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<title>
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Entry
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- *600133 - LAMININ, ALPHA-4; LAMA4
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- OMIM
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</ul>
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</nav>
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<div id="mimSearch" class="hidden-print">
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<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
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<div class="col-lg-8 col-md-8 col-sm-8 col-xs-8">
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<div class="form-group">
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<div class="input-group">
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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<div class="input-group-btn">
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<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
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<button type="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
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<ul class="dropdown-menu dropdown-menu-right">
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<li class="dropdown-header">
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Advanced Search
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<li role="separator" class="divider"></li>
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<a href="/history"> Search History </a>
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</ul>
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</form>
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<p />
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-2 hidden-sm hidden-xs">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*600133</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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</li>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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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>
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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="#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/600133">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>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000112769;t=ENST00000230538" 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=3910" 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=600133" 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=ENSG00000112769;t=ENST00000230538" 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_001105206,NM_001105207,NM_001105208,NM_001105209,NM_002290,XM_005266983,XM_005266984,XM_017010854,XM_047418769,XM_047418770,XM_047418771" 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_001105206" 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=600133" 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=02532&isoform_id=02532_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/LAMA4" 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/437805,509806,1042082,1212963,1684837,2440076,13278993,30582219,46362423,47115181,116283345,119568651,119568652,119568653,119568654,119568655,157419128,157419130,221044994,380503843,380503846,380503849,578812743,578812747,929654743,1034650228,2217361438,2217361441,2217361443,2462608443,2462608445,2462608447,2462608449,2462608451,2462608453,2904933605" 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/Q16363" 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=3910" 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=ENSG00000112769;t=ENST00000230538" 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=LAMA4" 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=LAMA4" 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+3910" 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/LAMA4" 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:3910" 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/3910" 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=chr6&hgg_gene=ENST00000230538.12&hgg_start=112107931&hgg_end=112254985&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:6484" 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=600133[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=600133[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/ENSG00000112769" 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=LAMA4" 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=LAMA4" 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=LAMA4" 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="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=LAMA4&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/PA30273" 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:6484" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:109321" 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/LAMA4#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:109321" 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/3910/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA002902/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=3910" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040724-213" 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">
|
|
<div style="display: table-row">
|
|
<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:3910" 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=LAMA4&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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</div>
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<div>
|
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<span class="h3">
|
|
<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
|
600133
|
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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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LAMININ, ALPHA-4; LAMA4
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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>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
LAMA3, FORMERLY
|
|
</span>
|
|
</h4>
|
|
</div>
|
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</div>
|
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=LAMA4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">LAMA4</a></em></strong>
|
|
</span>
|
|
</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/6/786?start=-3&limit=10&highlight=786">6q21</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr6:112107931-112254985&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'})">6:112,107,931-112,254,985</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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|
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
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|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/6/786?start=-3&limit=10&highlight=786">
|
|
6q21
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Cardiomyopathy, dilated, 1JJ
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
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<a href="/entry/615235"> 615235 </a>
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PheneGene Graphics <span class="caret"></span>
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<li><a href="/graph/linear/600133" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p>Laminin, a multidomain glycoprotein, is the major noncollagenous constituent of basement membranes. It is composed of 3 nonidentical chains: A (LAMA1; <a href="/entry/150320">150320</a>), B1 (LAMB1; <a href="/entry/150240">150240</a>), and B2 (LAMC1; <a href="/entry/150290">150290</a>). The 3 classical laminin chains form a cruciform structure consisting of 3 short arms, each of which is formed from different chains, and a long arm composed of all 3 chains. LAMA4 encodes a variant A chain (<a href="#5" class="mim-tip-reference" title="Richards, A. J., Al-Imara, L., Carter, N. P., Lloyd, J. C., Leversha, M. A., Pope, F. M. <strong>Localization of the gene (LAMA4) to chromosome 6q21 and isolation of a partial cDNA encoding a variant laminin A chain.</strong> Genomics 22: 237-239, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7959779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7959779</a>] [<a href="https://doi.org/10.1006/geno.1994.1372" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7959779">Richards et al., 1994</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7959779" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By screening a human keratinocyte cDNA library for type VII collagen sequences, <a href="#5" class="mim-tip-reference" title="Richards, A. J., Al-Imara, L., Carter, N. P., Lloyd, J. C., Leversha, M. A., Pope, F. M. <strong>Localization of the gene (LAMA4) to chromosome 6q21 and isolation of a partial cDNA encoding a variant laminin A chain.</strong> Genomics 22: 237-239, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7959779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7959779</a>] [<a href="https://doi.org/10.1006/geno.1994.1372" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7959779">Richards et al. (1994)</a> isolated a new laminin alpha chain variant gene, LAMA4 (formerly called LAMA3). Northern blot analysis indicated that a cDNA encoding LAMA4 hybridized to a 6.45-kb mRNA, significantly smaller than the 9.5- to 10-kb mRNA of laminin A (<a href="#1" class="mim-tip-reference" title="Haaparanta, T., Uitto, J., Ruoslahti, E., Engvall, E. <strong>Molecular cloning of the cDNA encoding human laminin A chain.</strong> Matrix 11: 151-160, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1714537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1714537</a>] [<a href="https://doi.org/10.1016/s0934-8832(11)80153-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1714537">Haaparanta et al., 1991</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1714537+7959779" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Iivanainen, A., Sainio, K., Sariola, H., Tryggvason, K. <strong>Primary structure and expression of a novel human laminin alpha-4 chain.</strong> FEBS Lett. 365: 183-188, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7781776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7781776</a>] [<a href="https://doi.org/10.1016/0014-5793(95)00462-i" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7781776">Iivanainen et al. (1995)</a> cloned the laminin alpha-4 cDNA by screening a fetal lung library with a PCR product generated from primers based on a partial laminin-like sequence reported by GenBank. The complete cDNA is approximately 6.2 kb long and encodes a predicted protein of 1,816 amino acids. The domain structure of the protein is similar to the alpha-3 chain (LAMA3, also called BM600), both of which resemble truncated versions of alpha-1 and alpha-2 in which approximately 1,200 residues at the amino end have been lost. Northern blots showed strong expression of the mRNA in adult heart, lung, ovary, small and large intestines, liver, and placenta. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7781776" 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="#4" class="mim-tip-reference" title="Richards, A., Luccarini, C., Pope, F. M. <strong>The structural organisation of LAMA4, the gene encoding laminin alpha4.</strong> Europ. J. Biochem. 248: 15-23, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9310354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9310354</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1997.t01-1-00015.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9310354">Richards et al. (1997)</a> determined that the LAMA4 gene contains 39 exons and spans 122 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9310354" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using PCR on genomic DNA, flow-sorted chromosomes, and fluorescence in situ hybridization, <a href="#6" class="mim-tip-reference" title="Richards, A. J., Al-Imara, L., Carter, N. P., Lloyd, J. C., Pope, F. M. <strong>A laminin A variant gene (LAMA3) is present on chromosome 6q21 (Abstract)</strong> J. Med. Genet. 31: 164 only, 1994."None>Richards et al. (1994)</a> localized the LAMA4 gene to human chromosome 6q21. In this abstract, the authors referred to the gene as LAMA3; in the related article, <a href="#5" class="mim-tip-reference" title="Richards, A. J., Al-Imara, L., Carter, N. P., Lloyd, J. C., Leversha, M. A., Pope, F. M. <strong>Localization of the gene (LAMA4) to chromosome 6q21 and isolation of a partial cDNA encoding a variant laminin A chain.</strong> Genomics 22: 237-239, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7959779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7959779</a>] [<a href="https://doi.org/10.1006/geno.1994.1372" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7959779">Richards et al. (1994)</a> used the corrected symbol, LAMA4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7959779" 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="#3" class="mim-tip-reference" title="Knoll, R., Postel, R., Wang, J., Kratzner, R., Hennecke, G., Vacaru, A. M., Vakeel, P., Schubert, C., Murthy, K., Rana, B. K., Kube, D., Knoll, G., and 17 others. <strong>Laminin-alpha-4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in cardiomyocytes and endothelial cells.</strong> Circulation 116: 515-525, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17646580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17646580</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.689984" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17646580">Knoll et al. (2007)</a> sequenced the LAMA4 gene in 180 Caucasian patients with severe dilated cardiomyopathy (CMD1JJ; <a href="/entry/615235">615235</a>) and identified a nonsense (R1073X; <a href="#0001">600133.0001</a>) and a missense (P943L; <a href="#0002">600133.0002</a>) mutation in 2 patients, respectively. Genotyping an additional 374 Caucasian CMD patients for those mutations identified 1 more patient with the P943L mutation. Screening the LAMA4 gene by SSCP in an additional 200 Japanese CMD patients revealed no variants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17646580" 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="#7" class="mim-tip-reference" title="Thyboll, J, Kortesmaa, J., Cao, R, Soininen, R., Wang, L., Iivanainen, A., Sorokin, L., Risling, M., Cao, Y., Tryggvason, K. <strong>Deletion of the laminin alpha4 chain leads to impaired microvessel maturation.</strong> Molec. Cell. Biol. 22: 1194-1202, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11809810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11809810</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11809810[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/10.1128/MCB.22.4.1194-1202.2002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11809810">Thyboll et al. (2002)</a> noted that LAMA4 is expressed in basement membranes such as those beneath endothelia, the perineurium of peripheral nerves, and around developing muscle fibers. Lama4-null mice presented with hemorrhages during the embryonic and neonatal period. Newborns were lethargic, pale, and yellowish (icteric). They showed extensive bleeding and deterioration of microvessel growth in experimental angiogenesis, as well as mild locomotion defects. Histologic examination of newborn mice revealed delayed deposition of type IV collagen (<a href="/entry/120130">120130</a>) and nidogen (<a href="/entry/131390">131390</a>) into capillary basement membranes. Electron microscopy showed discontinuities in the lamina densa. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11809810" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Wang, J., Hoshijima, M., Lam, J., Zhou, Z., Jokiel, A., Dalton, N. D., Hultenby, K., Ruiz-Lozano, P., Ross, J., Jr., Tryggvason, K., Chien, K. R. <strong>Cardiomyopathy associated with microcirculation dysfunction in laminin alpha-4 chain-deficient mice.</strong> J. Biol. Chem. 281: 213-220, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16204254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16204254</a>] [<a href="https://doi.org/10.1074/jbc.M505061200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16204254">Wang et al. (2006)</a> generated Lama4 -/- mice and observed gradual development of cardiac hypertrophy and impaired cardiac function by 40 weeks of age, with histology showing multiple foci of muscle degeneration and fibrosis throughout the heart. Cardiomyocytes isolated from Lama4 -/- hearts maintained their contractility in vivo. However, elevated levels of hypoxia-inducible factor-1-alpha (HIF1A; <a href="/entry/603348">603348</a>) and vascular endothelial growth factor-A (VEGFA; <a href="/entry/192240">192240</a>), along with multiple foci of cardiomyocyte degeneration and fibrosis, suggested sustained cardiac ischemia. Electron microscopy confirmed malformed blood vessels and wide pericapillary extracellular matrix (ECM) spaces, suggesting the presence of microcirculation abnormalities in Lama4 -/- mutant hearts. <a href="#8" class="mim-tip-reference" title="Wang, J., Hoshijima, M., Lam, J., Zhou, Z., Jokiel, A., Dalton, N. D., Hultenby, K., Ruiz-Lozano, P., Ross, J., Jr., Tryggvason, K., Chien, K. R. <strong>Cardiomyopathy associated with microcirculation dysfunction in laminin alpha-4 chain-deficient mice.</strong> J. Biol. Chem. 281: 213-220, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16204254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16204254</a>] [<a href="https://doi.org/10.1074/jbc.M505061200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16204254">Wang et al. (2006)</a> concluded that mutation in the laminin alpha-4 chain leads to an abnormal cardiovascular ECM structure that causes insufficient oxygen supply to the heart. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16204254" 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 Lama4 -/- mice to evaluate active and passive experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS; <a href="/entry/126200">126200</a>), by immunofluorescence, confocal, and electron microscopy and flow cytometric analysis, <a href="#9" class="mim-tip-reference" title="Wu, C., Ivars, F., Anderson, P., Hallmann, R., Vestweber, D., Nilsson, P., Robenek, H., Tryggvason, K., Song, J., Korpos, E., Loser, K., Beissert, S., Georges-Labouesse, E., Sorokin, L. M. <strong>Endothelial basement membrane laminin alpha-5 selectively inhibits T lymphocyte extravasation into the brain.</strong> Nature Med. 15: 519-527, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19396173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19396173</a>] [<a href="https://doi.org/10.1038/nm.1957" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19396173">Wu et al. (2009)</a> observed a compensatory ubiquitous expression of Lama5 (<a href="/entry/601033">601033</a>) in all blood vessels, independent of responses to proinflammatory cytokines. Lama4 -/- mice showed significantly lower susceptibility to active EAE and resistance to passive EAE by transfer of encephalitogenic wildtype T cells compared with wildtype mice. Elimination of integrin alpha-6 (ITGA6; <a href="/entry/147556">147556</a>)/beta-1 (ITGB1; <a href="/entry/135630">135630</a>)-positive T cells through Itga6 -/- bone marrow chimeras also resulted in lower EAE severity. <a href="#9" class="mim-tip-reference" title="Wu, C., Ivars, F., Anderson, P., Hallmann, R., Vestweber, D., Nilsson, P., Robenek, H., Tryggvason, K., Song, J., Korpos, E., Loser, K., Beissert, S., Georges-Labouesse, E., Sorokin, L. M. <strong>Endothelial basement membrane laminin alpha-5 selectively inhibits T lymphocyte extravasation into the brain.</strong> Nature Med. 15: 519-527, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19396173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19396173</a>] [<a href="https://doi.org/10.1038/nm.1957" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19396173">Wu et al. (2009)</a> concluded that LAMA5 directly inhibits integrin alpha-6/beta-1-mediated T-cell migration through LAMA4, and that T cells use mechanisms distinct from other immune cells to penetrate the endothelial basement membrane barrier. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19396173" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>2 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=600133[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 CARDIOMYOPATHY, DILATED, 1JJ</strong>
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<p>In a woman with severe dilated cardiomyopathy (CMD1JJ; <a href="/entry/615235">615235</a>), who had been diagnosed at 29 years of age and was a candidate for heart transplantation with an ejection fraction of only 20%, <a href="#3" class="mim-tip-reference" title="Knoll, R., Postel, R., Wang, J., Kratzner, R., Hennecke, G., Vacaru, A. M., Vakeel, P., Schubert, C., Murthy, K., Rana, B. K., Kube, D., Knoll, G., and 17 others. <strong>Laminin-alpha-4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in cardiomyocytes and endothelial cells.</strong> Circulation 116: 515-525, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17646580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17646580</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.689984" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17646580">Knoll et al. (2007)</a> identified heterozygosity for a 3217C-T transition in the LAMA4 gene, resulting in an arg1073-to-ter (R1073X) substitution predicted to delete 4 of the 5 LG domains at the C terminus of the LAMA4 protein and thus impair interaction with integrin molecules. The patient's deceased father was known to have had heart failure. The mutation was not found in her unaffected son or in 362 well-characterized Caucasian controls. Cell-attachment assay demonstrated a significant decrease of endothelial cell adherence with the R1073X mutant compared to wildtype, and the mutant had significantly higher equilibrium dissociation constants to immobilized alpha-3 (<a href="/entry/605025">605025</a>)-beta-1 (<a href="/entry/135630">135630</a>) integrin than wildtype. Immunohistochemistry on a myocardial biopsy sample revealed a significant loss of endothelial cells in the patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17646580" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387907365 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907365;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/rs387907365?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=rs387907365" 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=rs387907365" 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=RCV000043519" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000043519" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000043519</a>
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<p>In 2 unrelated men with severe dilated cardiomyopathy (CMD1JJ; <a href="/entry/615235">615235</a>), who were diagnosed at 53 years and 68 years of age and had ejection fractions of 29% and 31%, respectively, <a href="#3" class="mim-tip-reference" title="Knoll, R., Postel, R., Wang, J., Kratzner, R., Hennecke, G., Vacaru, A. M., Vakeel, P., Schubert, C., Murthy, K., Rana, B. K., Kube, D., Knoll, G., and 17 others. <strong>Laminin-alpha-4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in cardiomyocytes and endothelial cells.</strong> Circulation 116: 515-525, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17646580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17646580</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.107.689984" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17646580">Knoll et al. (2007)</a> identified heterozygosity for a 2828C-T transition in the LAMA4 gene, resulting in a pro943-to-leu (P943L) substitution at a highly conserved residue in the loop of the LG1 domain. The mutation was not found in 362 well-characterized Caucasian controls. Cell-attachment assay demonstrated a significant decrease of endothelial cell adherence with the P943L mutant compared to wildtype, and the mutant had significantly higher equilibrium dissociation constants to immobilized alpha-3 (<a href="/entry/605025">605025</a>)-beta-1 (<a href="/entry/135630">135630</a>) integrin than wildtype. Immunohistochemistry on a myocardial biopsy sample revealed a significant loss of endothelial cells in both patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17646580" 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="Haaparanta1991" class="mim-anchor"></a>
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Haaparanta, T., Uitto, J., Ruoslahti, E., Engvall, E.
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<strong>Molecular cloning of the cDNA encoding human laminin A chain.</strong>
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Matrix 11: 151-160, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1714537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1714537</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1714537" 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/s0934-8832(11)80153-8" target="_blank">Full Text</a>]
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Iivanainen, A., Sainio, K., Sariola, H., Tryggvason, K.
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<strong>Primary structure and expression of a novel human laminin alpha-4 chain.</strong>
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FEBS Lett. 365: 183-188, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7781776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7781776</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7781776" 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/10.1016/0014-5793(95)00462-i" target="_blank">Full Text</a>]
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Knoll, R., Postel, R., Wang, J., Kratzner, R., Hennecke, G., Vacaru, A. M., Vakeel, P., Schubert, C., Murthy, K., Rana, B. K., Kube, D., Knoll, G., and 17 others.
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<strong>Laminin-alpha-4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in cardiomyocytes and endothelial cells.</strong>
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Circulation 116: 515-525, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17646580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17646580</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17646580" 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/10.1161/CIRCULATIONAHA.107.689984" target="_blank">Full Text</a>]
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Richards, A., Luccarini, C., Pope, F. M.
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<strong>The structural organisation of LAMA4, the gene encoding laminin alpha4.</strong>
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Europ. J. Biochem. 248: 15-23, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9310354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9310354</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9310354" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1432-1033.1997.t01-1-00015.x" target="_blank">Full Text</a>]
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Richards, A. J., Al-Imara, L., Carter, N. P., Lloyd, J. C., Leversha, M. A., Pope, F. M.
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<strong>Localization of the gene (LAMA4) to chromosome 6q21 and isolation of a partial cDNA encoding a variant laminin A chain.</strong>
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Genomics 22: 237-239, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7959779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7959779</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7959779" 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/10.1006/geno.1994.1372" target="_blank">Full Text</a>]
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Richards, A. J., Al-Imara, L., Carter, N. P., Lloyd, J. C., Pope, F. M.
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<strong>A laminin A variant gene (LAMA3) is present on chromosome 6q21 (Abstract)</strong>
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J. Med. Genet. 31: 164 only, 1994.
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<a id="7" class="mim-anchor"></a>
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<a id="Thyboll2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Thyboll, J, Kortesmaa, J., Cao, R, Soininen, R., Wang, L., Iivanainen, A., Sorokin, L., Risling, M., Cao, Y., Tryggvason, K.
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<strong>Deletion of the laminin alpha4 chain leads to impaired microvessel maturation.</strong>
|
|
Molec. Cell. Biol. 22: 1194-1202, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11809810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11809810</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11809810[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=11809810" 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/10.1128/MCB.22.4.1194-1202.2002" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="8" class="mim-anchor"></a>
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<a id="Wang2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wang, J., Hoshijima, M., Lam, J., Zhou, Z., Jokiel, A., Dalton, N. D., Hultenby, K., Ruiz-Lozano, P., Ross, J., Jr., Tryggvason, K., Chien, K. R.
|
|
<strong>Cardiomyopathy associated with microcirculation dysfunction in laminin alpha-4 chain-deficient mice.</strong>
|
|
J. Biol. Chem. 281: 213-220, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16204254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16204254</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16204254" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M505061200" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="9" class="mim-anchor"></a>
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<a id="Wu2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wu, C., Ivars, F., Anderson, P., Hallmann, R., Vestweber, D., Nilsson, P., Robenek, H., Tryggvason, K., Song, J., Korpos, E., Loser, K., Beissert, S., Georges-Labouesse, E., Sorokin, L. M.
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<strong>Endothelial basement membrane laminin alpha-5 selectively inhibits T lymphocyte extravasation into the brain.</strong>
|
|
Nature Med. 15: 519-527, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19396173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19396173</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19396173" 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/nm.1957" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 5/16/2013
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Paul J. Converse - updated : 5/28/2009<br>Patricia A. Hartz - updated : 11/12/2002<br>Alan F. Scott - updated : 9/26/1995
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 10/3/1994
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 05/16/2013
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 5/16/2013<br>mgross : 5/29/2009<br>terry : 5/28/2009<br>cwells : 11/12/2002<br>dkim : 7/2/1998<br>joanna : 5/8/1998<br>mark : 2/2/1996<br>mark : 12/5/1995<br>mark : 10/4/1995<br>mark : 9/26/1995<br>carol : 10/7/1994<br>carol : 10/6/1994
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 600133
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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LAMININ, ALPHA-4; LAMA4
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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LAMA3, FORMERLY
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</span>
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</h4>
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</div>
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<div>
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<br />
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: LAMA4</em></strong>
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</span>
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</p>
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</div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 6q21
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Genomic coordinates <span class="small">(GRCh38)</span> : 6:112,107,931-112,254,985 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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6q21
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</span>
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</td>
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<td>
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<span class="mim-font">
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Cardiomyopathy, dilated, 1JJ
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</span>
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</td>
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<td>
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<span class="mim-font">
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615235
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Laminin, a multidomain glycoprotein, is the major noncollagenous constituent of basement membranes. It is composed of 3 nonidentical chains: A (LAMA1; 150320), B1 (LAMB1; 150240), and B2 (LAMC1; 150290). The 3 classical laminin chains form a cruciform structure consisting of 3 short arms, each of which is formed from different chains, and a long arm composed of all 3 chains. LAMA4 encodes a variant A chain (Richards et al., 1994). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By screening a human keratinocyte cDNA library for type VII collagen sequences, Richards et al. (1994) isolated a new laminin alpha chain variant gene, LAMA4 (formerly called LAMA3). Northern blot analysis indicated that a cDNA encoding LAMA4 hybridized to a 6.45-kb mRNA, significantly smaller than the 9.5- to 10-kb mRNA of laminin A (Haaparanta et al., 1991). </p><p>Iivanainen et al. (1995) cloned the laminin alpha-4 cDNA by screening a fetal lung library with a PCR product generated from primers based on a partial laminin-like sequence reported by GenBank. The complete cDNA is approximately 6.2 kb long and encodes a predicted protein of 1,816 amino acids. The domain structure of the protein is similar to the alpha-3 chain (LAMA3, also called BM600), both of which resemble truncated versions of alpha-1 and alpha-2 in which approximately 1,200 residues at the amino end have been lost. Northern blots showed strong expression of the mRNA in adult heart, lung, ovary, small and large intestines, liver, and placenta. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Richards et al. (1997) determined that the LAMA4 gene contains 39 exons and spans 122 kb. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using PCR on genomic DNA, flow-sorted chromosomes, and fluorescence in situ hybridization, Richards et al. (1994) localized the LAMA4 gene to human chromosome 6q21. In this abstract, the authors referred to the gene as LAMA3; in the related article, Richards et al. (1994) used the corrected symbol, LAMA4. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Molecular Genetics</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Knoll et al. (2007) sequenced the LAMA4 gene in 180 Caucasian patients with severe dilated cardiomyopathy (CMD1JJ; 615235) and identified a nonsense (R1073X; 600133.0001) and a missense (P943L; 600133.0002) mutation in 2 patients, respectively. Genotyping an additional 374 Caucasian CMD patients for those mutations identified 1 more patient with the P943L mutation. Screening the LAMA4 gene by SSCP in an additional 200 Japanese CMD patients revealed no variants. </p>
|
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</span>
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<div>
|
|
<br />
|
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<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">
|
|
<p>Thyboll et al. (2002) noted that LAMA4 is expressed in basement membranes such as those beneath endothelia, the perineurium of peripheral nerves, and around developing muscle fibers. Lama4-null mice presented with hemorrhages during the embryonic and neonatal period. Newborns were lethargic, pale, and yellowish (icteric). They showed extensive bleeding and deterioration of microvessel growth in experimental angiogenesis, as well as mild locomotion defects. Histologic examination of newborn mice revealed delayed deposition of type IV collagen (120130) and nidogen (131390) into capillary basement membranes. Electron microscopy showed discontinuities in the lamina densa. </p><p>Wang et al. (2006) generated Lama4 -/- mice and observed gradual development of cardiac hypertrophy and impaired cardiac function by 40 weeks of age, with histology showing multiple foci of muscle degeneration and fibrosis throughout the heart. Cardiomyocytes isolated from Lama4 -/- hearts maintained their contractility in vivo. However, elevated levels of hypoxia-inducible factor-1-alpha (HIF1A; 603348) and vascular endothelial growth factor-A (VEGFA; 192240), along with multiple foci of cardiomyocyte degeneration and fibrosis, suggested sustained cardiac ischemia. Electron microscopy confirmed malformed blood vessels and wide pericapillary extracellular matrix (ECM) spaces, suggesting the presence of microcirculation abnormalities in Lama4 -/- mutant hearts. Wang et al. (2006) concluded that mutation in the laminin alpha-4 chain leads to an abnormal cardiovascular ECM structure that causes insufficient oxygen supply to the heart. </p><p>Using Lama4 -/- mice to evaluate active and passive experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS; 126200), by immunofluorescence, confocal, and electron microscopy and flow cytometric analysis, Wu et al. (2009) observed a compensatory ubiquitous expression of Lama5 (601033) in all blood vessels, independent of responses to proinflammatory cytokines. Lama4 -/- mice showed significantly lower susceptibility to active EAE and resistance to passive EAE by transfer of encephalitogenic wildtype T cells compared with wildtype mice. Elimination of integrin alpha-6 (ITGA6; 147556)/beta-1 (ITGB1; 135630)-positive T cells through Itga6 -/- bone marrow chimeras also resulted in lower EAE severity. Wu et al. (2009) concluded that LAMA5 directly inhibits integrin alpha-6/beta-1-mediated T-cell migration through LAMA4, and that T cells use mechanisms distinct from other immune cells to penetrate the endothelial basement membrane barrier. </p>
|
|
</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>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>2 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 CARDIOMYOPATHY, DILATED, 1JJ</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
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|
LAMA4, ARG1073TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs372615994,
|
|
|
|
|
|
gnomAD: rs372615994,
|
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|
|
ClinVar: RCV000043518, RCV002321538, RCV003430653
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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 woman with severe dilated cardiomyopathy (CMD1JJ; 615235), who had been diagnosed at 29 years of age and was a candidate for heart transplantation with an ejection fraction of only 20%, Knoll et al. (2007) identified heterozygosity for a 3217C-T transition in the LAMA4 gene, resulting in an arg1073-to-ter (R1073X) substitution predicted to delete 4 of the 5 LG domains at the C terminus of the LAMA4 protein and thus impair interaction with integrin molecules. The patient's deceased father was known to have had heart failure. The mutation was not found in her unaffected son or in 362 well-characterized Caucasian controls. Cell-attachment assay demonstrated a significant decrease of endothelial cell adherence with the R1073X mutant compared to wildtype, and the mutant had significantly higher equilibrium dissociation constants to immobilized alpha-3 (605025)-beta-1 (135630) integrin than wildtype. Immunohistochemistry on a myocardial biopsy sample revealed a significant loss of endothelial cells in the patient. </p>
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<strong>.0002 CARDIOMYOPATHY, DILATED, 1JJ</strong>
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<span class="mim-text-font">
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LAMA4, PRO943LEU
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<br />
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SNP: rs387907365,
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gnomAD: rs387907365,
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ClinVar: RCV000043519
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<p>In 2 unrelated men with severe dilated cardiomyopathy (CMD1JJ; 615235), who were diagnosed at 53 years and 68 years of age and had ejection fractions of 29% and 31%, respectively, Knoll et al. (2007) identified heterozygosity for a 2828C-T transition in the LAMA4 gene, resulting in a pro943-to-leu (P943L) substitution at a highly conserved residue in the loop of the LG1 domain. The mutation was not found in 362 well-characterized Caucasian controls. Cell-attachment assay demonstrated a significant decrease of endothelial cell adherence with the P943L mutant compared to wildtype, and the mutant had significantly higher equilibrium dissociation constants to immobilized alpha-3 (605025)-beta-1 (135630) integrin than wildtype. Immunohistochemistry on a myocardial biopsy sample revealed a significant loss of endothelial cells in both patients. </p>
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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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<p />
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<p class="mim-text-font">
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Haaparanta, T., Uitto, J., Ruoslahti, E., Engvall, E.
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<strong>Molecular cloning of the cDNA encoding human laminin A chain.</strong>
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Matrix 11: 151-160, 1991.
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[PubMed: 1714537]
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[Full Text: https://doi.org/10.1016/s0934-8832(11)80153-8]
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<li>
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Iivanainen, A., Sainio, K., Sariola, H., Tryggvason, K.
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<strong>Primary structure and expression of a novel human laminin alpha-4 chain.</strong>
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FEBS Lett. 365: 183-188, 1995.
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[PubMed: 7781776]
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[Full Text: https://doi.org/10.1016/0014-5793(95)00462-i]
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<p class="mim-text-font">
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Knoll, R., Postel, R., Wang, J., Kratzner, R., Hennecke, G., Vacaru, A. M., Vakeel, P., Schubert, C., Murthy, K., Rana, B. K., Kube, D., Knoll, G., and 17 others.
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<strong>Laminin-alpha-4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in cardiomyocytes and endothelial cells.</strong>
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Circulation 116: 515-525, 2007.
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[PubMed: 17646580]
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[Full Text: https://doi.org/10.1161/CIRCULATIONAHA.107.689984]
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<li>
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<p class="mim-text-font">
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Richards, A., Luccarini, C., Pope, F. M.
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<strong>The structural organisation of LAMA4, the gene encoding laminin alpha4.</strong>
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Europ. J. Biochem. 248: 15-23, 1997.
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[PubMed: 9310354]
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[Full Text: https://doi.org/10.1111/j.1432-1033.1997.t01-1-00015.x]
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Richards, A. J., Al-Imara, L., Carter, N. P., Lloyd, J. C., Leversha, M. A., Pope, F. M.
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<strong>Localization of the gene (LAMA4) to chromosome 6q21 and isolation of a partial cDNA encoding a variant laminin A chain.</strong>
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Genomics 22: 237-239, 1994.
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[PubMed: 7959779]
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[Full Text: https://doi.org/10.1006/geno.1994.1372]
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Richards, A. J., Al-Imara, L., Carter, N. P., Lloyd, J. C., Pope, F. M.
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<strong>A laminin A variant gene (LAMA3) is present on chromosome 6q21 (Abstract)</strong>
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J. Med. Genet. 31: 164 only, 1994.
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Thyboll, J, Kortesmaa, J., Cao, R, Soininen, R., Wang, L., Iivanainen, A., Sorokin, L., Risling, M., Cao, Y., Tryggvason, K.
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<strong>Deletion of the laminin alpha4 chain leads to impaired microvessel maturation.</strong>
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Molec. Cell. Biol. 22: 1194-1202, 2002.
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[PubMed: 11809810]
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[Full Text: https://doi.org/10.1128/MCB.22.4.1194-1202.2002]
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Wang, J., Hoshijima, M., Lam, J., Zhou, Z., Jokiel, A., Dalton, N. D., Hultenby, K., Ruiz-Lozano, P., Ross, J., Jr., Tryggvason, K., Chien, K. R.
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<strong>Cardiomyopathy associated with microcirculation dysfunction in laminin alpha-4 chain-deficient mice.</strong>
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J. Biol. Chem. 281: 213-220, 2006.
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[PubMed: 16204254]
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[Full Text: https://doi.org/10.1074/jbc.M505061200]
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Wu, C., Ivars, F., Anderson, P., Hallmann, R., Vestweber, D., Nilsson, P., Robenek, H., Tryggvason, K., Song, J., Korpos, E., Loser, K., Beissert, S., Georges-Labouesse, E., Sorokin, L. M.
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<strong>Endothelial basement membrane laminin alpha-5 selectively inhibits T lymphocyte extravasation into the brain.</strong>
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Nature Med. 15: 519-527, 2009.
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[PubMed: 19396173]
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[Full Text: https://doi.org/10.1038/nm.1957]
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Marla J. F. O'Neill - updated : 5/16/2013<br>Paul J. Converse - updated : 5/28/2009<br>Patricia A. Hartz - updated : 11/12/2002<br>Alan F. Scott - updated : 9/26/1995
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Victor A. McKusick : 10/3/1994
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