranslational modification of dystroglycan. They suggested that aberrant processing of dystroglycan caused by a mislocalized FKRP mutant could be a novel mechanism that causes congenital muscular dystrophy. </p><p>Kanagawa et al. (2004) showed that both the N-terminal domain and a portion of the mucin-like domain of alpha-dystroglycan are essential for high affinity laminin receptor function. They found that posttranslational modification of alpha-dystroglycan by LARGE (603590) occurs within the mucin-like domain, but the N-terminal domain interacts with LARGE, defining an intracellular enzyme-substrate recognition motif necessary to initiate functional glycosylation. Gene replacement in dystroglycan-deficient muscle demonstrated that the dystroglycan C-terminal domain is sufficient only for dystrophin-glycoprotein complex assembly. To prevent muscle degeneration, expression of a functional dystroglycan through LARGE recognition and glycosylation was required. The authors concluded that molecular recognition of dystroglycan by LARGE is a key determinant in the biosynthetic pathway to produce mature and functional dystroglycan. </p><p>The ribbon synapse is a specialized structure where photoreceptors transfer information to bipolar and horizontal cells. By immunofluorescence analysis of mouse retina, Sato et al. (2008) found that expression of pikachurin (EGFLAM; 617683) at the ribbon synapse overlapped with that of dystrophin and beta-dystroglycan. Pull-down and coimmunoprecipitation assays using eye extracts demonstrated that pikachurin bound alpha-dystroglycan. Inhibition studies suggested that binding of pikachurin to alpha-dystroglycan was dependent on glycosylation. </p><p>Using protein overlay assays, Hu et al. (2011) observed impaired binding of pikachurin to alpha-dystroglycan in brains from Pomgnt1 (606822)-knockout or Large-deficient mice and in neural stem cells from Pomt2 (607439)-knockout mice, suggesting that O-mannosylglycosylation of alpha-dystroglycan is required for its interaction with pikachurin. Overexpression of human LARGE rescued interaction of pikachurin with alpha-dystroglycan in Pomgnt1-knockout cells. Immunofluorescence analysis revealed that localization of pikachurin to the photoreceptor synapse in the outer plexiform layer was lost or diminished in retinas of Pomgnt1-knockout, Large-deficient, or Dag1 conditional-knockout mice. Hu et al. (2011) concluded that proper glycosylation of alpha-dystroglycan is required for its interaction with pikachurin and for localization of pikachurin to the photoreceptor ribbon synapse. </p><p>Using mass spectrometry- and nuclear magnetic resonance-based structural analyses, Yoshida-Moriguchi et al. (2010) identified a phosphorylated O-mannosyl glycan on the mucin-like domain of recombinant alpha-DG, which was required for laminin binding. Yoshida-Moriguchi et al. (2010) demonstrated that patients with muscle-eye-brain disease (MDDGA3; 253280) and Fukuyama congenital muscular dystrophy (MDDGA4; 253800), as well as mice with myodystrophy, commonly have defects in a postphosphoryl modification of this phosphorylated O-linked mannose, and that this modification is mediated by the LARGE protein. Yoshida-Moriguchi et al. (2010) concluded that their findings expand knowledge of the mechanisms that underlie congenital muscular dystrophy. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>Muscular Dystrophy-Dystroglycanopathy (Limb-Girdle), Type C9</em></strong></p><p>
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In a Turkish woman with limb-girdle muscular dystrophy-dystroglycanopathy type C9 (MDDGC9; 613818) and severe cognitive impairment, also symbolized LGMDR16 and LGMD2P, reported by Dincer et al. (2003), Hara et al. (2011) identified a homozygous mutation in the DAG1 gene (T192M; 128239.0001). Functional expression analysis in vitro and in mice indicated that the mutation decreased LARGE (603590)-mediated posttranslational O-mannosyl glycosylation of DAG1, interfering with its receptor function and laminin binding in skeletal muscle and brain. </p><p>In a 7-year-old Japanese boy with a very mild form of MDDGC9 presenting only as asymptomatic increased serum creatine kinase, Dong et al. (2015) identified compound heterozygous missense mutations in the DAG1 gene (V74I, 128239.0002 and D111N, 128239.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were found at a low frequency in the dbSNP, 1000 Genomes Project, and HapMap databases. In vitro functional expression studies indicated that the mutations did not influence expression of dystroglycan, but did cause a defect in posttranslational modification. </p><p><strong><em>Muscular Dystrophy-Dystroglycanopathy (Congenital with Brain and Eye Anomalies), Type A9</em></strong></p><p>
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In 2 sisters, born of presumably unrelated Libyan parents, with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type A9 (MDDGA9; 616538), Geis et al. (2013) identified a homozygous missense mutation in the DAG1 gene (C669F; 128239.0004). The mutation was found by whole-exome sequencing and confirmed by direct sequencing. The unaffected mother was heterozygous for the mutation. The cys669 residue, postulated to form a covalent disulfide bond with cys713 of beta-dystroglycan, is important for the structure of beta-dystroglycan and thus most likely also for the function of the alpha- and beta-dystroglycan complex. Functional studies of the variant were not performed. </p><p>In 5 female infants from a consanguineous Israeli-Arab family with MDDGA9 resulting in death soon after birth, Riemersma et al. (2015) identified a homozygous truncating mutation in the DAG1 gene (128239.0005). The mutation was found by a combination of homozygosity mapping and whole-exome sequencing. Patient fibroblasts that were transformed to myoblasts showed no detectable properly glycosylated alpha-dystroglycan and no detectable alpha- or beta-dystroglycan protein, consistent with complete absence of both protein isoforms. </p>
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</span>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Williamson et al. (1997) found that heterozygous Dag1-null mice were viable and fertile. In contrast, homozygous embryos exhibited gross developmental abnormalities beginning around 6.5 days' gestation. They found that an early defect in the development of homozygous embryos was a disruption of the Reichert membrane, an extra-embryonic basement membrane. Consistent with the functional defects observed in Reichert membrane, dystroglycan protein was localized in apposition to this structure in normal egg cylinder-stage embryos. They also showed that the localization of 2 critical structural elements of Reichert membrane, laminin and collagen IV, were specifically disrupted in the homozygous Dag1 embryos. The data indicated that dystroglycan is required for the development of Reichert membrane and that disruption of basement membrane organization is a common feature of muscular dystrophies linked to the dystrophin-glycoprotein complex. </p><p>Henry and Campbell (1998) found that Dag1-null murine embryonic stem cells had defective formation of basement membranes in embryoid bodies. These results further indicated that dystroglycan-laminin interactions are prerequisites for the deposition of other basement membrane proteins. Dystroglycan may exert its influence on basement membrane assembly by binding soluble laminin and organizing it on the cell surface. </p><p>Cote et al. (1999) reported that chimeric mice generated with ES cells targeted for both dystroglycan alleles have skeletal muscles essentially devoid of dystroglycans and develop a progressive muscle pathology with changes emblematic of muscular dystrophies in humans. In addition, many neuromuscular junctions are disrupted in these mice. The ultrastructure of basement membranes and the deposition of laminin within them, however, appears unaffected in dystroglycan-deficient muscles. Cote et al. (1999) concluded that dystroglycans are necessary for myofiber survival and synapse differentiation or stability, but not for the formation of the muscle basement membrane, and that dystroglycans may have more than a purely structural function in maintaining muscle integrity. </p><p>Moore et al. (2002) showed that brain-selective deletion of dystroglycan in mice is sufficient to cause congenital muscular dystrophy-like brain malformations, including disarray of cerebral cortical layering, fusion of cerebral hemispheres and cerebellar folia, and aberrant migration of granule cells. Dystroglycan-null brain loses its high affinity binding to the extracellular matrix protein laminin (see 150240) and shows discontinuities in the pial surface basal lamina (glia limitans) that probably underlie the neuronal migration errors. Furthermore, mutant mice have severely blunted hippocampal long-term potentiation with electrophysiologic characterization, indicating that dystroglycan might have a postsynaptic role in learning and memory. Moore et al. (2002) concluded that these data strongly supported the hypothesis that defects in dystroglycan are central to the pathogenesis of structural and functional brain abnormalities seen in congenital muscular dystrophies. </p><p>Michele et al. (2002) demonstrated in both muscle-eye-brain disease (MDDGA3; 253280) and Fukuyama congenital muscular dystrophy (MDDGA4; 253800) patients that alpha-dystroglycan is expressed at the muscle membrane, but similar hypoglycosylation in the diseases directly abolishes binding activity of dystroglycan for the ligands laminin, neurexin (see 600565), and agrin (103320). Michele et al. (2002) showed that this posttranslational biochemical and functional disruption of alpha-dystroglycan is recapitulated in the muscle and central nervous system of mutant myodystrophy (myd) mice, who have a mutation in the LARGE gene. Michele et al. (2002) demonstrated that myd mice have abnormal neuronal migration in the cerebral cortex, cerebellum, and hippocampus, and show disruption of the basal lamina. In addition, myd mice reveal that dystroglycan targets proteins to functional sites in brain through its interactions with extracellular matrix proteins. Michele et al. (2002) suggested that at least 3 mammalian genes function within a convergent posttranslational processing pathway during the biosynthesis of dystroglycan and that abnormal dystroglycan-ligand interactions underlie the pathogenic mechanism of muscular dystrophy with brain abnormalities. </p><p>Cohn et al. (2002) found that striated muscle-specific disruption of the Dag1 gene in mice resulted in loss of the dystrophin-glycoprotein complex in differentiated muscle and a remarkably mild muscular dystrophy with hypertrophy and without tissue fibrosis. They found that satellite cells, expressing dystroglycan, supported continued efficient regeneration of skeletal muscle along with transient expression of dystroglycan in regenerating muscle fibers. Cohn et al. (2002) demonstrated a similar phenomenon of reexpression of functional dystroglycan in regenerating muscle fibers in a mild form of human muscular dystrophy caused by disruption of posttranslational dystroglycan processing. They concluded that maintenance of regenerative capacity by satellite cells expressing dystroglycan is likely responsible for mild disease progression in mice and possibly humans. Cohn et al. (2002) suggested that inadequate repair of skeletal muscle by satellite cells represents an important mechanism affecting the pathogenesis of muscular dystrophy. </p><p>Hara et al. (2011) demonstrated that mice with a homozygous T190M mutation in the Dag1 gene, which corresponds to the human T192M mutation (128239.0001), developed muscular dystrophy and neurologic motor impairment. The mutation decreased LARGE (603590)-mediated posttranslational O-mannosyl glycosylation of Dag1, interfering with its receptor function and laminin binding in skeletal muscle and brain. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>5 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 9</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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DAG1, THR192MET ({dbSNP rs193922955})
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<br />
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SNP: rs193922955,
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ClinVar: RCV000022532, RCV000024453, RCV001044548
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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 woman with limb-girdle muscular dystrophy-dystroglycanopathy (MDDGC9; 613818) and cognitive impairment, who was previously reported by Dincer et al. (2003), Hara et al. (2011) identified a homozygous 575C-T transition in the DAG1 gene, resulting in a thr192-to-met (T192M) substitution in a highly conserved residue in the N terminus of the protein. Each unaffected parent was heterozygous for the mutation, which was not found in 200 control chromosomes. Functional expression analysis in vitro and in mice indicated that the mutation decreased LARGE (603590)-mediated posttranslational O-mannosyl glycosylation of DAG1, interfering with its receptor function and laminin binding in skeletal muscle and brain. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 9</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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DAG1, VAL74ILE ({dbSNP rs189360006})
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<br />
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SNP: rs189360006,
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gnomAD: rs189360006,
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ClinVar: RCV000190545, RCV001857671, RCV003144154
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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 7-year-old Japanese boy with a very mild form of limb-girdle muscular dystrophy-dystroglycanopathy type C9 (MDDGC9; 613818) presenting only as asymptomatic increased serum creatine kinase, Dong et al. (2015) identified compound heterozygous mutations in the DAG1 gene: a c.220G-A transition, resulting in a val74-to-ile (V74I) substitution, and a c.331G-A transition, resulting in an asp111-to-asn (D111N; 128239.0003) substitution. Both mutations occurred at highly conserved residues in the N terminal domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were annotated in the dbSNP, 1000 Genomes Project, and HapMap databases: c.331G-A has a frequency of 0.005 in all populations in the 1000 Genomes Project database and a higher frequency (0.028) in the Japanese population in the Human Genetic Variation Database. Patient skeletal muscle biopsy stained negatively with an antibody for the glycoepitope of DAG1, and Western blot analysis showed decreased glycosylation of alpha-dystroglycan compared to controls. Transfection of either mutation into DAG1-null cells did not restore alpha-dystroglycan immunoreactivity. Beta-dystroglycan was unaffected, indicating that the mutations did not influence expression of dystroglycan, but did cause a defect in posttranslational modification. </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 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 9</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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DAG1, ASP111ASN ({dbSNP rs117209107})
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<br />
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SNP: rs117209107,
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gnomAD: rs117209107,
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ClinVar: RCV000190546, RCV000335532, RCV000556875, RCV001723761, RCV003907668
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the asp111-to-asn (D111N) mutation in the DAG1 gene that was found in compound heterozygous state in a patient with a very mild form of limb-girdle muscular dystrophy-dystroglycanopathy type C9 (MDDGC9; 613818) by Dong et al. (2015), see 128239.0002. </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 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 9</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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DAG1, CYS669PHE
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<br />
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SNP: rs797045023,
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ClinVar: RCV000190547, RCV001224389, RCV001781562
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 sisters, born of presumably unrelated Libyan parents, with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type A9 (MDDGA9; 616538), Geis et al. (2013) identified a homozygous c.2006G-T transversion in exon 2 of the DAG1 gene (c.2006G-T, NM_004393.4), resulting in a cys669-to-phe (C669F) substitution at a highly conserved residue in the extracellular portion of the beta-dystroglycan domain. The mutation, which was found by whole-exome sequencing and confirmed by direct sequencing, was not found in publicly available databases, including dbSNP, or in 52 control individuals. The unaffected mother was heterozygous for the mutation. The cys669 residue is postulated to form a covalent disulfide bond with cys713 of beta-dystroglycan and is important for the structure of beta-dystroglycan. Functional studies of the variant were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0005 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 9</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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DAG1, 1-BP DEL, 743C
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<br />
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SNP: rs869320680,
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ClinVar: RCV000190548
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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 5 female infants from a consanguineous Israeli-Arab family with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type A9 (MDDGA9; 616538) resulting in death soon after birth, Riemersma et al. (2015) identified a homozygous 1-bp deletion (c.743delC, NM_004393.4) in exon 3 of the DAG1 gene, resulting in a frameshift and premature termination (Ala248GlufsTer19). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was filtered against the dbSNP (build 132) database and an in-house database of 1,142 exomes. Analysis of patient cells showed the presence of the mutant transcript, indicating that it is not completely degraded by nonsense-mediated mRNA decay. Patient fibroblasts that were transformed to myoblasts showed no detectable properly glycosylated alpha-dystroglycan and no detectable alpha- or beta-dystroglycan protein, consistent with complete absence of both protein isoforms. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Arahata, K., Hayashi, Y. K., Mizuno, Y., Yoshida, M., Ozawa, E.
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<strong>Dystrophin-associated glycoprotein and dystrophin co-localisation at sarcolemma in Fukuyama congenital muscular dystrophy. (Letter)</strong>
|
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Lancet 342: 623-624, 1993.
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[PubMed: 8102757]
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[Full Text: https://doi.org/10.1016/0140-6736(93)91454-t]
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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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Campanelli, J. T., Roberds, S. L., Campbell, K. P., Scheller, R. H.
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<strong>A role for dystrophin-associated glycoproteins and utrophin in agrin-induced AChR clustering.</strong>
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Cell 77: 663-674, 1994.
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[PubMed: 8205616]
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[Full Text: https://doi.org/10.1016/0092-8674(94)90051-5]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Cao, W., Henry, M. D., Borrow, P., Yamada, H., Elder, J. H., Ravkov, E. V., Nichol, S. T., Compans, R. W., Campbell, K. P., Oldstone, M. B. A.
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<strong>Identification of alpha-dystroglycan as a receptor for lymphocytic choriomeningitis virus and Lassa fever virus.</strong>
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Science 282: 2079-2081, 1998.
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[PubMed: 9851928]
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[Full Text: https://doi.org/10.1093/hmg/6.6.831]
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Wright, K. M., Lyon, K. A., Leung, H., Leahy, D. J., Ma, L., Ginty, D. D.
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<strong>Dystroglycan organizes axon guidance cue localization and axonal pathfinding.</strong>
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Yamada, H., Denzer, A. J., Hori, H., Tanaka, T., Anderson, L. V. B., Fujita, S., Fukuta-Ohi, H., Shimizu, T., Ruegg, M. A., Matsumura, K.
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Yamada, H., Saito, F., Fukuta-Ohi, H., Zhong, D., Hase, A., Arai, K., Okuyama, A., Maekawa, R., Shimizu, T., Matsumura, K.
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Yoshida-Moriguchi, T., Yu, L., Stalnaker, S. H., Davis, S., Kunz, S., Madson, M., Oldstone, M. B. A., Schachter, H., Wells, L., Campbell, K. P.
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<strong>O-Mannosyl phosphorylation of alpha-dystroglycan is required for laminin binding.</strong>
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Matthew B. Gross - updated : 01/25/2022<br>Ada Hamosh - updated : 01/26/2018<br>Jane A. Welch - updated : 09/20/2017<br>Cassandra L. Kniffin - updated : 8/31/2015<br>Ada Hamosh - updated : 8/6/2014<br>Patricia A. Hartz - updated : 8/1/2013<br>Cassandra L. Kniffin - updated : 1/29/2013<br>Cassandra L. Kniffin - updated : 3/21/2011<br>Cassandra L. Kniffin - updated : 11/15/2010<br>Ada Hamosh - updated : 1/26/2010<br>George E. Tiller - updated : 1/16/2007<br>George E. Tiller - updated : 9/13/2004<br>Stylianos E. Antonarakis - updated : 8/4/2004<br>Cassandra L. Kniffin - updated : 10/15/2002<br>Stylianos E. Antonarakis - updated : 9/13/2002<br>Ada Hamosh - updated : 9/13/2002<br>Ada Hamosh - updated : 9/11/2002<br>George E. Tiller - updated : 12/17/2001<br>Ada Hamosh - updated : 11/1/1999<br>Stylianos E. Antonarakis - updated : 12/22/1998<br>Victor A. McKusick - updated : 12/9/1998<br>Victor A. McKusick - updated : 6/23/1997<br>Mark H. Paalman - updated : 10/14/1996
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