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Entry
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- *303630 - COLLAGEN, TYPE IV, ALPHA-5; COL4A5
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*303630</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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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/303630">Table View</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<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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</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=ENSG00000188153;t=ENST00000328300" 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=1287" 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=303630" 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=ENSG00000188153;t=ENST00000328300" 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_000495,NM_033380,XM_011530849,XM_017029259,XM_017029260,XM_017029261,XM_017029262,XM_047441810,XM_047441811" 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_033380" 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=303630" 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=02363&isoform_id=02363_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/COL4A5" 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/177924,180825,461675,463430,545096,553234,587204,913883,1314210,4261609,4502955,7676171,7717227,15890086,71296881,119623088,119623089,119623090,119623091,156230677,194376530,703556897,1034673478,1034673480,1034673482,1034673484,1034673486,2217390979,2217390983,2440732674,2440732677,2440732679,2462628161,2462628163,2462628165,2462628167,2462628169,2462628171,2462628173" 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/P29400" 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=1287" 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=ENSG00000188153;t=ENST00000328300" 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=COL4A5" 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=COL4A5" 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+1287" 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/COL4A5" 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:1287" 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/1287" 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=chrX&hgg_gene=ENST00000328300.11&hgg_start=108439838&hgg_end=108697545&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/gene-dosage/HGNC:2207" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:2207" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/col4a5" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=303630[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=303630[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/COL4A5/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000188153" 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=COL4A5" 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=COL4A5" 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=COL4A5" 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="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://www.LOVD.nl/COL4A5" title="Collagen, type IV, alpha 5 (COL4A5) Mental Retardation Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Collagen, type IV, alpha 5…</a></div><div style="margin-left: 0.5em;"><a href="http://www.arup.utah.edu/database/ALPORT/ALPORT_welcome.php" title="ALPORT syndrome and COL4A5 gene Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">ALPORT syndrome and COL4A5…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=COL4A5&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/PA26722" 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:2207" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0000299.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:88456" 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/COL4A5#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:88456" 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/1287/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/OMIA001112/" 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=1287" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00001263;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00001263 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00002280;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00002280 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-2281" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:1287" 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=COL4A5&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">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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303630
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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COLLAGEN, TYPE IV, ALPHA-5; COL4A5
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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COLLAGEN OF BASEMENT MEMBRANE, ALPHA-5 CHAIN
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=COL4A5" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">COL4A5</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
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<em>
|
|
Cytogenetic location: <a href="/geneMap/X/560?start=-3&limit=10&highlight=560">Xq22.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:108439838-108697545&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'})">X:108,439,838-108,697,545</a> </span>
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
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Location
|
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</th>
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<th>
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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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<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>COL4A5 encodes an alpha chain of type IV collagen, the major component of basement membranes (<a href="#12" class="mim-tip-reference" title="Hostikka, S. L., Eddy, R. L., Byers, M. G., Hoyhtya, M., Shows, T. B., Tryggvason, K. <strong>Identification of a distinct type IV collagen alpha chain with restricted kidney distribution and assignment of its gene to the locus of X chromosome-linked Alport syndrome.</strong> Proc. Nat. Acad. Sci. 87: 1606-1610, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1689491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1689491</a>] [<a href="https://doi.org/10.1073/pnas.87.4.1606" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1689491">Hostikka et al., 1990</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1689491" 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="#12" class="mim-tip-reference" title="Hostikka, S. L., Eddy, R. L., Byers, M. G., Hoyhtya, M., Shows, T. B., Tryggvason, K. <strong>Identification of a distinct type IV collagen alpha chain with restricted kidney distribution and assignment of its gene to the locus of X chromosome-linked Alport syndrome.</strong> Proc. Nat. Acad. Sci. 87: 1606-1610, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1689491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1689491</a>] [<a href="https://doi.org/10.1073/pnas.87.4.1606" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1689491">Hostikka et al. (1990)</a> identified a distinct type IV collagen alpha chain, which they referred to as alpha-5. From analysis of cDNA clones, they found that the collagenous Gly-Xaa-Yaa repeat sequence has 5 'imperfections' that coincide with those in the corresponding portion of the alpha-1(IV) chain. The noncollagenous (NC) domain has 12 conserved cysteine residues and 83% and 63% sequence identity to the NC portions of the alpha-1(IV) (<a href="/entry/120130">120130</a>) and alpha-2(IV) (<a href="/entry/120090">120090</a>) chains. Antiserum against an alpha-5(IV) synthetic peptide stained a polypeptide chain of about 185 kD by immunoblot analysis. Immunolocalization in the human kidney was almost completely restricted to the glomerulus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1689491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Zhou, J., Hertz, J. M., Leinonen, A., Tryggvason, K. <strong>Complete amino acid sequence of the human alpha-5(IV) collagen chain and identification of a single-base mutation in exon 23 converting glycine 521 in the collagenous domain to cysteine in an Alport syndrome patient.</strong> J. Biol. Chem. 267: 12475-12481, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1352287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1352287</a>]" pmid="1352287">Zhou et al. (1992)</a> found that the cDNA for the COL4A5 gene predicts a translation product with 1,685 amino acid residues: a 26-residue signal peptide, a 1,430-residue collagenous domain starting with a 14-residue noncollagenous sequence, and a gly-Xaa-Yaa-repeat sequence interrupted at 22 locations, followed by a 229-residue carboxyl-terminal noncollagenous domain. The calculated molecular mass of the mature chain is 158,303 Da. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1352287" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#35" class="mim-tip-reference" title="Zhou, J., Hostikka, S. L., Chow, L. T., Tryggvason, K. <strong>Characterization of the 3-prime half of the human type IV collagen alpha-5 gene that is affected in the Alport syndrome.</strong> Genomics 9: 1-9, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2004755/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2004755</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90214-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2004755">Zhou et al. (1991)</a> described the 3-prime half of the human COL4A5 gene, including the intron-exon structure. They determined the sequence of the 19 3-prime-most exons and their flanking sequences from genomic phage clones, with the exception of exon 15, which was sequenced after amplification from genomic DNA by PCR. The exon sizes in the 3-prime half of the gene bear a remarkable similarity to those observed in the alpha-1(IV) chain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2004755" 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="#29" class="mim-tip-reference" title="Vetrie, D., Flinter, F., Bobrow, M., Harris, A. <strong>Long-range mapping of the gene for the human alpha-5(IV) collagen chain at Xq22-q23.</strong> Genomics 12: 130-138, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1733850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1733850</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90415-o" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1733850">Vetrie et al. (1992)</a> constructed a 2.4-Mb long-range restriction map around the COL4A5 gene. High-resolution PFGE mapping with the rare-cutting enzyme XhoI showed that the gene is at least 110 kb long, one of the largest collagen genes characterized to date. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1733850" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Zhou, J., Leinonen, A., Tryggvason, K. <strong>Structure of the human type IV collagen COL4A5 gene.</strong> J. Biol. Chem. 269: 6608-6614, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8120014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8120014</a>]" pmid="8120014">Zhou et al. (1994)</a> determined that the COL4A5 gene contains 51 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8120014" 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 Southern analysis of somatic cell hybrids and by in situ hybridization, <a href="#12" class="mim-tip-reference" title="Hostikka, S. L., Eddy, R. L., Byers, M. G., Hoyhtya, M., Shows, T. B., Tryggvason, K. <strong>Identification of a distinct type IV collagen alpha chain with restricted kidney distribution and assignment of its gene to the locus of X chromosome-linked Alport syndrome.</strong> Proc. Nat. Acad. Sci. 87: 1606-1610, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1689491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1689491</a>] [<a href="https://doi.org/10.1073/pnas.87.4.1606" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1689491">Hostikka et al. (1990)</a> assigned the COL4A5 locus to Xq22. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1689491" 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>SLITs (see SLIT1; <a href="/entry/603742">603742</a>) are secreted glycoproteins that bind and activate ROBO receptors (see ROBO1; <a href="/entry/602430">602430</a>) and function in axon guidance during development. Using a zebrafish model, <a href="#30" class="mim-tip-reference" title="Xiao, T., Staub, W., Robles, E., Gosse, N. J., Cole, G. J., Baier, H. <strong>Assembly of lamina-specific neuronal connections by slit bound to type IV collagen.</strong> Cell 146: 164-176, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21729787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21729787</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21729787[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2011.06.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21729787">Xiao et al. (2011)</a> showed that Col4a5 on the surface of the tectum basement membrane bound Slit1 and guided retinal ganglion cell axons expressing Robo2 (<a href="/entry/602431">602431</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21729787" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#17" class="mim-tip-reference" title="Lemmink, H. H., Schroder, C. H., Monnens, L. A. H., Smeets, H. J. M. <strong>The clinical spectrum of type IV collagen mutations.</strong> Hum. Mutat. 9: 477-499, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9195222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9195222</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)9:6<477::AID-HUMU1>3.0.CO;2-#" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9195222">Lemmink et al. (1997)</a> gave a comprehensive review of the clinical manifestations associated with mutations in type IV collagen genes. The features vary from the severe clinically and genetically heterogeneous renal disorder Alport syndrome (see, e.g., <a href="/entry/301050">301050</a>), to autosomal dominant familial benign hematuria (BFH; <a href="/entry/141200">141200</a>). The authors stated that more than 160 different mutations had been identified in the COL4A5 gene. To the previously reported COL4A5 mutations, <a href="#17" class="mim-tip-reference" title="Lemmink, H. H., Schroder, C. H., Monnens, L. A. H., Smeets, H. J. M. <strong>The clinical spectrum of type IV collagen mutations.</strong> Hum. Mutat. 9: 477-499, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9195222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9195222</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)9:6<477::AID-HUMU1>3.0.CO;2-#" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9195222">Lemmink et al. (1997)</a> added 8 new ones identified in their group of patients with X-linked Alport syndrome (ALS1; <a href="/entry/301050">301050</a>). The spectrum of mutations was broad and provided insight into the clinical variability of Alport syndrome with respect to age at renal failure and accompanying features. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9195222" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>X-Linked Alport Syndrome</em></strong></p><p>
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Because X-linked Alport syndrome (ALS1; <a href="/entry/301050">301050</a>) had been mapped to Xq22, where the COL4A5 gene maps, <a href="#12" class="mim-tip-reference" title="Hostikka, S. L., Eddy, R. L., Byers, M. G., Hoyhtya, M., Shows, T. B., Tryggvason, K. <strong>Identification of a distinct type IV collagen alpha chain with restricted kidney distribution and assignment of its gene to the locus of X chromosome-linked Alport syndrome.</strong> Proc. Nat. Acad. Sci. 87: 1606-1610, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1689491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1689491</a>] [<a href="https://doi.org/10.1073/pnas.87.4.1606" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1689491">Hostikka et al. (1990)</a> sought a defect in the COL4A5 gene; no major rearrangement was found in a single male patient. However, <a href="#5" class="mim-tip-reference" title="Barker, D. F., Hostikka, S. L., Zhou, J., Chow, L. T., Oliphant, A. R., Gerken, S. C., Gregory, M. C., Skolnick, M. H., Atkin, C. L., Tryggvason, K. <strong>Identification of mutations in the COL4A5 collagen gene in Alport syndrome.</strong> Science 248: 1224-1227, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2349482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2349482</a>] [<a href="https://doi.org/10.1126/science.2349482" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2349482">Barker et al. (1990)</a> clinched the association between the COL4A5 gene and at least 1 form of Alport syndrome by demonstrating 3 structural aberrations in the COL4A5 gene (<a href="#0001">303630.0001</a>-<a href="#0003">303630.0003</a>) in separate families with Alport syndrome in Utah: an intragenic deletion, a PstI site variant, and an uncharacterized abnormality. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2349482+1689491" 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="Antignac, C., Knebelmann, B., Drouot, L., Gros, F., Deschenes, G., Hors-Cayla, M.-C., Zhou, J., Tryggvason, K., Grunfeld, J.-P., Broyer, M., Gubler, M.-C. <strong>Deletions in the COL4A5 collagen gene in X-linked Alport syndrome: characterization of the pathological transcripts in nonrenal cells and correlation with disease expression.</strong> J. Clin. Invest. 93: 1195-1207, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8132760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8132760</a>] [<a href="https://doi.org/10.1172/JCI117073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8132760">Antignac et al. (1994)</a> tested the COL4A5 gene in 88 unrelated male patients with X-linked Alport syndrome for major gene rearrangements by Southern blot analysis using COL4A5 cDNA probes. They detected 14 different deletions, providing a 16% deletion rate in that patient population. The deletions were dispersed all over the gene with different sizes ranging from 1 kb to the complete absence of the gene (more than 250 kb) in 1 patient. In 4 patients with intragenic deletions, absence of the alpha-3(IV) chain in the glomerular basement membrane was demonstrated by immunohistochemical methods. This finding supported the hypothesis that abnormalities of the alpha-5(IV) chain may prevent normal incorporation of the alpha-3(IV) chain into the glomerular basement membrane. Direct sequencing of cDNA amplified from lymphoblast mRNA of 4 patients with internal gene deletions, using appropriate combinations of primers amplifying across the predicted boundaries of the deletions, allowed <a href="#2" class="mim-tip-reference" title="Antignac, C., Knebelmann, B., Drouot, L., Gros, F., Deschenes, G., Hors-Cayla, M.-C., Zhou, J., Tryggvason, K., Grunfeld, J.-P., Broyer, M., Gubler, M.-C. <strong>Deletions in the COL4A5 collagen gene in X-linked Alport syndrome: characterization of the pathological transcripts in nonrenal cells and correlation with disease expression.</strong> J. Clin. Invest. 93: 1195-1207, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8132760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8132760</a>] [<a href="https://doi.org/10.1172/JCI117073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8132760">Antignac et al. (1994)</a> to determine the effect of genomic rearrangements on the transcripts and, by inference, on the alpha-5(IV) chain. Regardless of the extent of deletion and of the putative protein product, the 14 deletions occurred in patients with juvenile-type Alport syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8132760" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Lemmink, H. H., Mochizuki, T., van den Heuvel, L. P. W. J., Schroder, C. H., Barrientos, A., Monnens, L. A. H., van Oost, B. A., Brunner, H. G., Reeders, S. T., Smeets, H. J. M. <strong>Mutations in the type IV collagen alpha-3 (COL4A3) gene in autosomal recessive Alport syndrome.</strong> Hum. Molec. Genet. 3: 1269-1273, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7987301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7987301</a>] [<a href="https://doi.org/10.1093/hmg/3.8.1269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7987301">Lemmink et al. (1994)</a> stated that more than 60 different mutations had been detected in the COL4A5 gene in Alport patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7987301" 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="#14" class="mim-tip-reference" title="Knebelmann, B., Breillat, C., Forestier, L., Arrondel, C., Jacassier, D., Giatras, I., Drouot, L, Deschenes, G., Grunfeld, J.-P., Broyer, M., Gubler, M.-C., Antignac, C. <strong>Spectrum of mutations in the COL4A5 collagen gene in X-linked Alport syndrome.</strong> Am. J. Hum. Genet. 59: 1221-1232, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8940267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8940267</a>]" pmid="8940267">Knebelmann et al. (1996)</a> screened 48 of the 51 exons of the COL4A5 gene by SSCP analysis and identified 64 mutations and 10 sequence variants among 131 unrelated patients with X-linked Alport syndrome. They noted that the mutation detection rate was approximately 50%. <a href="#14" class="mim-tip-reference" title="Knebelmann, B., Breillat, C., Forestier, L., Arrondel, C., Jacassier, D., Giatras, I., Drouot, L, Deschenes, G., Grunfeld, J.-P., Broyer, M., Gubler, M.-C., Antignac, C. <strong>Spectrum of mutations in the COL4A5 collagen gene in X-linked Alport syndrome.</strong> Am. J. Hum. Genet. 59: 1221-1232, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8940267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8940267</a>]" pmid="8940267">Knebelmann et al. (1996)</a> hypothesized that this incomplete detection could be in part due to sensitivity of the SSCP technique, or to lack of detection of splice site mutations because of primer design. They noted that intronic changes such as inversions (shown to be pathogenic in hemophilia; see <a href="/entry/306700">306700</a> and <a href="#19" class="mim-tip-reference" title="Naylor, J., Brinke, A., Hassock, S., Green, P. M., Giannelli, F. <strong>Characteristic mRNA abnormality found in half the patients with severe haemophilia A is due to large DNA inversions.</strong> Hum. Molec. Genet. 2: 1773-1778, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8281136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8281136</a>] [<a href="https://doi.org/10.1093/hmg/2.11.1773" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8281136">Naylor et al., 1993</a>) and unstable trinucleotide repeat expansions (shown to be pathogenic in Friedreich ataxia; see <a href="/entry/229300">229300</a> and <a href="#8" class="mim-tip-reference" title="Campuzano, V., Montermini, L., Molto, M. D., Pianese, L., Cossee, M., Cavalcanti, F., Monros, E., Rodius, F., Duclos, F., Monticelli, A., Zara, F., Canizares, J., and 15 others. <strong>Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.</strong> Science 271: 1423-1427, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8596916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8596916</a>] [<a href="https://doi.org/10.1126/science.271.5254.1423" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8596916">Campuzano et al., 1996</a>) had not been ruled out as disease-causing changes in COL4A5. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8281136+8596916+8940267" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The large multiexonic COL4A5 gene had been difficult to screen; several studies detected only approximately 50% of the mutations in this gene. A partial explanation for this was suggested by the findings of <a href="#13" class="mim-tip-reference" title="King, K., Flinter, F. A., Nihalani, V., Green, P. M. <strong>Unusual deep intronic mutations in the COL4A5 gene cause X linked Alport syndrome.</strong> Hum. Genet. 111: 548-554, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12436246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12436246</a>] [<a href="https://doi.org/10.1007/s00439-002-0830-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12436246">King et al. (2002)</a>: they identified 3 novel intronic mutations that demonstrated that single base changes deep within introns can, and do, cause X-linked Alport syndrome. One mutation created a new donor splice site within an intron resulting in the inclusion of a novel in-frame cryptic exon; a second mutation resulted in a new exon splice enhancer sequence (ESE) that promoted splicing of a cryptic exon containing a stop codon; a third mutation was a base substitution within the polypyrimidine tract that precedes the acceptor splice site that resulted in exon skipping. All 3 cases would have been missed using an exon-by-exon DNA screening approach. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12436246" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Contiguous Gene Deletion Syndromes Involving COL4A5</em></strong></p><p>
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Antignac et al. (<a href="#1" class="mim-tip-reference" title="Antignac, C., Gros, F., Geffriaud, C., Kashtan, C., Proesmans, W., Tryggvason, K., Gubler, M. C. <strong>Alport syndrome (AS) and diffuse esophageal leiomyomatosis (DL): deletions in the 5-prime end and upstream region of the COL4A5 collagen gene. (Abstract)</strong> Am. J. Hum. Genet. 51 (suppl.): A7, 1992."None>1992</a>, <a href="#3" class="mim-tip-reference" title="Antignac, C., Zhou, J., Sanak, M., Cochat, P., Roussel, B., Deschenes, G., Gros, F., Knebelmann, B., Hors-Cayla, M.-C., Tryggvason, K., Gubler, M.-C. <strong>Alport syndrome and diffuse leiomyomatosis: deletions in the 5-prime end of the COL4A5 collagen gene.</strong> Kidney Int. 42: 1178-1183, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1453602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1453602</a>] [<a href="https://doi.org/10.1038/ki.1992.402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1453602">1992</a>) presented evidence that the syndrome of diffuse esophageal leiomyomatosis and Alport syndrome (<a href="/entry/308940">308940</a>), which had been reported in 24 patients, most of whom also suffered from congenital cataract, represents a contiguous gene deletion syndrome. They found patients with deletion in the 5-prime part of the COL4A5 gene, extending upstream for at least 700 bp. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1453602" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Zhou, J., Mochizuki, T., Smeets, H., Antignac, C., Laurila, P., de Paepe, A., Tryggvason, K., Reeders, S. T. <strong>Deletion of the paired alpha-5(IV) and alpha-6(IV) collagen genes in inherited smooth muscle tumors.</strong> Science 261: 1167-1169, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8356449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8356449</a>] [<a href="https://doi.org/10.1126/science.8356449" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8356449">Zhou et al. (1993)</a> demonstrated that the leiomyomatosis-nephropathy syndrome represents a contiguous gene syndrome due to deletions that disrupt the COL4A5 and COL4A6 (<a href="/entry/303631">303631</a>) genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8356449" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Evidence for Digenic Inheritance</em></strong></p><p>
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Using massively parallel sequencing, <a href="#18" class="mim-tip-reference" title="Mencarelli, M. A., Heidet, L., Storey, H., van Geel, M., Knebelmann, B., Fallerini, C., Miglietti, N., Antonucci, M. F., Cetta, F., Sayer, J. A., van den Wijngaard, A., Yau, S., Mari, F., Bruttini, M., Ariani, F., Dahan, K., Smeets, B., Antignac, C., Flinter, F., Renieri, A. <strong>Evidence of digenic inheritance in Alport syndrome.</strong> J. Med. Genet. 52: 163-174, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25575550/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25575550</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102822" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25575550">Mencarelli et al. (2015)</a> identified 11 patients with Alport syndrome who had pathogenic mutations in 2 of the 3 collagen IV genes. Seven patients had a combination of mutations in COL4A3 (<a href="/entry/120070">120070</a>) and COL4A4 (<a href="/entry/120131">120131</a>), whereas 4 patients had 1 or 2 mutations in COL4A4 associated with mutation in COL4A5. In no case were there simultaneous COL4A3 and COL4A5 mutations. For each of these 11 probands, between 1 and 12 family members were recruited, for an average of 4 members per family (56 individuals ranging from 5-80 years). Altogether, 23 unique mutations were found, including 7 in COL4A3, 12 in COL4A4, and 4 in COL4A5. The mutations involved all domains of the collagen molecules, although the majority of missense mutations (11 of 13) affected the triple-helical collagenous domain, and 11 missense mutations substituted a critical glycine residue in this domain. Thirteen mutations had been previously reported and 10 were novel. Among the 8 patients with mutations in COL4A4 and COL4A5 (4 probands and 4 family members), the phenotypes included hematuria with proteinuria in 6 individuals and end-stage renal disease in 2 individuals. In 1 family, the proband carried 2 in trans mutations in COL4A4 in addition to the mutation in COL4A5. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25575550" 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>Canine X-linked hereditary nephritis is an animal model for Alport syndrome. <a href="#31" class="mim-tip-reference" title="Zheng, K., Thorner, P. S., Marrano, P., Baumal, R., McInnes, R. R. <strong>Canine X chromosome-linked hereditary nephritis: a genetic model for human X-linked hereditary nephritis resulting from a single base mutation in the gene encoding the alpha-5 chain of collagen type IV.</strong> Proc. Nat. Acad. Sci. 91: 3989-3993, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8171024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8171024</a>] [<a href="https://doi.org/10.1073/pnas.91.9.3989" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8171024">Zheng et al. (1994)</a> used information on the nucleotide sequence for human COL4A5 cDNA to construct a set of primers for dog kidney cDNA. They found that the nucleotide sequence encoding the noncollagenous domain NC1 hybridized to the human X chromosome and was 93% identical at the DNA level and 97% identical at the protein level to the human NC1 domain. Sequence analysis demonstrated a G-to-T transversion in affected dogs, changing a codon in exon 35 from GGA (glycine) to a stop codon (TGA). Transcription of the COL4A5 gene was reduced by a factor of approximately 10 in the affected dog. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8171024" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Thorner, P. S., Zheng, K., Kalluri, R., Jacobs, R., Hudson, B. G. <strong>Coordinate gene expression of the alpha-3, alpha-4, and alpha-5 chains if collagen type IV.</strong> J. Biol. Chem. 271: 13821-13828, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8662866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8662866</a>] [<a href="https://doi.org/10.1074/jbc.271.23.13821" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8662866">Thorner et al. (1996)</a> examined expression of the canine collagen type IV genes in the kidney. They detected alpha-3 (<a href="/entry/120070">120070</a>), alpha-4 (<a href="/entry/120131">120131</a>), and alpha-5 chains in the noncollagenous domain of type IV collagen isolated from normal dog glomeruli but not in affected dog glomeruli. In addition to a significantly reduced level of COL4A5 gene expression (approximately 10% of normal), expression of the COL4A3 and COL4A4 genes was also decreased to 14-23% and 11-17%, respectively. These findings suggested to <a href="#26" class="mim-tip-reference" title="Thorner, P. S., Zheng, K., Kalluri, R., Jacobs, R., Hudson, B. G. <strong>Coordinate gene expression of the alpha-3, alpha-4, and alpha-5 chains if collagen type IV.</strong> J. Biol. Chem. 271: 13821-13828, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8662866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8662866</a>] [<a href="https://doi.org/10.1074/jbc.271.23.13821" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8662866">Thorner et al. (1996)</a> a mechanism which coordinates the expression of these 3 basement membrane proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8662866" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0001 ALPORT SYNDROME 1, X-LINKED</strong>
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COL4A5, EX5-10DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000011199" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011199" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011199</a>
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<p>In Utah kindred EP with Alport syndrome (ALS1; <a href="/entry/301050">301050</a>), <a href="#5" class="mim-tip-reference" title="Barker, D. F., Hostikka, S. L., Zhou, J., Chow, L. T., Oliphant, A. R., Gerken, S. C., Gregory, M. C., Skolnick, M. H., Atkin, C. L., Tryggvason, K. <strong>Identification of mutations in the COL4A5 collagen gene in Alport syndrome.</strong> Science 248: 1224-1227, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2349482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2349482</a>] [<a href="https://doi.org/10.1126/science.2349482" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2349482">Barker et al. (1990)</a> found deletion of the portion of the COL4A5 gene containing exons 5 through 10 (exons having been numbered with exon 1 being the most 3-prime exon). The deafness in the proband with the large deletion was among the most profound encountered in Alport kindreds, implying that the severity of deafness is correlated with the severity of the defect in COL4A5. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2349482" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 ALPORT SYNDROME 1, X-LINKED</strong>
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COL4A5, CYS108SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104886287 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104886287;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104886287" 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=rs104886287" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000021640 OR RCV001047411" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000021640, RCV001047411" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000021640...</a>
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<p>In the historic kindred P in Utah studied by Perkoff et al. (<a href="#22" class="mim-tip-reference" title="Perkoff, G. T., Stephens, F. E., Dolowitz, D. A., Tyler, F. H. <strong>A clinical study of hereditary interstitial pyelonephritis.</strong> Arch. Intern. Med. 88: 191-200, 1951.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14856448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14856448</a>] [<a href="https://doi.org/10.1001/archinte.1951.03810080059006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14856448">1951</a>, <a href="#21" class="mim-tip-reference" title="Perkoff, G. T., Nugent, C. A., Jr., Dolowitz, D. A., Stephens, F. E., Carnes, W. H., Tyler, F. H. <strong>A follow-up study of hereditary chronic nephritis.</strong> Arch. Intern. Med. 102: 733-746, 1958.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13582260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13582260</a>] [<a href="https://doi.org/10.1001/archinte.1958.00260220049005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13582260">1958</a>) and later by <a href="#10" class="mim-tip-reference" title="Hasstedt, S. J., Atkin, C. L. <strong>X-linked inheritance of Alport syndrome: family P revisited.</strong> Am. J. Hum. Genet. 35: 1241-1251, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6650503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6650503</a>]" pmid="6650503">Hasstedt and Atkin (1983)</a>, <a href="#5" class="mim-tip-reference" title="Barker, D. F., Hostikka, S. L., Zhou, J., Chow, L. T., Oliphant, A. R., Gerken, S. C., Gregory, M. C., Skolnick, M. H., Atkin, C. L., Tryggvason, K. <strong>Identification of mutations in the COL4A5 collagen gene in Alport syndrome.</strong> Science 248: 1224-1227, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2349482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2349482</a>] [<a href="https://doi.org/10.1126/science.2349482" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2349482">Barker et al. (1990)</a> demonstrated that a PstI site variant segregated in complete linkage with the presence or absence of the Alport phenotype (ALS1; <a href="/entry/301050">301050</a>). All 23 gene-carrying mothers were heterozygous; a total of 45 sons showed complete linkage. In an addendum, <a href="#5" class="mim-tip-reference" title="Barker, D. F., Hostikka, S. L., Zhou, J., Chow, L. T., Oliphant, A. R., Gerken, S. C., Gregory, M. C., Skolnick, M. H., Atkin, C. L., Tryggvason, K. <strong>Identification of mutations in the COL4A5 collagen gene in Alport syndrome.</strong> Science 248: 1224-1227, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2349482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2349482</a>] [<a href="https://doi.org/10.1126/science.2349482" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2349482">Barker et al. (1990)</a> stated that by PCR amplification and DNA sequencing, the PstI variant had been shown to be due to a single basepair change that converted a highly conserved cysteine codon in the noncollagenase (NC) domain to a codon for serine (C108S). (The NC domain of glomerular basement membrane type IV collagen has been shown to be absent or altered in Alport syndrome on the basis of studies with antibodies directed against this portion of the molecule.) <a href="#32" class="mim-tip-reference" title="Zhou, J., Barker, D. F., Hostikka, S. L., Gregory, M. C., Atkin, C. L., Tryggvason, K. <strong>Single base mutation in alpha-5(IV) collagen chain gene converting a conserved cysteine to serine in Alport syndrome.</strong> Genomics 9: 10-18, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1672282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1672282</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90215-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1672282">Zhou et al. (1991)</a> described the generation of a new BglII site and showed that the cys-to-ser change occurred in the third to the last exon. <a href="#7" class="mim-tip-reference" title="Boye, E., Vetrie, D., Flinter, F., Buckle, B., Pihlajaniemi, T., Hamalainen, E.-R., Myers, J. C., Bobrow, M., Harris, A. <strong>Major rearrangements in the alpha-5-(IV) collagen gene in three patients with Alport syndrome.</strong> Genomics 11: 1125-1132, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1783380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1783380</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90040-l" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1783380">Boye et al. (1991)</a> commented that the defect had been defined as a G-to-C transition in exon 3 that created both a PstI and a BglII site. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1783380+1672282+2349482+13582260+14856448+6650503" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 ALPORT SYNDROME 1, X-LINKED</strong>
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COL4A5, 10-15-KB INS, 40-KB DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000011201 OR RCV000011206" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011201, RCV000011206" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011201...</a>
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<p>Through an analysis of the 3-prime end of the COL4A5 gene using 3 cDNA clones, <a href="#7" class="mim-tip-reference" title="Boye, E., Vetrie, D., Flinter, F., Buckle, B., Pihlajaniemi, T., Hamalainen, E.-R., Myers, J. C., Bobrow, M., Harris, A. <strong>Major rearrangements in the alpha-5-(IV) collagen gene in three patients with Alport syndrome.</strong> Genomics 11: 1125-1132, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1783380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1783380</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90040-l" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1783380">Boye et al. (1991)</a> found mutations in 3 of 38 patients with Alport syndrome (ALS1; <a href="/entry/301050">301050</a>). One patient had a complex insertion/deletion mutation. Using pulsed field gel electrophoresis, <a href="#28" class="mim-tip-reference" title="Vetrie, D., Boye, E., Flinter, F., Bobrow, M., Harris, A. <strong>DNA rearrangements in the alpha-5(IV) collagen gene (COL4A5) of individuals with Alport syndrome: further refinement using pulsed-field gel electrophoresis.</strong> Genomics 14: 624-633, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1330889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1330889</a>] [<a href="https://doi.org/10.1016/s0888-7543(05)80161-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1330889">Vetrie et al. (1992)</a> found that the mutation involved an intragenic insertion of 10 to 15 kb and an extragenic deletion of 40 kb, with an overall deletion of 25 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1783380+1330889" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 ALPORT SYNDROME 1, X-LINKED</strong>
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COL4A5, 450-KB DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000011202" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011202" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011202</a>
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<p>Through an analysis of the 3-prime end of the COL4A5 gene using 3 cDNA clones, <a href="#7" class="mim-tip-reference" title="Boye, E., Vetrie, D., Flinter, F., Buckle, B., Pihlajaniemi, T., Hamalainen, E.-R., Myers, J. C., Bobrow, M., Harris, A. <strong>Major rearrangements in the alpha-5-(IV) collagen gene in three patients with Alport syndrome.</strong> Genomics 11: 1125-1132, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1783380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1783380</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90040-l" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1783380">Boye et al. (1991)</a> found mutations in 3 of 38 patients with Alport syndrome (ALS1; <a href="/entry/301050">301050</a>). One patient had a deletion of at least 35 kb. Using pulsed field gel electrophoresis, <a href="#28" class="mim-tip-reference" title="Vetrie, D., Boye, E., Flinter, F., Bobrow, M., Harris, A. <strong>DNA rearrangements in the alpha-5(IV) collagen gene (COL4A5) of individuals with Alport syndrome: further refinement using pulsed-field gel electrophoresis.</strong> Genomics 14: 624-633, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1330889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1330889</a>] [<a href="https://doi.org/10.1016/s0888-7543(05)80161-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1330889">Vetrie et al. (1992)</a> found that the mutation involved deletion of 450-kb, including approximately 12 kb of the 3-prime end (exons 1-6). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1783380+1330889" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 ALPORT SYNDROME 1, X-LINKED</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000011203" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011203" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011203</a>
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<p>In a 12-year-old Italian boy with Alport syndrome (ALS1; <a href="/entry/301050">301050</a>), <a href="#24" class="mim-tip-reference" title="Renieri, A., Seri, M., Myers, J. C., Pihlajaniemi, T., Sessa, A., Rizzoni, G., De Marchi, M. <strong>Alport syndrome caused by a 5-prime deletion within the COL4A5 gene.</strong> Hum. Genet. 89: 120-121, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1577459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1577459</a>] [<a href="https://doi.org/10.1007/BF00207059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1577459">Renieri et al. (1992)</a> found a large deletion (more than 38 kb) that included the 5-prime part of the COL4A5 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1577459" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 ALPORT SYNDROME 1, X-LINKED</strong>
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COL4A5, GLY1143ASP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104886229 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104886229;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104886229" 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=rs104886229" 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=RCV000011204" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011204" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011204</a>
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<p>In 1 of 20 Danish kindreds with Alport syndrome (ALS1; <a href="/entry/301050">301050</a>), <a href="#34" class="mim-tip-reference" title="Zhou, J., Hertz, J. M., Tryggvason, K. <strong>Mutation in the alpha-5(IV) collagen chain in juvenile-onset Alport syndrome without hearing loss or ocular lesions: detection by denaturing gradient gel electrophoresis of a PCR product.</strong> Am. J. Hum. Genet. 50: 1291-1300, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1598909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1598909</a>]" pmid="1598909">Zhou et al. (1992)</a> found a GGC-to-GAC mutation changing glycine-1143 to aspartate. Substitution of any amino acid for glycine-1143, located in the collagenous domain of the alpha-5(IV) chain, would be expected to interfere with the maintenance of the triple-helical conformation of the collagen molecule and, in turn, weaken the glomerular basement membrane framework, leading to increased permeability. The proband was a 27-year-old male who developed hematuria in childhood and terminal renal failure at the age of 25 years. He had no hearing loss or ocular lesions. Electron microscopy demonstrated splitting of the lamina densa of the glomerular basement membrane. The proband's mother had had persistent microscopic hematuria since the age of 40 years but no other manifestations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1598909" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 ALPORT SYNDROME 1, X-LINKED</strong>
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COL4A5, GLY325ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104886088 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104886088;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104886088" 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=rs104886088" 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=RCV000011205 OR RCV000521446 OR RCV004609294" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011205, RCV000521446, RCV004609294" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011205...</a>
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<span class="mim-text-font">
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<p>In a kindred with many members affected with adult-type X-linked Alport syndrome (ALS1; <a href="/entry/301050">301050</a>), <a href="#15" class="mim-tip-reference" title="Knebelmann, B., Deschenes, G., Gros, F., Hors, M.-C., Grunfeld, J.-P., Zhou, J., Tryggvason, K., Gubler, M.-C., Antignac, C. <strong>Substitution of arginine for glycine 325 in the collagen alpha-5 (IV) chain associated with X-linked Alport syndrome: characterization of the mutation by direct sequencing of PCR-amplified lymphoblast cDNA fragments.</strong> Am. J. Hum. Genet. 51: 135-142, 1992. Note: Erratum: Am. J. Hum. Genet. 51: 942 only, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1376965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1376965</a>]" pmid="1376965">Knebelmann et al. (1992)</a> found by Southern blot analysis a loss of an MspI restriction site in the COL4A5 gene. Direct sequencing of cDNA demonstrated a gly325-to-arg (G325R) mutation. <a href="#15" class="mim-tip-reference" title="Knebelmann, B., Deschenes, G., Gros, F., Hors, M.-C., Grunfeld, J.-P., Zhou, J., Tryggvason, K., Gubler, M.-C., Antignac, C. <strong>Substitution of arginine for glycine 325 in the collagen alpha-5 (IV) chain associated with X-linked Alport syndrome: characterization of the mutation by direct sequencing of PCR-amplified lymphoblast cDNA fragments.</strong> Am. J. Hum. Genet. 51: 135-142, 1992. Note: Erratum: Am. J. Hum. Genet. 51: 942 only, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1376965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1376965</a>]" pmid="1376965">Knebelmann et al. (1992)</a> commented that this type of mutation in the COL1A1 and COL1A2 genes is often associated with osteogenesis imperfecta. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1376965" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0008" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0008 ALPORT SYNDROME 1, X-LINKED</strong>
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COL4A5, 3-PRIME AND PARTIAL 5-PRIME DELETION
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000011206" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011206" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011206</a>
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<p>In a patient with severe Alport syndrome (ALS1; <a href="/entry/301050">301050</a>) and end-stage renal disease (ESRD) by age 17, accompanied by deafness, <a href="#25" class="mim-tip-reference" title="Smeets, H. J. M., Melenhorst, J. J., Lemmink, H. H., Schroder, C. H., Nelen, M. R., Zhou, J., Hostikka, S. L., Tryggvason, K., Ropers, H.-H., Jansweijer, M. C. E., Monnens, L. A. H., Brunner, H. G., van Oost, B. A. <strong>Different mutations in the COL4A5 collagen gene in two patients with different features of Alport syndrome.</strong> Kidney Int. 42: 83-88, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1635357/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1635357</a>] [<a href="https://doi.org/10.1038/ki.1992.264" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1635357">Smeets et al. (1992)</a> found deletion of exons encoding the noncollagenous domain and part of the collagenous region of the collagen IV alpha-5 chain. Transplantation with the kidney of an unrelated donor was followed by rapidly progressive anti-glomerular basement membrane nephritis, leading to loss of the transplant almost 7 months after grafting. His affected maternal grandfather died from renal failure at the age of 26 years. The deletion appeared to be present in heterozygous form in the mother and sister, both of whom displayed hematuria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1635357" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0009" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0009 ALPORT SYNDROME 1, X-LINKED</strong>
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</h4>
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COL4A5, TRP1538SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104886293 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104886293;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104886293" 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=rs104886293" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000021630" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000021630" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000021630</a>
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<span class="mim-text-font">
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<p>In 2 brothers with Alport syndrome (ALS1; <a href="/entry/301050">301050</a>) without deafness and with relatively late onset, as well as in their carrier mother, <a href="#25" class="mim-tip-reference" title="Smeets, H. J. M., Melenhorst, J. J., Lemmink, H. H., Schroder, C. H., Nelen, M. R., Zhou, J., Hostikka, S. L., Tryggvason, K., Ropers, H.-H., Jansweijer, M. C. E., Monnens, L. A. H., Brunner, H. G., van Oost, B. A. <strong>Different mutations in the COL4A5 collagen gene in two patients with different features of Alport syndrome.</strong> Kidney Int. 42: 83-88, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1635357/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1635357</a>] [<a href="https://doi.org/10.1038/ki.1992.264" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1635357">Smeets et al. (1992)</a> identified a C-to-G transversion changing a tryptophan codon (TGG) to a serine codon (TCG) in exon 4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1635357" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0010" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0010 ALPORT SYNDROME 1, X-LINKED</strong>
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COL4A5, GLY521CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104886121 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104886121;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104886121" 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=rs104886121" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000011208" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011208" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011208</a>
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<p>By analysis of genomic DNA from affected members of a kindred with Alport syndrome (ALS1; <a href="/entry/301050">301050</a>), <a href="#33" class="mim-tip-reference" title="Zhou, J., Hertz, J. M., Leinonen, A., Tryggvason, K. <strong>Complete amino acid sequence of the human alpha-5(IV) collagen chain and identification of a single-base mutation in exon 23 converting glycine 521 in the collagenous domain to cysteine in an Alport syndrome patient.</strong> J. Biol. Chem. 267: 12475-12481, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1352287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1352287</a>]" pmid="1352287">Zhou et al. (1992)</a> demonstrated a new HindIII cleavage site. The mutation was found to be located in exon 23: a G-to-T transversion changing the GGT codon of glycine-521 to cysteine (G521C). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1352287" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0011 ALPORT SYNDROME 1, X-LINKED</strong>
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COL4A5, GLY325GLU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104886091 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104886091;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104886091" 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=rs104886091" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000011209" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011209" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011209</a>
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<span class="mim-text-font">
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<p>In a 6-year-old Italian patient with Alport syndrome (ALS1; <a href="/entry/301050">301050</a>), <a href="#23" class="mim-tip-reference" title="Renieri, A., Seri, M., Myers, J. C., Pihlajaniemi, T., Massella, L., Rizzoni, G., De Marchi, M. <strong>De novo mutation in the COL4A5 gene converting glycine 325 to glutamic acid in Alport syndrome.</strong> Hum. Molec. Genet. 1: 127-129, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1363780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1363780</a>] [<a href="https://doi.org/10.1093/hmg/1.2.127" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1363780">Renieri et al. (1992)</a> demonstrated a de novo mutation resulting in substitution of a glutamic acid for a glycine residue at position 325 (G325E) in the triple helical region of the alpha-5(IV) chain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1363780" 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">rs104886450 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104886450;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104886450" 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=rs104886450" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs144282156 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs144282156;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/rs144282156?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=rs144282156" 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=rs144282156" 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=RCV000011210 OR RCV000782218 OR RCV001580476 OR RCV003417844 OR RCV003886365" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011210, RCV000782218, RCV001580476, RCV003417844, RCV003886365" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011210...</a>
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<p><a href="#9" class="mim-tip-reference" title="Guo, C., Van Damme, B., Vanrenterghem, Y., Devriendt, K., Cassiman, J.-J., Marynen, P. <strong>Severe Alport phenotype in a woman with two missense mutations in the same COL4A5 gene and preponderant inactivation of the X chromosome carrying the normal allele.</strong> J. Clin. Invest. 95: 1832-1837, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7706490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7706490</a>] [<a href="https://doi.org/10.1172/JCI117862" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7706490">Guo et al. (1995)</a> found 2 de novo missense mutations in the COL4A5 gene in a female patient who presented at the age of 19 with microscopic hematuria and nephrotic syndrome. The diagnosis of Alport syndrome (ALS1; <a href="/entry/301050">301050</a>) was confirmed by the finding of typical glomerular basement membrane abnormalities on a renal biopsy taken at that age. Renal function deteriorated progressively and chronic hemodialysis was started at the age of 30. A cadaveric kidney transplantation was done 2 years later. There was no hearing loss and there were no clinical features of Turner syndrome. Her height was 162 cm and she had a normal menstrual pattern. Family history showed that her father died at age 36 of renal failure associated with sensorineural hearing loss. An elder sister had microscopic hematuria, proteinuria with normal kidney function, and hearing loss. One mutation (G289V) occurred in exon 15 and converted a glycine in the collagenous domain of COL4A5 to a valine. The second mutation, located in exon 46, substituted a cysteine proximal to the NC1 domain of COL4A5 for an arginine (R1421C). Both mutations were present in more than 90% of the mRNA of white blood cells and kidney, while at the genomic level, the patient was heterozygous for both mutations. The 2 mutations therefore occurred in the same COL4A5 allele. <a href="#9" class="mim-tip-reference" title="Guo, C., Van Damme, B., Vanrenterghem, Y., Devriendt, K., Cassiman, J.-J., Marynen, P. <strong>Severe Alport phenotype in a woman with two missense mutations in the same COL4A5 gene and preponderant inactivation of the X chromosome carrying the normal allele.</strong> J. Clin. Invest. 95: 1832-1837, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7706490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7706490</a>] [<a href="https://doi.org/10.1172/JCI117862" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7706490">Guo et al. (1995)</a> found no mutations in the COL4A5 promoter region by sequencing, nor did they detect a major rearrangement of the normal allele. A skewed pattern of X inactivation was demonstrated in DNA isolated from the patient's kidney and white blood cells; a normal COL4A5 allele was inactivated in more than 90% of the X chromosomes. The skewed inactivation pattern was thought to be responsible for the absence of detectable normal COL4A5 mRNA and, hence, for the severe phenotype in this woman. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7706490" 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">rs104886043 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104886043;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104886043" 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=rs104886043" 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=RCV000011211" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011211" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011211</a>
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<p><a href="#27" class="mim-tip-reference" title="Turco, A. E., Rossetti, S., Biasi, M. O., Rizzoni, G., Massella, L., Saarinen, N. H., Renieri, A., Pignatti, P. F., De Marchi, M. <strong>A novel missense mutation in exon 3 of the COL4A5 gene associated with late-onset Alport syndrome.</strong> Clin. Genet. 48: 261-263, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8825605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8825605</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1995.tb04101.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8825605">Turco et al. (1995)</a> found a novel missense mutation in exon 3 of the COL4A5 gene in a male patient with late-onset Alport syndrome (ALS1; <a href="/entry/301050">301050</a>). Microhematuria was first discovered at age 22 years. He reached end-stage renal disease at age 40, and had a successful transplant at age 41. He had bilateral sensorineural hearing loss and subcapsular posterior lens opacities. The proband had 2 daughters, aged 15 and 13 years. The older daughter had had mild irregular microhematuria since age 2, with normal renal function; a renal biopsy at age 8 showed a thinning of the glomerular basement membrane. In the other daughter, microhematuria was discovered at age 7. Ocular and auditory assessments were normal in both sisters. The proband's mother was known to have microhematuria. The mutation was a G-to-A transition which resulted in a gly54-to-asp (G54D) substitution and abolished a BstNI restriction site. The findings were consistent with the generalization that more slowly progressive forms of Alport syndrome tend to be associated with missense mutations rather than large deletions or frameshifts. The authors stated that this was the first mutation described in the N-terminus triple-helical 7S domain of the COL4A5 gene in an Alport syndrome patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8825605" 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">rs104886303 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104886303;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104886303" 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=rs104886303" 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=RCV000011212 OR RCV000440813 OR RCV001195698 OR RCV003398479" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011212, RCV000440813, RCV001195698, RCV003398479" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011212...</a>
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<p><a href="#6" class="mim-tip-reference" title="Barker, D. F., Pruchno, C. J., Jiang, X., Atkin, C. L., Stone, E. M., Denison, J. C., Fain, P. R., Gregory, M. C. <strong>A mutation causing Alport syndrome with tardive hearing loss is common in the western United States.</strong> Am. J. Hum. Genet. 58: 1157-1165, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8651292/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8651292</a>]" pmid="8651292">Barker et al. (1996)</a> identified a novel leu1649-to-arg (L1649R) mutation in the COL4A5 gene in Alport syndrome (ALS1; <a href="/entry/301050">301050</a>) patients. In contrast to most described COL4A5 mutations in Alport syndrome, each of which accounts for the disease in a single family, the L1649R mutation was found in over 7% of the 121 families studied. In males with the L1649R mutation, renal failure preceded hearing loss by approximately 10 years, and the cumulative frequency of hearing loss is 60% by age 60. <a href="#6" class="mim-tip-reference" title="Barker, D. F., Pruchno, C. J., Jiang, X., Atkin, C. L., Stone, E. M., Denison, J. C., Fain, P. R., Gregory, M. C. <strong>A mutation causing Alport syndrome with tardive hearing loss is common in the western United States.</strong> Am. J. Hum. Genet. 58: 1157-1165, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8651292/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8651292</a>]" pmid="8651292">Barker et al. (1996)</a> noted that substantial variability occurs in the ages at appearance of end-stage renal disease and functional hearing loss among individuals with identical mutations, emphasizing the fallibility of generalizations about the phenotype associated with a specific mutation that is observed in only a small number of Alport syndrome patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8651292" 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> rs104886308 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104886308;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/rs104886308?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=rs104886308" 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=rs104886308" 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=RCV000011213 OR RCV000518046 OR RCV001328066 OR RCV003934823" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011213, RCV000518046, RCV001328066, RCV003934823" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011213...</a>
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<p>Nearly all cases of Alport syndrome (ALS1; <a href="/entry/301050">301050</a>) involve distinct mutations, as expected for an X-linked disease that significantly reduces the fitness of affected males. A few COL4A5 mutations appear to be associated with reduced disease severity and may account for an appreciable proportion of late-onset Alport syndrome in populations where a founder effect has occurred. <a href="#4" class="mim-tip-reference" title="Barker, D. F., Denison, J. C., Atkin, C. L., Gregory, M. C. <strong>Common ancestry of three Ashkenazi-American families with Alport syndrome and COL4A5 R1677Q.</strong> Hum. Genet. 99: 681-684, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9150741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9150741</a>] [<a href="https://doi.org/10.1007/s004390050429" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9150741">Barker et al. (1997)</a> reported a novel mutation in the COL4A5 gene, R1677Q. It was detected in 3 independently ascertained Ashkenazi-American families, caused a relatively mild form of nephritis with typical onset in the fourth or fifth decade, and may be involved in the etiology of a large proportion of adult-onset hereditary nephritis in Ashkenazi Jews. The mutation was a G-to-A transition in nucleotide 5232 and represented a change at a CpG dinucleotide. The same haplotype of COL4A5-linked markers was found in affected males of the 3 kindreds. No genealogic connection could be established. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9150741" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Ohkubo, S., Takeda, H., Higashide, T., Ito, M., Sakurai, M., Shirao, Y., Yanagida, T., Oda, Y., Sado, Y. <strong>Immunohistochemical and molecular genetic evidence for type IV collagen alpha-5 chain abnormality in the anterior lenticonus associated with Alport syndrome.</strong> Arch. Ophthal. 121: 846-850, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12796257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12796257</a>] [<a href="https://doi.org/10.1001/archopht.121.6.846" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12796257">Ohkubo et al. (2003)</a> found immunohistochemical evidence that the normal anterior lens capsule expressed all of the A4 collagen chains. They also examined the anterior lens capsule of a patient with Alport syndrome due to the R1677X nonsense mutation. The patient's anterior lenticonus resulted in a lack of immunoreactivity to 4A3 to 4A6 chains in the anterior lens capsule. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12796257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Hertz2005" class="mim-tip-reference" title="Hertz, J. M., Persson, U., Juncker, I., Segelmark, M. <strong>Alport syndrome caused by inversion of a 21 Mb fragment of the long arm of the X-chromosome comprising exon 9 through 51 of the COL4A5 gene.</strong> Hum. Genet. 118: 23-28, 2005.">Hertz et al. (2005)</a>
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<strong>Alport syndrome (AS) and diffuse esophageal leiomyomatosis (DL): deletions in the 5-prime end and upstream region of the COL4A5 collagen gene. (Abstract)</strong>
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Antignac, C., Knebelmann, B., Drouot, L., Gros, F., Deschenes, G., Hors-Cayla, M.-C., Zhou, J., Tryggvason, K., Grunfeld, J.-P., Broyer, M., Gubler, M.-C.
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[<a href="https://doi.org/10.1172/JCI117073" target="_blank">Full Text</a>]
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Antignac, C., Zhou, J., Sanak, M., Cochat, P., Roussel, B., Deschenes, G., Gros, F., Knebelmann, B., Hors-Cayla, M.-C., Tryggvason, K., Gubler, M.-C.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1453602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1453602</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1453602" 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/ki.1992.402" target="_blank">Full Text</a>]
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Barker, D. F., Denison, J. C., Atkin, C. L., Gregory, M. C.
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<strong>Common ancestry of three Ashkenazi-American families with Alport syndrome and COL4A5 R1677Q.</strong>
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Hum. Genet. 99: 681-684, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9150741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9150741</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9150741" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004390050429" target="_blank">Full Text</a>]
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Barker, D. F., Hostikka, S. L., Zhou, J., Chow, L. T., Oliphant, A. R., Gerken, S. C., Gregory, M. C., Skolnick, M. H., Atkin, C. L., Tryggvason, K.
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<strong>Identification of mutations in the COL4A5 collagen gene in Alport syndrome.</strong>
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Science 248: 1224-1227, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2349482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2349482</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2349482" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.2349482" target="_blank">Full Text</a>]
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Barker, D. F., Pruchno, C. J., Jiang, X., Atkin, C. L., Stone, E. M., Denison, J. C., Fain, P. R., Gregory, M. C.
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<strong>A mutation causing Alport syndrome with tardive hearing loss is common in the western United States.</strong>
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Am. J. Hum. Genet. 58: 1157-1165, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8651292/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8651292</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8651292" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Boye, E., Vetrie, D., Flinter, F., Buckle, B., Pihlajaniemi, T., Hamalainen, E.-R., Myers, J. C., Bobrow, M., Harris, A.
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<strong>Major rearrangements in the alpha-5-(IV) collagen gene in three patients with Alport syndrome.</strong>
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Genomics 11: 1125-1132, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1783380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1783380</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1783380" 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/10.1016/0888-7543(91)90040-l" target="_blank">Full Text</a>]
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Campuzano, V., Montermini, L., Molto, M. D., Pianese, L., Cossee, M., Cavalcanti, F., Monros, E., Rodius, F., Duclos, F., Monticelli, A., Zara, F., Canizares, J., and 15 others.
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<strong>Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8596916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8596916</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8596916" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.271.5254.1423" target="_blank">Full Text</a>]
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Guo, C., Van Damme, B., Vanrenterghem, Y., Devriendt, K., Cassiman, J.-J., Marynen, P.
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<strong>Severe Alport phenotype in a woman with two missense mutations in the same COL4A5 gene and preponderant inactivation of the X chromosome carrying the normal allele.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7706490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7706490</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7706490" 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/10.1172/JCI117862" target="_blank">Full Text</a>]
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Hasstedt, S. J., Atkin, C. L.
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<strong>X-linked inheritance of Alport syndrome: family P revisited.</strong>
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Am. J. Hum. Genet. 35: 1241-1251, 1983.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6650503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6650503</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6650503" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Hertz, J. M., Persson, U., Juncker, I., Segelmark, M.
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<strong>Alport syndrome caused by inversion of a 21 Mb fragment of the long arm of the X-chromosome comprising exon 9 through 51 of the COL4A5 gene.</strong>
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Hum. Genet. 118: 23-28, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16133187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16133187</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16133187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00439-005-0013-0" target="_blank">Full Text</a>]
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Hostikka, S. L., Eddy, R. L., Byers, M. G., Hoyhtya, M., Shows, T. B., Tryggvason, K.
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<strong>Identification of a distinct type IV collagen alpha chain with restricted kidney distribution and assignment of its gene to the locus of X chromosome-linked Alport syndrome.</strong>
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Proc. Nat. Acad. Sci. 87: 1606-1610, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1689491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1689491</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1689491" 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/10.1073/pnas.87.4.1606" target="_blank">Full Text</a>]
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King, K., Flinter, F. A., Nihalani, V., Green, P. M.
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<strong>Unusual deep intronic mutations in the COL4A5 gene cause X linked Alport syndrome.</strong>
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Hum. Genet. 111: 548-554, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12436246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12436246</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12436246" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00439-002-0830-3" target="_blank">Full Text</a>]
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Knebelmann, B., Breillat, C., Forestier, L., Arrondel, C., Jacassier, D., Giatras, I., Drouot, L, Deschenes, G., Grunfeld, J.-P., Broyer, M., Gubler, M.-C., Antignac, C.
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<strong>Spectrum of mutations in the COL4A5 collagen gene in X-linked Alport syndrome.</strong>
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)9:6<477::AID-HUMU1>3.0.CO;2-#" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archopht.121.6.846" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archinte.1951.03810080059006" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/1.2.127" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00207059" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.271.23.13821" target="_blank">Full Text</a>]
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</li>
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<a id="31" class="mim-anchor"></a>
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<a id="Zheng1994" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zheng, K., Thorner, P. S., Marrano, P., Baumal, R., McInnes, R. R.
|
|
<strong>Canine X chromosome-linked hereditary nephritis: a genetic model for human X-linked hereditary nephritis resulting from a single base mutation in the gene encoding the alpha-5 chain of collagen type IV.</strong>
|
|
Proc. Nat. Acad. Sci. 91: 3989-3993, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8171024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8171024</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8171024" 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/10.1073/pnas.91.9.3989" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="32" class="mim-anchor"></a>
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<a id="Zhou1991" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhou, J., Barker, D. F., Hostikka, S. L., Gregory, M. C., Atkin, C. L., Tryggvason, K.
|
|
<strong>Single base mutation in alpha-5(IV) collagen chain gene converting a conserved cysteine to serine in Alport syndrome.</strong>
|
|
Genomics 9: 10-18, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1672282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1672282</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1672282" 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/10.1016/0888-7543(91)90215-z" target="_blank">Full Text</a>]
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<li>
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<a id="33" class="mim-anchor"></a>
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<a id="Zhou1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhou, J., Hertz, J. M., Leinonen, A., Tryggvason, K.
|
|
<strong>Complete amino acid sequence of the human alpha-5(IV) collagen chain and identification of a single-base mutation in exon 23 converting glycine 521 in the collagenous domain to cysteine in an Alport syndrome patient.</strong>
|
|
J. Biol. Chem. 267: 12475-12481, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1352287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1352287</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1352287" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="34" class="mim-anchor"></a>
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<a id="Zhou1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhou, J., Hertz, J. M., Tryggvason, K.
|
|
<strong>Mutation in the alpha-5(IV) collagen chain in juvenile-onset Alport syndrome without hearing loss or ocular lesions: detection by denaturing gradient gel electrophoresis of a PCR product.</strong>
|
|
Am. J. Hum. Genet. 50: 1291-1300, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1598909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1598909</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1598909" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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<li>
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<a id="35" class="mim-anchor"></a>
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<a id="Zhou1991" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhou, J., Hostikka, S. L., Chow, L. T., Tryggvason, K.
|
|
<strong>Characterization of the 3-prime half of the human type IV collagen alpha-5 gene that is affected in the Alport syndrome.</strong>
|
|
Genomics 9: 1-9, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2004755/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2004755</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2004755" 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/10.1016/0888-7543(91)90214-y" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="36" class="mim-anchor"></a>
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<a id="Zhou1994" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhou, J., Leinonen, A., Tryggvason, K.
|
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<strong>Structure of the human type IV collagen COL4A5 gene.</strong>
|
|
J. Biol. Chem. 269: 6608-6614, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8120014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8120014</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8120014" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="37" class="mim-anchor"></a>
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<a id="Zhou1993" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhou, J., Mochizuki, T., Smeets, H., Antignac, C., Laurila, P., de Paepe, A., Tryggvason, K., Reeders, S. T.
|
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<strong>Deletion of the paired alpha-5(IV) and alpha-6(IV) collagen genes in inherited smooth muscle tumors.</strong>
|
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Science 261: 1167-1169, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8356449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8356449</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8356449" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.8356449" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
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Matthew B. Gross - updated : 10/17/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 07/10/2015<br>Patricia A. Hartz - updated : 1/30/2012<br>Cassandra L. Kniffin - updated : 6/29/2010<br>Marla J. F. O'Neill - updated : 12/28/2005<br>Jane Kelly - updated : 10/23/2003<br>Victor A. McKusick - updated : 6/23/1997<br>Victor A. McKusick - updated : 5/16/1997<br>Moyra Smith - updated : 1/31/1997<br>Perseveranda M. Cagas - updated : 9/4/1996<br>Moyra Smith - updated : 6/17/1996
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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 : 3/2/1990
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</span>
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</div>
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</div>
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</div>
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<div>
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<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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mgross : 10/17/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 10/06/2023<br>alopez : 10/06/2023<br>alopez : 10/06/2023<br>carol : 01/31/2019<br>alopez : 09/23/2016<br>alopez : 07/10/2015<br>terry : 3/14/2013<br>mgross : 3/7/2012<br>terry : 1/30/2012<br>carol : 9/29/2010<br>carol : 6/29/2010<br>carol : 5/28/2010<br>carol : 5/27/2010<br>carol : 5/27/2010<br>ckniffin : 5/21/2010<br>alopez : 1/12/2010<br>alopez : 1/12/2010<br>wwang : 1/9/2006<br>wwang : 1/3/2006<br>terry : 12/28/2005<br>cwells : 10/23/2003<br>tkritzer : 12/10/2002<br>tkritzer : 12/4/2002<br>terry : 11/27/2002<br>carol : 1/3/2000<br>carol : 6/22/1999<br>carol : 6/22/1999<br>dkim : 12/9/1998<br>terry : 1/20/1998<br>jenny : 6/23/1997<br>mark : 5/26/1997<br>terry : 5/16/1997<br>mark : 1/31/1997<br>jamie : 1/16/1997<br>jamie : 1/16/1997<br>mark : 9/4/1996<br>carol : 6/18/1996<br>carol : 6/17/1996<br>mark : 3/7/1996<br>mark : 1/17/1996<br>mark : 1/17/1996<br>mark : 12/20/1995<br>mark : 6/9/1995<br>terry : 10/17/1994<br>jason : 7/19/1994<br>mimadm : 2/27/1994<br>carol : 9/13/1993<br>carol : 7/21/1993
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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 class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 303630
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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COLLAGEN, TYPE IV, ALPHA-5; COL4A5
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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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COLLAGEN OF BASEMENT MEMBRANE, ALPHA-5 CHAIN
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: COL4A5</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: Xq22.3
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Genomic coordinates <span class="small">(GRCh38)</span> : X:108,439,838-108,697,545 </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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Xq22.3
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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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Alport syndrome 1, X-linked
|
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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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301050
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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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X-linked 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>COL4A5 encodes an alpha chain of type IV collagen, the major component of basement membranes (Hostikka et al., 1990). </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>Hostikka et al. (1990) identified a distinct type IV collagen alpha chain, which they referred to as alpha-5. From analysis of cDNA clones, they found that the collagenous Gly-Xaa-Yaa repeat sequence has 5 'imperfections' that coincide with those in the corresponding portion of the alpha-1(IV) chain. The noncollagenous (NC) domain has 12 conserved cysteine residues and 83% and 63% sequence identity to the NC portions of the alpha-1(IV) (120130) and alpha-2(IV) (120090) chains. Antiserum against an alpha-5(IV) synthetic peptide stained a polypeptide chain of about 185 kD by immunoblot analysis. Immunolocalization in the human kidney was almost completely restricted to the glomerulus. </p><p>Zhou et al. (1992) found that the cDNA for the COL4A5 gene predicts a translation product with 1,685 amino acid residues: a 26-residue signal peptide, a 1,430-residue collagenous domain starting with a 14-residue noncollagenous sequence, and a gly-Xaa-Yaa-repeat sequence interrupted at 22 locations, followed by a 229-residue carboxyl-terminal noncollagenous domain. The calculated molecular mass of the mature chain is 158,303 Da. </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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<h4>
|
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<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</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>Zhou et al. (1991) described the 3-prime half of the human COL4A5 gene, including the intron-exon structure. They determined the sequence of the 19 3-prime-most exons and their flanking sequences from genomic phage clones, with the exception of exon 15, which was sequenced after amplification from genomic DNA by PCR. The exon sizes in the 3-prime half of the gene bear a remarkable similarity to those observed in the alpha-1(IV) chain. </p><p>Vetrie et al. (1992) constructed a 2.4-Mb long-range restriction map around the COL4A5 gene. High-resolution PFGE mapping with the rare-cutting enzyme XhoI showed that the gene is at least 110 kb long, one of the largest collagen genes characterized to date. </p><p>Zhou et al. (1994) determined that the COL4A5 gene contains 51 exons. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By Southern analysis of somatic cell hybrids and by in situ hybridization, Hostikka et al. (1990) assigned the COL4A5 locus to Xq22. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>SLITs (see SLIT1; 603742) are secreted glycoproteins that bind and activate ROBO receptors (see ROBO1; 602430) and function in axon guidance during development. Using a zebrafish model, Xiao et al. (2011) showed that Col4a5 on the surface of the tectum basement membrane bound Slit1 and guided retinal ganglion cell axons expressing Robo2 (602431). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Lemmink et al. (1997) gave a comprehensive review of the clinical manifestations associated with mutations in type IV collagen genes. The features vary from the severe clinically and genetically heterogeneous renal disorder Alport syndrome (see, e.g., 301050), to autosomal dominant familial benign hematuria (BFH; 141200). The authors stated that more than 160 different mutations had been identified in the COL4A5 gene. To the previously reported COL4A5 mutations, Lemmink et al. (1997) added 8 new ones identified in their group of patients with X-linked Alport syndrome (ALS1; 301050). The spectrum of mutations was broad and provided insight into the clinical variability of Alport syndrome with respect to age at renal failure and accompanying features. </p><p><strong><em>X-Linked Alport Syndrome</em></strong></p><p>
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|
Because X-linked Alport syndrome (ALS1; 301050) had been mapped to Xq22, where the COL4A5 gene maps, Hostikka et al. (1990) sought a defect in the COL4A5 gene; no major rearrangement was found in a single male patient. However, Barker et al. (1990) clinched the association between the COL4A5 gene and at least 1 form of Alport syndrome by demonstrating 3 structural aberrations in the COL4A5 gene (303630.0001-303630.0003) in separate families with Alport syndrome in Utah: an intragenic deletion, a PstI site variant, and an uncharacterized abnormality. </p><p>Antignac et al. (1994) tested the COL4A5 gene in 88 unrelated male patients with X-linked Alport syndrome for major gene rearrangements by Southern blot analysis using COL4A5 cDNA probes. They detected 14 different deletions, providing a 16% deletion rate in that patient population. The deletions were dispersed all over the gene with different sizes ranging from 1 kb to the complete absence of the gene (more than 250 kb) in 1 patient. In 4 patients with intragenic deletions, absence of the alpha-3(IV) chain in the glomerular basement membrane was demonstrated by immunohistochemical methods. This finding supported the hypothesis that abnormalities of the alpha-5(IV) chain may prevent normal incorporation of the alpha-3(IV) chain into the glomerular basement membrane. Direct sequencing of cDNA amplified from lymphoblast mRNA of 4 patients with internal gene deletions, using appropriate combinations of primers amplifying across the predicted boundaries of the deletions, allowed Antignac et al. (1994) to determine the effect of genomic rearrangements on the transcripts and, by inference, on the alpha-5(IV) chain. Regardless of the extent of deletion and of the putative protein product, the 14 deletions occurred in patients with juvenile-type Alport syndrome. </p><p>Lemmink et al. (1994) stated that more than 60 different mutations had been detected in the COL4A5 gene in Alport patients. </p><p>Knebelmann et al. (1996) screened 48 of the 51 exons of the COL4A5 gene by SSCP analysis and identified 64 mutations and 10 sequence variants among 131 unrelated patients with X-linked Alport syndrome. They noted that the mutation detection rate was approximately 50%. Knebelmann et al. (1996) hypothesized that this incomplete detection could be in part due to sensitivity of the SSCP technique, or to lack of detection of splice site mutations because of primer design. They noted that intronic changes such as inversions (shown to be pathogenic in hemophilia; see 306700 and Naylor et al., 1993) and unstable trinucleotide repeat expansions (shown to be pathogenic in Friedreich ataxia; see 229300 and Campuzano et al., 1996) had not been ruled out as disease-causing changes in COL4A5. </p><p>The large multiexonic COL4A5 gene had been difficult to screen; several studies detected only approximately 50% of the mutations in this gene. A partial explanation for this was suggested by the findings of King et al. (2002): they identified 3 novel intronic mutations that demonstrated that single base changes deep within introns can, and do, cause X-linked Alport syndrome. One mutation created a new donor splice site within an intron resulting in the inclusion of a novel in-frame cryptic exon; a second mutation resulted in a new exon splice enhancer sequence (ESE) that promoted splicing of a cryptic exon containing a stop codon; a third mutation was a base substitution within the polypyrimidine tract that precedes the acceptor splice site that resulted in exon skipping. All 3 cases would have been missed using an exon-by-exon DNA screening approach. </p><p><strong><em>Contiguous Gene Deletion Syndromes Involving COL4A5</em></strong></p><p>
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Antignac et al. (1992, 1992) presented evidence that the syndrome of diffuse esophageal leiomyomatosis and Alport syndrome (308940), which had been reported in 24 patients, most of whom also suffered from congenital cataract, represents a contiguous gene deletion syndrome. They found patients with deletion in the 5-prime part of the COL4A5 gene, extending upstream for at least 700 bp. </p><p>Zhou et al. (1993) demonstrated that the leiomyomatosis-nephropathy syndrome represents a contiguous gene syndrome due to deletions that disrupt the COL4A5 and COL4A6 (303631) genes. </p><p><strong><em>Evidence for Digenic Inheritance</em></strong></p><p>
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|
Using massively parallel sequencing, Mencarelli et al. (2015) identified 11 patients with Alport syndrome who had pathogenic mutations in 2 of the 3 collagen IV genes. Seven patients had a combination of mutations in COL4A3 (120070) and COL4A4 (120131), whereas 4 patients had 1 or 2 mutations in COL4A4 associated with mutation in COL4A5. In no case were there simultaneous COL4A3 and COL4A5 mutations. For each of these 11 probands, between 1 and 12 family members were recruited, for an average of 4 members per family (56 individuals ranging from 5-80 years). Altogether, 23 unique mutations were found, including 7 in COL4A3, 12 in COL4A4, and 4 in COL4A5. The mutations involved all domains of the collagen molecules, although the majority of missense mutations (11 of 13) affected the triple-helical collagenous domain, and 11 missense mutations substituted a critical glycine residue in this domain. Thirteen mutations had been previously reported and 10 were novel. Among the 8 patients with mutations in COL4A4 and COL4A5 (4 probands and 4 family members), the phenotypes included hematuria with proteinuria in 6 individuals and end-stage renal disease in 2 individuals. In 1 family, the proband carried 2 in trans mutations in COL4A4 in addition to the mutation in COL4A5. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Canine X-linked hereditary nephritis is an animal model for Alport syndrome. Zheng et al. (1994) used information on the nucleotide sequence for human COL4A5 cDNA to construct a set of primers for dog kidney cDNA. They found that the nucleotide sequence encoding the noncollagenous domain NC1 hybridized to the human X chromosome and was 93% identical at the DNA level and 97% identical at the protein level to the human NC1 domain. Sequence analysis demonstrated a G-to-T transversion in affected dogs, changing a codon in exon 35 from GGA (glycine) to a stop codon (TGA). Transcription of the COL4A5 gene was reduced by a factor of approximately 10 in the affected dog. </p><p>Thorner et al. (1996) examined expression of the canine collagen type IV genes in the kidney. They detected alpha-3 (120070), alpha-4 (120131), and alpha-5 chains in the noncollagenous domain of type IV collagen isolated from normal dog glomeruli but not in affected dog glomeruli. In addition to a significantly reduced level of COL4A5 gene expression (approximately 10% of normal), expression of the COL4A3 and COL4A4 genes was also decreased to 14-23% and 11-17%, respectively. These findings suggested to Thorner et al. (1996) a mechanism which coordinates the expression of these 3 basement membrane proteins. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>15 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0001 ALPORT SYNDROME 1, X-LINKED</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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COL4A5, EX5-10DEL
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<br />
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ClinVar: RCV000011199
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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 Utah kindred EP with Alport syndrome (ALS1; 301050), Barker et al. (1990) found deletion of the portion of the COL4A5 gene containing exons 5 through 10 (exons having been numbered with exon 1 being the most 3-prime exon). The deafness in the proband with the large deletion was among the most profound encountered in Alport kindreds, implying that the severity of deafness is correlated with the severity of the defect in COL4A5. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0002 ALPORT SYNDROME 1, X-LINKED</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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COL4A5, CYS108SER
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<br />
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|
SNP: rs104886287,
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ClinVar: RCV000021640, RCV001047411
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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 the historic kindred P in Utah studied by Perkoff et al. (1951, 1958) and later by Hasstedt and Atkin (1983), Barker et al. (1990) demonstrated that a PstI site variant segregated in complete linkage with the presence or absence of the Alport phenotype (ALS1; 301050). All 23 gene-carrying mothers were heterozygous; a total of 45 sons showed complete linkage. In an addendum, Barker et al. (1990) stated that by PCR amplification and DNA sequencing, the PstI variant had been shown to be due to a single basepair change that converted a highly conserved cysteine codon in the noncollagenase (NC) domain to a codon for serine (C108S). (The NC domain of glomerular basement membrane type IV collagen has been shown to be absent or altered in Alport syndrome on the basis of studies with antibodies directed against this portion of the molecule.) Zhou et al. (1991) described the generation of a new BglII site and showed that the cys-to-ser change occurred in the third to the last exon. Boye et al. (1991) commented that the defect had been defined as a G-to-C transition in exon 3 that created both a PstI and a BglII site. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0003 ALPORT SYNDROME 1, X-LINKED</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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COL4A5, 10-15-KB INS, 40-KB DEL
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<br />
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ClinVar: RCV000011201, RCV000011206
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>Through an analysis of the 3-prime end of the COL4A5 gene using 3 cDNA clones, Boye et al. (1991) found mutations in 3 of 38 patients with Alport syndrome (ALS1; 301050). One patient had a complex insertion/deletion mutation. Using pulsed field gel electrophoresis, Vetrie et al. (1992) found that the mutation involved an intragenic insertion of 10 to 15 kb and an extragenic deletion of 40 kb, with an overall deletion of 25 kb. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0004 ALPORT SYNDROME 1, X-LINKED</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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COL4A5, 450-KB DEL
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<br />
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|
|
ClinVar: RCV000011202
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Through an analysis of the 3-prime end of the COL4A5 gene using 3 cDNA clones, Boye et al. (1991) found mutations in 3 of 38 patients with Alport syndrome (ALS1; 301050). One patient had a deletion of at least 35 kb. Using pulsed field gel electrophoresis, Vetrie et al. (1992) found that the mutation involved deletion of 450-kb, including approximately 12 kb of the 3-prime end (exons 1-6). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 ALPORT SYNDROME 1, X-LINKED</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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|
<span class="mim-text-font">
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|
COL4A5, 38-KB DEL
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<br />
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|
|
ClinVar: RCV000011203
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|
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|
|
</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 12-year-old Italian boy with Alport syndrome (ALS1; 301050), Renieri et al. (1992) found a large deletion (more than 38 kb) that included the 5-prime part of the COL4A5 gene. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
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|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 ALPORT SYNDROME 1, X-LINKED</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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|
COL4A5, GLY1143ASP
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<br />
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|
|
SNP: rs104886229,
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|
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ClinVar: RCV000011204
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 1 of 20 Danish kindreds with Alport syndrome (ALS1; 301050), Zhou et al. (1992) found a GGC-to-GAC mutation changing glycine-1143 to aspartate. Substitution of any amino acid for glycine-1143, located in the collagenous domain of the alpha-5(IV) chain, would be expected to interfere with the maintenance of the triple-helical conformation of the collagen molecule and, in turn, weaken the glomerular basement membrane framework, leading to increased permeability. The proband was a 27-year-old male who developed hematuria in childhood and terminal renal failure at the age of 25 years. He had no hearing loss or ocular lesions. Electron microscopy demonstrated splitting of the lamina densa of the glomerular basement membrane. The proband's mother had had persistent microscopic hematuria since the age of 40 years but no other manifestations. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 ALPORT SYNDROME 1, X-LINKED</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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COL4A5, GLY325ARG
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<br />
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|
|
SNP: rs104886088,
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|
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ClinVar: RCV000011205, RCV000521446, RCV004609294
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a kindred with many members affected with adult-type X-linked Alport syndrome (ALS1; 301050), Knebelmann et al. (1992) found by Southern blot analysis a loss of an MspI restriction site in the COL4A5 gene. Direct sequencing of cDNA demonstrated a gly325-to-arg (G325R) mutation. Knebelmann et al. (1992) commented that this type of mutation in the COL1A1 and COL1A2 genes is often associated with osteogenesis imperfecta. </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 ALPORT SYNDROME 1, X-LINKED</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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|
COL4A5, 3-PRIME AND PARTIAL 5-PRIME DELETION
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<br />
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|
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ClinVar: RCV000011206
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</span>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a patient with severe Alport syndrome (ALS1; 301050) and end-stage renal disease (ESRD) by age 17, accompanied by deafness, Smeets et al. (1992) found deletion of exons encoding the noncollagenous domain and part of the collagenous region of the collagen IV alpha-5 chain. Transplantation with the kidney of an unrelated donor was followed by rapidly progressive anti-glomerular basement membrane nephritis, leading to loss of the transplant almost 7 months after grafting. His affected maternal grandfather died from renal failure at the age of 26 years. The deletion appeared to be present in heterozygous form in the mother and sister, both of whom displayed hematuria. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 ALPORT SYNDROME 1, X-LINKED</strong>
|
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</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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COL4A5, TRP1538SER
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<br />
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SNP: rs104886293,
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ClinVar: RCV000021630
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 brothers with Alport syndrome (ALS1; 301050) without deafness and with relatively late onset, as well as in their carrier mother, Smeets et al. (1992) identified a C-to-G transversion changing a tryptophan codon (TGG) to a serine codon (TCG) in exon 4. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0010 ALPORT SYNDROME 1, X-LINKED</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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COL4A5, GLY521CYS
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<br />
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SNP: rs104886121,
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ClinVar: RCV000011208
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>By analysis of genomic DNA from affected members of a kindred with Alport syndrome (ALS1; 301050), Zhou et al. (1992) demonstrated a new HindIII cleavage site. The mutation was found to be located in exon 23: a G-to-T transversion changing the GGT codon of glycine-521 to cysteine (G521C). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0011 ALPORT SYNDROME 1, X-LINKED</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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COL4A5, GLY325GLU
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<br />
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SNP: rs104886091,
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ClinVar: RCV000011209
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 6-year-old Italian patient with Alport syndrome (ALS1; 301050), Renieri et al. (1992) demonstrated a de novo mutation resulting in substitution of a glutamic acid for a glycine residue at position 325 (G325E) in the triple helical region of the alpha-5(IV) chain. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 ALPORT SYNDROME 1, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
COL4A5, GLY289VAL AND ARG1421CYS
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<br />
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SNP: rs104886450, rs144282156,
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gnomAD: rs144282156,
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ClinVar: RCV000011210, RCV000782218, RCV001580476, RCV003417844, RCV003886365
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>Guo et al. (1995) found 2 de novo missense mutations in the COL4A5 gene in a female patient who presented at the age of 19 with microscopic hematuria and nephrotic syndrome. The diagnosis of Alport syndrome (ALS1; 301050) was confirmed by the finding of typical glomerular basement membrane abnormalities on a renal biopsy taken at that age. Renal function deteriorated progressively and chronic hemodialysis was started at the age of 30. A cadaveric kidney transplantation was done 2 years later. There was no hearing loss and there were no clinical features of Turner syndrome. Her height was 162 cm and she had a normal menstrual pattern. Family history showed that her father died at age 36 of renal failure associated with sensorineural hearing loss. An elder sister had microscopic hematuria, proteinuria with normal kidney function, and hearing loss. One mutation (G289V) occurred in exon 15 and converted a glycine in the collagenous domain of COL4A5 to a valine. The second mutation, located in exon 46, substituted a cysteine proximal to the NC1 domain of COL4A5 for an arginine (R1421C). Both mutations were present in more than 90% of the mRNA of white blood cells and kidney, while at the genomic level, the patient was heterozygous for both mutations. The 2 mutations therefore occurred in the same COL4A5 allele. Guo et al. (1995) found no mutations in the COL4A5 promoter region by sequencing, nor did they detect a major rearrangement of the normal allele. A skewed pattern of X inactivation was demonstrated in DNA isolated from the patient's kidney and white blood cells; a normal COL4A5 allele was inactivated in more than 90% of the X chromosomes. The skewed inactivation pattern was thought to be responsible for the absence of detectable normal COL4A5 mRNA and, hence, for the severe phenotype in this woman. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 ALPORT SYNDROME 1, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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|
<span class="mim-text-font">
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|
COL4A5, GLY54ASP
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<br />
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|
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SNP: rs104886043,
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|
|
|
|
|
ClinVar: RCV000011211
|
|
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|
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Turco et al. (1995) found a novel missense mutation in exon 3 of the COL4A5 gene in a male patient with late-onset Alport syndrome (ALS1; 301050). Microhematuria was first discovered at age 22 years. He reached end-stage renal disease at age 40, and had a successful transplant at age 41. He had bilateral sensorineural hearing loss and subcapsular posterior lens opacities. The proband had 2 daughters, aged 15 and 13 years. The older daughter had had mild irregular microhematuria since age 2, with normal renal function; a renal biopsy at age 8 showed a thinning of the glomerular basement membrane. In the other daughter, microhematuria was discovered at age 7. Ocular and auditory assessments were normal in both sisters. The proband's mother was known to have microhematuria. The mutation was a G-to-A transition which resulted in a gly54-to-asp (G54D) substitution and abolished a BstNI restriction site. The findings were consistent with the generalization that more slowly progressive forms of Alport syndrome tend to be associated with missense mutations rather than large deletions or frameshifts. The authors stated that this was the first mutation described in the N-terminus triple-helical 7S domain of the COL4A5 gene in an Alport syndrome patient. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 ALPORT SYNDROME 1, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
COL4A5, LEU1649ARG
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<br />
|
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|
|
SNP: rs104886303,
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|
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|
|
|
|
|
ClinVar: RCV000011212, RCV000440813, RCV001195698, RCV003398479
|
|
|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Barker et al. (1996) identified a novel leu1649-to-arg (L1649R) mutation in the COL4A5 gene in Alport syndrome (ALS1; 301050) patients. In contrast to most described COL4A5 mutations in Alport syndrome, each of which accounts for the disease in a single family, the L1649R mutation was found in over 7% of the 121 families studied. In males with the L1649R mutation, renal failure preceded hearing loss by approximately 10 years, and the cumulative frequency of hearing loss is 60% by age 60. Barker et al. (1996) noted that substantial variability occurs in the ages at appearance of end-stage renal disease and functional hearing loss among individuals with identical mutations, emphasizing the fallibility of generalizations about the phenotype associated with a specific mutation that is observed in only a small number of Alport syndrome patients. </p>
|
|
</span>
|
|
</div>
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 ALPORT SYNDROME 1, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
COL4A5, ARG1677GLN
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs104886308,
|
|
|
|
|
|
gnomAD: rs104886308,
|
|
|
|
|
|
ClinVar: RCV000011213, RCV000518046, RCV001328066, RCV003934823
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Nearly all cases of Alport syndrome (ALS1; 301050) involve distinct mutations, as expected for an X-linked disease that significantly reduces the fitness of affected males. A few COL4A5 mutations appear to be associated with reduced disease severity and may account for an appreciable proportion of late-onset Alport syndrome in populations where a founder effect has occurred. Barker et al. (1997) reported a novel mutation in the COL4A5 gene, R1677Q. It was detected in 3 independently ascertained Ashkenazi-American families, caused a relatively mild form of nephritis with typical onset in the fourth or fifth decade, and may be involved in the etiology of a large proportion of adult-onset hereditary nephritis in Ashkenazi Jews. The mutation was a G-to-A transition in nucleotide 5232 and represented a change at a CpG dinucleotide. The same haplotype of COL4A5-linked markers was found in affected males of the 3 kindreds. No genealogic connection could be established. </p><p>Ohkubo et al. (2003) found immunohistochemical evidence that the normal anterior lens capsule expressed all of the A4 collagen chains. They also examined the anterior lens capsule of a patient with Alport syndrome due to the R1677X nonsense mutation. The patient's anterior lenticonus resulted in a lack of immunoreactivity to 4A3 to 4A6 chains in the anterior lens capsule. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
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|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Hertz et al. (2005)
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
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|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Antignac, C., Gros, F., Geffriaud, C., Kashtan, C., Proesmans, W., Tryggvason, K., Gubler, M. C.
|
|
<strong>Alport syndrome (AS) and diffuse esophageal leiomyomatosis (DL): deletions in the 5-prime end and upstream region of the COL4A5 collagen gene. (Abstract)</strong>
|
|
Am. J. Hum. Genet. 51 (suppl.): A7, 1992.
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|
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Antignac, C., Knebelmann, B., Drouot, L., Gros, F., Deschenes, G., Hors-Cayla, M.-C., Zhou, J., Tryggvason, K., Grunfeld, J.-P., Broyer, M., Gubler, M.-C.
|
|
<strong>Deletions in the COL4A5 collagen gene in X-linked Alport syndrome: characterization of the pathological transcripts in nonrenal cells and correlation with disease expression.</strong>
|
|
J. Clin. Invest. 93: 1195-1207, 1994.
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|
|
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[PubMed: 8132760]
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[Full Text: https://doi.org/10.1172/JCI117073]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Antignac, C., Zhou, J., Sanak, M., Cochat, P., Roussel, B., Deschenes, G., Gros, F., Knebelmann, B., Hors-Cayla, M.-C., Tryggvason, K., Gubler, M.-C.
|
|
<strong>Alport syndrome and diffuse leiomyomatosis: deletions in the 5-prime end of the COL4A5 collagen gene.</strong>
|
|
Kidney Int. 42: 1178-1183, 1992.
|
|
|
|
|
|
[PubMed: 1453602]
|
|
|
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|
|
[Full Text: https://doi.org/10.1038/ki.1992.402]
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</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Barker, D. F., Denison, J. C., Atkin, C. L., Gregory, M. C.
|
|
<strong>Common ancestry of three Ashkenazi-American families with Alport syndrome and COL4A5 R1677Q.</strong>
|
|
Hum. Genet. 99: 681-684, 1997.
|
|
|
|
|
|
[PubMed: 9150741]
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|
[Full Text: https://doi.org/10.1007/s004390050429]
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</p>
|
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</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Barker, D. F., Hostikka, S. L., Zhou, J., Chow, L. T., Oliphant, A. R., Gerken, S. C., Gregory, M. C., Skolnick, M. H., Atkin, C. L., Tryggvason, K.
|
|
<strong>Identification of mutations in the COL4A5 collagen gene in Alport syndrome.</strong>
|
|
Science 248: 1224-1227, 1990.
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|
[PubMed: 2349482]
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|
[Full Text: https://doi.org/10.1126/science.2349482]
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</p>
|
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</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Barker, D. F., Pruchno, C. J., Jiang, X., Atkin, C. L., Stone, E. M., Denison, J. C., Fain, P. R., Gregory, M. C.
|
|
<strong>A mutation causing Alport syndrome with tardive hearing loss is common in the western United States.</strong>
|
|
Am. J. Hum. Genet. 58: 1157-1165, 1996.
|
|
|
|
|
|
[PubMed: 8651292]
|
|
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Boye, E., Vetrie, D., Flinter, F., Buckle, B., Pihlajaniemi, T., Hamalainen, E.-R., Myers, J. C., Bobrow, M., Harris, A.
|
|
<strong>Major rearrangements in the alpha-5-(IV) collagen gene in three patients with Alport syndrome.</strong>
|
|
Genomics 11: 1125-1132, 1991.
|
|
|
|
|
|
[PubMed: 1783380]
|
|
|
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|
|
[Full Text: https://doi.org/10.1016/0888-7543(91)90040-l]
|
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Campuzano, V., Montermini, L., Molto, M. D., Pianese, L., Cossee, M., Cavalcanti, F., Monros, E., Rodius, F., Duclos, F., Monticelli, A., Zara, F., Canizares, J., and 15 others.
|
|
<strong>Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.</strong>
|
|
Science 271: 1423-1427, 1996.
|
|
|
|
|
|
[PubMed: 8596916]
|
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|
|
|
[Full Text: https://doi.org/10.1126/science.271.5254.1423]
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</p>
|
|
</li>
|
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|
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<li>
|
|
<p class="mim-text-font">
|
|
Guo, C., Van Damme, B., Vanrenterghem, Y., Devriendt, K., Cassiman, J.-J., Marynen, P.
|
|
<strong>Severe Alport phenotype in a woman with two missense mutations in the same COL4A5 gene and preponderant inactivation of the X chromosome carrying the normal allele.</strong>
|
|
J. Clin. Invest. 95: 1832-1837, 1995.
|
|
|
|
|
|
[PubMed: 7706490]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1172/JCI117862]
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hasstedt, S. J., Atkin, C. L.
|
|
<strong>X-linked inheritance of Alport syndrome: family P revisited.</strong>
|
|
Am. J. Hum. Genet. 35: 1241-1251, 1983.
|
|
|
|
|
|
[PubMed: 6650503]
|
|
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Hertz, J. M., Persson, U., Juncker, I., Segelmark, M.
|
|
<strong>Alport syndrome caused by inversion of a 21 Mb fragment of the long arm of the X-chromosome comprising exon 9 through 51 of the COL4A5 gene.</strong>
|
|
Hum. Genet. 118: 23-28, 2005.
|
|
|
|
|
|
[PubMed: 16133187]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s00439-005-0013-0]
|
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|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hostikka, S. L., Eddy, R. L., Byers, M. G., Hoyhtya, M., Shows, T. B., Tryggvason, K.
|
|
<strong>Identification of a distinct type IV collagen alpha chain with restricted kidney distribution and assignment of its gene to the locus of X chromosome-linked Alport syndrome.</strong>
|
|
Proc. Nat. Acad. Sci. 87: 1606-1610, 1990.
|
|
|
|
|
|
[PubMed: 1689491]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.87.4.1606]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
King, K., Flinter, F. A., Nihalani, V., Green, P. M.
|
|
<strong>Unusual deep intronic mutations in the COL4A5 gene cause X linked Alport syndrome.</strong>
|
|
Hum. Genet. 111: 548-554, 2002.
|
|
|
|
|
|
[PubMed: 12436246]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s00439-002-0830-3]
|
|
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|
|
</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
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