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Entry
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- *191845 - UROMODULIN; UMOD
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- OMIM
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</form>
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*191845</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/191845">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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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=ENSG00000169344;t=ENST00000396138" 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=7369" 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=191845" 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=ENSG00000169344;t=ENST00000396138" 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_001008389,NM_001278614,NM_001378232,NM_001378233,NM_001378234,NM_001378235,NM_001378237,NM_003361,NR_165456,XM_011545937,XM_011545938,XM_024450433" 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_003361" 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=191845" 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=11771&isoform_id=11771_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/UMOD" 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/137116,340164,340166,20384858,23243412,29470294,34534645,56550049,59850812,119570699,119570700,193785388,193786277,193787245,193788308,519666794,767988779,767988781,1370469157,1563211447,1563211449,1804891957,1804891959,1804891982,1804891994,1804892006,2462550591,2462550593,2462550595,2462550597,2462550599" 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/P07911" 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=7369" 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=ENSG00000169344;t=ENST00000396138" 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=UMOD" 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=UMOD" 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+7369" 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/UMOD" 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:7369" 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/7369" 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=chr16&hgg_gene=ENST00000396138.9&hgg_start=20333051&hgg_end=20356301&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:12559" 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/umod" 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=191845[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=191845[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000169344" 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=UMOD" 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=UMOD" 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=UMOD" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=UMOD&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/PA37199" 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:12559" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:102674" 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/UMOD#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:102674" 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/7369/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=7369" 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>
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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://reactome.org/content/query?q=UMOD&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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191845
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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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UROMODULIN; UMOD
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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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TAMM-HORSFALL GLYCOPROTEIN; THP; THGP
|
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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=UMOD" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">UMOD</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>
|
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Cytogenetic location: <a href="/geneMap/16/243?start=-3&limit=10&highlight=243">16p12.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr16:20333051-20356301&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'})">16:20,333,051-20,356,301</a> </span>
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</div>
|
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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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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<a href="/geneMap/16/243?start=-3&limit=10&highlight=243">
|
|
16p12.3
|
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</a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Tubulointerstitial kidney disease, autosomal dominant, 1
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/162000"> 162000 </a>
|
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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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|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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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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|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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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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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/191845" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/191845" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<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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</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="text" class="mim-anchor"></a>
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<h4>
|
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|
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<span class="mim-font">
|
|
<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</span>
|
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</h4>
|
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<div>
|
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<a id="description" class="mim-anchor"></a>
|
|
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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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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<div id="mimDescriptionFold" class="collapse in ">
|
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<span class="mim-text-font">
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<p>The Tamm-Horsfall glycoprotein (<a href="#28" class="mim-tip-reference" title="Tamm, I., Horsfall, F. L., Jr. <strong>A mucoprotein derived from human urine which reacts with influenza, mumps, and Newcastle disease viruses.</strong> J. Exp. Med. 95: 71-97, 1952.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14907962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14907962</a>] [<a href="https://doi.org/10.1084/jem.95.1.71" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14907962">Tamm and Horsfall, 1952</a>), also referred to as uromodulin (<a href="#18" class="mim-tip-reference" title="Muchmore, A. V., Decker, J. M. <strong>Uromodulin: a unique 85-kilodalton immunosuppressive glycoprotein isolated from urine of pregnant women.</strong> Science 229: 479-481, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2409603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2409603</a>] [<a href="https://doi.org/10.1126/science.2409603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2409603">Muchmore and Decker, 1985</a>), is a GPI-anchored glycoprotein and the most abundant protein in normal urine. Uromodulin, uropontin, and nephrocalcin are the 3 known urinary glycoproteins that affect the formation of calcium-containing kidney stones (<a href="/entry/167030">167030</a>). Uromodulin is synthesized by kidney and localizes in cells lining the ascending limb of Henle and distal convoluted tubule (<a href="#15" class="mim-tip-reference" title="McKenzie, J. K., McQueen, E. G. <strong>Immunofluorescent localization of Tamm-Horsfall mucoprotein in human kidney.</strong> J. Clin. Path. 22: 334-339, 1969.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4891482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4891482</a>] [<a href="https://doi.org/10.1136/jcp.22.3.334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4891482">McKenzie and McQueen, 1969</a>; <a href="#23" class="mim-tip-reference" title="Schenk, E. A., Schwartz, R. H., Lewis, R. A. <strong>Tamm-Horsfall mucoprotein. I. Localization in the kidney.</strong> Lab Invest. 25: 92-95, 1971.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4933557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4933557</a>]" pmid="4933557">Schenk et al., 1971</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4933557+2409603+4891482+14907962" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#19" class="mim-tip-reference" title="Pennica, D., Kohr, W. J., Kuang, W.-J., Glaister, D., Aggarwal, B. B., Chen, E. Y., Goeddel, D. V. <strong>Identification of human uromodulin as the Tamm-Horsfall urinary glycoprotein.</strong> Science 236: 83-88, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3453112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3453112</a>] [<a href="https://doi.org/10.1126/science.3453112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3453112">Pennica et al. (1987)</a> cloned uromodulin from human kidney total RNA. The deduced 639-amino acid protein contains an N-terminal signal peptide and regions of similarity with LDL receptor (LDLR; <a href="/entry/606945">606945</a>) and the EGF precursor protein (<a href="/entry/131530">131530</a>). Uromodulin has 48 cysteines and 8 potential N-glycosylation sites. Northern blot analysis of about 150 different epithelial, connective, and hematopoietic tissues and tumor-derived cell lines detected a 2.6-kb transcript in adult kidney only. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3453112" 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="Yang, H., Wu, C., Zhao, S., Guo, J. <strong>Identification and characterization of D8C, a novel domain present in liver-specific LZP, uromodulin and glycoprotein 2, mutated in familial juvenile hyperuricaemic nephropathy.</strong> FEBS Lett. 578: 236-238, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15589826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15589826</a>] [<a href="https://doi.org/10.1016/j.febslet.2004.10.092" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15589826">Yang et al. (2004)</a> described the domain structure of the UMOD protein. It has an N-terminal signal sequence, followed by 3 EGF-like repeats, a domain with 8 conserved cysteines (D8C), and a C-terminal zona pellucida (ZP) domain. The D8C domain is about 130 amino acids long, and the 8 cysteines are predicted to form 4 pairs of disulfide bridges. The secondary structure is composed mainly of beta strands. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15589826" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#19" class="mim-tip-reference" title="Pennica, D., Kohr, W. J., Kuang, W.-J., Glaister, D., Aggarwal, B. B., Chen, E. Y., Goeddel, D. V. <strong>Identification of human uromodulin as the Tamm-Horsfall urinary glycoprotein.</strong> Science 236: 83-88, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3453112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3453112</a>] [<a href="https://doi.org/10.1126/science.3453112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3453112">Pennica et al. (1987)</a> reported that UMOD gene contains 11 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3453112" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Hart, T. C., Gorry, M. C., Hart, P. S., Woodard, A. S., Shihabi, Z., Sandhu, J., Shirts, B., Xu, L., Zhu, H., Barmada, M. M., Bleyer, A. J. <strong>Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy.</strong> J. Med. Genet. 39: 882-892, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12471200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12471200</a>] [<a href="https://doi.org/10.1136/jmg.39.12.882" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12471200">Hart et al. (2002)</a> subsequently determined that the UMOD gene contains 12 exons, with the novel exon being exon 2. Exons 1 and 2 are noncoding; the ATG translation initiation site is located in exon 3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12471200" 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="#10" class="mim-tip-reference" title="Jeanpierre, C., Whitmore, S. A., Austruy, E., Cohen-Salmon, M., Callen, D. F., Junien, C. <strong>Chromosomal assignment of the uromodulin gene (UMOD) to 16p13.11.</strong> Cytogenet. Cell Genet. 62: 185-187, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8382593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8382593</a>] [<a href="https://doi.org/10.1159/000133470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8382593">Jeanpierre et al. (1993)</a> mapped the UMOD gene to chromosome 16p13.11 by somatic cell hybrid analysis. By study of a different mapping panel, <a href="#20" class="mim-tip-reference" title="Pook, M. A., Jeremiah, S., Scheinman, S. J., Povey, S., Thakker, R. V. <strong>Localization of the Tamm-Horsfall glycoprotein (uromodulin) gene to chromosome 16p12.3-16p13.11.</strong> Ann. Hum. Genet. 57: 285-290, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8179291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8179291</a>] [<a href="https://doi.org/10.1111/j.1469-1809.1993.tb00902.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8179291">Pook et al. (1993)</a> mapped the gene to chromosome 16p12.3-qter. Combining the results of the 2 studies suggested that the gene is located in the region 16p13.11-p12.3. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8382593+8179291" 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="#6" class="mim-tip-reference" title="Fukuoka, S.-I., Matsuda, Y. <strong>Assignment of the Tamm-Horsfall protein/uromodulin gene (Umod) to mouse chromosome bands 7F1-F2 and rat chromosome bands 1q36-q37 by in situ hybridization.</strong> Cytogenet. Cell Genet. 79: 241-242, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9605864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9605864</a>] [<a href="https://doi.org/10.1159/000134735" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9605864">Fukuoka and Matsuda (1997)</a> assigned the Umod gene to mouse chromosome 7F1-F2 and rat chromosome 1q36-q37 by fluorescence in situ hybridization. The result was discordant with the previous localization of the gene to mouse chromosome 17 by somatic cell hybrid analysis (<a href="#4" class="mim-tip-reference" title="Deng, Z., Johnson, K., Engleward, B. P., Lane, S., Callen, D. F., Samson, L. D., Davisson, M. T., Siciliano, M. J. <strong>New regions of conserved synteny and linkage between human chromosome 16p12-p13 and mouse chromosomes 16 and 11. (Abstract)</strong> Cytogenet. Cell Genet. 68: 180 only, 1995."None>Deng et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9605864" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#18" class="mim-tip-reference" title="Muchmore, A. V., Decker, J. M. <strong>Uromodulin: a unique 85-kilodalton immunosuppressive glycoprotein isolated from urine of pregnant women.</strong> Science 229: 479-481, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2409603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2409603</a>] [<a href="https://doi.org/10.1126/science.2409603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2409603">Muchmore and Decker (1985)</a> purified 85-kD uromodulin from urine of pregnant women and found that it showed immunoregulatory potential. Uromodulin had a broad dose-response curve in inhibition of antigen-specific T-cell proliferation. It also inhibited monocyte reactivity in vitro and spontaneous monocyte cytotoxicity. It had no effect on B-cell function or cell viability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2409603" 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="#7" class="mim-tip-reference" title="Greimel, P., Jabs, S., Storch, S., Cherif, S., Honke, K., Braulke, T., Thiem, J. <strong>In vitro sulfation of N-acetyllactosaminide by soluble recombinant human beta-Gal-3-prime-sulfotransferase.</strong> Carbohydr. Res. 341: 918-924, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16516177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16516177</a>] [<a href="https://doi.org/10.1016/j.carres.2006.02.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16516177">Greimel et al. (2006)</a> stated that approximately 30% of the mass of THP consists of sulfated N-linked glycans. They showed that both membrane-bound and soluble recombinant human GP3ST (GAL3ST2; <a href="/entry/608237">608237</a>) incorporated radiolabeled SO4 into purified human urine THP in a concentration-dependent manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16516177" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using immunohistochemical studies, <a href="#3" class="mim-tip-reference" title="Dahan, K., Devuyst, O., Smaers, M., Vertommen, D., Loute, G., Poux, J. M., Viron, B., Jacquot, C., Gagnadoux, M. F., Chauveau, D., Buchler, M., Cochat, P., Cosyns, J. P., Mougenot, B., Rider, M. H., Antignac, C., Verellen-Dumoulin, C., Pirson, Y. <strong>A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin.</strong> J. Am. Soc. Nephrol. 14: 2883-2893, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14569098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14569098</a>] [<a href="https://doi.org/10.1097/01.asn.0000092147.83480.b5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14569098">Dahan et al. (2003)</a> found that uromodulin is distributed primarily at the apical membrane of the thick ascending loop and distal convoluted tubule in the human kidney. Uromodulin is a GPI-anchor-linked protein. It has putative roles in cell adhesion, signal transduction, inhibition of calcium oxalate crystal aggregation, defense against urinary tract infection, and modulation of urine-concentrating ability. It may also act as a potential nephritogenic antigen. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14569098" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Zaucke, F., Boehnlein, J. M., Steffens, S., Polishchuk, R. S., Rampoldi, L., Fischer, A., Pasch, A., Boehm, C. W. A., Baasner, A., Attanasio, M., Hoppe, B., Hopfer, H., Beck, B. B., Sayer, J. A., Hildebrandt, F., Wolf, M. T. F. <strong>Uromodulin is expressed in renal primary cilia and UMOD mutations result in decreased ciliary uromodulin expression.</strong> Hum. Molec. Genet. 19: 1985-1997, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20172860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20172860</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20172860[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq077" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20172860">Zaucke et al. (2010)</a> demonstrated that UMOD was expressed in the primary cilia of renal tubules. Immunofluorescent and ultrastructural studies confirmed ciliary expression of UMOD, with localization to the mitotic spindle poles and colocalization with ciliary proteins nephrocystin-1 (NPHP1; <a href="/entry/607100">607100</a>) and kinesin family member 3A (KIF3A; <a href="/entry/604683">604683</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20172860" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using cryoelectron tomography, <a href="#31" class="mim-tip-reference" title="Weiss, G. L., Stanisich, J. J., Sauer, M. M., Lin, C.-W., Eras, J., Zyla, D. S., Truck, J., Devuyst, O., Aebi, M., Pilhofer, M., Glockshuber, R. <strong>Architecture and function of human uromodulin filaments in urinary tract infections.</strong> Science 369: 1005-1010, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32616672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32616672</a>] [<a href="https://doi.org/10.1126/science.aaz9866" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32616672">Weiss et al. (2020)</a> showed that the human uromodulin filament consisted of a zigzag-shaped backbone with laterally protruding arms. N-glycosylation mapping and biophysical assays revealed that uromodulin acted as a multivalent ligand for the bacterial type-1 pilus adhesin, presenting specific epitopes on the regularly spaced arms. Imaging of uromodulin-uropathogen interactions in vitro and in patient urine showed that uromodulin filaments associated with uropathogens and mediated bacterial aggregation, likely preventing adhesion and allowing clearance by micturition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32616672" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of 4 unrelated families with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; <a href="/entry/162000">162000</a>), <a href="#9" class="mim-tip-reference" title="Hart, T. C., Gorry, M. C., Hart, P. S., Woodard, A. S., Shihabi, Z., Sandhu, J., Shirts, B., Xu, L., Zhu, H., Barmada, M. M., Bleyer, A. J. <strong>Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy.</strong> J. Med. Genet. 39: 882-892, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12471200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12471200</a>] [<a href="https://doi.org/10.1136/jmg.39.12.882" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12471200">Hart et al. (2002)</a> identified 4 different heterozygous mutations in exon 4 of the UMOD gene (<a href="#0001">191845.0001</a>-<a href="#0004">191845.0004</a>). The mutations, which were found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the families. Three families had a clinical diagnosis of familial juvenile hyperuricemic nephropathy (FJHN, HNFJ), whereas the fourth family was diagnosed clinically with medullary cystic kidney disease (MCKD). In all families, the phenotype was characterized mainly by juvenile onset of hyperuricemia, polyuria, gout, and progressive renal insufficiency that was tubulointerstitial in origin. Renal biopsies showed tubular atrophy and interstitial fibrosis. Global glomerulosclerosis was also observed, although there was no evidence of glomerulonephritis. Necroscopy showed sheathing of the renal tubules by dense acellular hyaline fibrous tissue that likely represented abnormal deposition of the UMOD protein. Medullary cysts were present in 1 family. The authors noted that the disorder is associated with impaired urinary concentrating ability, which likely causes increased proximal tubular reabsorption of uric acid and hyperuricemia. Functional studies of the variants and studies of patient cells were not performed, but the authors postulated that the mutations caused tertiary structural changes in the uromodulin protein that could alter cytokine binding and ultimately lead to fibrosis and progressive renal failure. The report established that the clinical entities of FJHN and MCKD not only share clinical features, but are also either allelic or variable manifestations of the same disease. Noting that hyperuricemia and medullary cysts are variable features and that the conditions result from mutations in the same gene, the authors suggested the designation 'uromodulin-associated kidney disease.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12471200" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 5 unrelated kindreds with ADTKD1, 2 from Austria and 3 from Spain, <a href="#29" class="mim-tip-reference" title="Turner, J. J. O., Stacey, J. M., Harding, B., Kotanko, P., Lhotta, K., Puig, J. G., Roberts, I., Torres, R. J., Thakker, R. V. <strong>UROMODULIN mutations cause familial juvenile hyperuricemic nephropathy.</strong> J. Clin. Endocr. Metab. 88: 1398-1401, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12629136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12629136</a>] [<a href="https://doi.org/10.1210/jc.2002-021973" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12629136">Turner et al. (2003)</a> identified 5 heterozygous missense mutations in the UMOD gene (<a href="#0005">191845.0005</a>-<a href="#0009">191845.0009</a>) that altered evolutionary conserved residues. These mutations were not found in 110 alleles from 55 unrelated normal individuals. Functional studies of the variants were not performed, but the authors postulated a loss-of-function effect. The families had previously been reported by <a href="#25" class="mim-tip-reference" title="Stacey, J. M., Turner, J. J. O., Harding, B., Nesbit, M. A., Kotanko, P., Lhotta, K., Puig, J. G., Torres, R. J., Thakker, R. V. <strong>Genetic mapping studies of familial juvenile hyperuricemic nephropathy on chromosome 16p11-p13.</strong> J. Clin. Endocr. Metab. 88: 464-470, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12519891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12519891</a>] [<a href="https://doi.org/10.1210/jc.2002-021268" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12519891">Stacey et al. (2003)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12629136+12519891" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 4 unrelated Italian families with variable manifestations of ADTKD1, <a href="#21" class="mim-tip-reference" title="Rampoldi, L., Caridi, G., Santon, D., Boaretto, F., Bernascone, I., Lamorte, G., Tardanico, R., Dagnino, M., Colussi, G., Scolari, F., Ghiggeri, G. M., Amoroso, A., Casari, G. <strong>Allelism of MCKD, FJHN and GCKD caused by impairment of uromodulin export dynamics.</strong> Hum. Molec. Genet. 12: 3369-3384, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14570709/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14570709</a>] [<a href="https://doi.org/10.1093/hmg/ddg353" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14570709">Rampoldi et al. (2003)</a> identified heterozygous missense mutations in the UMOD gene (see, e.g., C315R, <a href="#0010">191845.0010</a> and C148W, <a href="#0015">191845.0015</a>). All mutations affected highly conserved cysteine residues and were predicted to affect protein structure. Immunohistochemistry of kidney biopsies revealed dense intracellular accumulation of uromodulin in tubular epithelia of the thick ascending limb of Henle loop. Electron microscopy showed accumulation of dense fibrillar material within the endoplasmic reticulum (ER), and patient urine samples consistently showed a severe reduction of excreted uromodulin. Experiments in transfected cells showed that all 4 mutations caused a delay in protein export to the plasma membrane due to a longer retention time in the ER. The protein maturation impairment and retention in the ER, which may trigger ubiquitination and ER stress, suggested a pathogenetic mechanism leading to these kidney diseases. <a href="#21" class="mim-tip-reference" title="Rampoldi, L., Caridi, G., Santon, D., Boaretto, F., Bernascone, I., Lamorte, G., Tardanico, R., Dagnino, M., Colussi, G., Scolari, F., Ghiggeri, G. M., Amoroso, A., Casari, G. <strong>Allelism of MCKD, FJHN and GCKD caused by impairment of uromodulin export dynamics.</strong> Hum. Molec. Genet. 12: 3369-3384, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14570709/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14570709</a>] [<a href="https://doi.org/10.1093/hmg/ddg353" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14570709">Rampoldi et al. (2003)</a> postulated that hyperuricemia is a secondary effect of volume contraction resulting from UMOD dysfunction in the thick ascending loop of Henle. Three families had a clinical diagnosis of MCKD/FJHN (including a family previously reported by <a href="#24" class="mim-tip-reference" title="Scolari, F., Puzzer, D., Amoroso, A., Caridi, G., Ghiggeri, G. M., Maiorca, R., Aridon, P., De Fusco, M., Ballabio, A., Casari, G. <strong>Identification of a new locus for medullary cystic disease, on chromosome 16p12.</strong> Am. J. Hum. Genet. 64: 1655-1660, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10330352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10330352</a>] [<a href="https://doi.org/10.1086/302414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10330352">Scolari et al., 1999</a>), and 1 family had a clinical diagnosis of glomerulocystic kidney disease (GCKD), thus demonstrating that these clinical entities are allelic and are different manifestations of the same disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10330352+14570709" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In patients from 11 families with ADTKD1, <a href="#3" class="mim-tip-reference" title="Dahan, K., Devuyst, O., Smaers, M., Vertommen, D., Loute, G., Poux, J. M., Viron, B., Jacquot, C., Gagnadoux, M. F., Chauveau, D., Buchler, M., Cochat, P., Cosyns, J. P., Mougenot, B., Rider, M. H., Antignac, C., Verellen-Dumoulin, C., Pirson, Y. <strong>A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin.</strong> J. Am. Soc. Nephrol. 14: 2883-2893, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14569098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14569098</a>] [<a href="https://doi.org/10.1097/01.asn.0000092147.83480.b5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14569098">Dahan et al. (2003)</a> identified 11 different heterozygous UMOD mutations, including 10 novel ones (see, e.g., <a href="#0012">191845.0012</a>). All of the mutations occurred at highly conserved residues in exon 4, and 5 of the mutations affected a conserved cysteine residue. The families were ascertained from a larger group of 25 families with a similar phenotype; thus, UMOD mutations were found in 44% of families. Patient kidney samples showed abnormal uromodulin immunostaining within enlarged or cystic profiles within tubules in the thick ascending loop, and not at the apical membrane as observed in controls. Mutant UMOD was not found in proximal tubules. Patients also showed decreased urinary excretion of wildtype uromodulin. The findings indicated that mutant uromodulin accumulates within renal tubular cells in patients with UMOD mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14569098" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 4 unrelated Spanish families with variable clinical manifestations of ADTKD1, <a href="#11" class="mim-tip-reference" title="Lens, X. M., Banet, J. F., Outeda, P., Barrio-Lucia, V. <strong>A novel pattern of mutation in uromodulin disorders: autosomal dominant medullary cystic kidney disease type 2, familial juvenile hyperuricemic nephropathy, and autosomal dominant glomerulocystic kidney disease.</strong> Am. J. Kidney Dis. 46: 52-57, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15983957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15983957</a>] [<a href="https://doi.org/10.1053/j.ajkd.2005.04.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15983957">Lens et al. (2005)</a> identified heterozygous missense mutations in the UMOD gene (see, e.g., C300G, <a href="#0009">191845.0009</a> and Q316P, <a href="#0014">191845.0014</a>). The mutations, which were found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in available family members. Two families (F1 and F2) with the same mutation (Q316P) had clinical phenotypes consistent with MCKD (F1) and FJHN (F2). Family 4 had a phenotype consistent with FJHN, and F3, with the C300G mutation, had a phenotype consistent with GCKD. These genetic findings further supported the idea that MCKD, FJHN, and GCKD represent the same disease entity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15983957" 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="#30" class="mim-tip-reference" title="Vylet'al, P., Kublova, M., Kalbacova, M., Hodanova, K., Baresova, V., Stiburkova, B., Sikora, J., Hulkova, H., Zivny, J., Majewski, J., Simmonds, A., Fryns, J.-P., Venkat-Raman, G., Elleder, M., Kmoch, S. <strong>Alterations of uromodulin biology: a common denominator of the genetically heterogeneous FJHN/MCKD syndrome.</strong> Kidney Int. 70: 1155-1169, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16883323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16883323</a>] [<a href="https://doi.org/10.1038/sj.ki.5001728" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16883323">Vylet'al et al. (2006)</a> sequenced the UMOD gene in 19 families with variable manifestations of ADTKD1 and identified heterozygous mutations in 6 families, 5 of which had been previously reported (kindred 6 from <a href="#14" class="mim-tip-reference" title="McBride, M. B., Ridgen, S., Haycock, G. B., Dalton, N., Van't Hoff, W., Rees, L., Venkat-Raman, G. V., Moro, F., Ogg, C. S., Cameron, J. S., Simmonds, H. A. <strong>Presymptomatic detection of familial juvenile hyperuricaemic nephropathy in children.</strong> Pediat. Nephrol. 12: 357-364, 1998."None>McBride et al., 1998</a>; kindreds A and B from <a href="#27" class="mim-tip-reference" title="Stiburkova, B., Majewski, J., Sebesta, I., Zhang, W., Ott, J., Kmoch, S. <strong>Familial juvenile hyperuricemic nephropathy: localization of the gene on chromosome 16p11.2--and evidence for genetic heterogeneity.</strong> Am. J. Hum. Genet. 66: 1989-1994, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10780922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10780922</a>] [<a href="https://doi.org/10.1086/302936" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10780922">Stiburkova et al., 2000</a>; <a href="#5" class="mim-tip-reference" title="Fairbanks, L. D., Cameron, J. S., Venkat-Raman, G., Rigden, S. P. A., Rees, L., Van't Hoff, W., Mansell, M., Pattison, J., Goldsmith, D. J. A., Simmonds, H. A. <strong>Early treatment with allopurinol in familial juvenile hyperuricaemic nephropathy (FJHN) ameliorates the long-term progression of renal disease.</strong> Quart. J. Med. 95: 597-607, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12205338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12205338</a>] [<a href="https://doi.org/10.1093/qjmed/95.9.597" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12205338">Fairbanks et al., 2002</a>; and family BE2 from <a href="#26" class="mim-tip-reference" title="Stiburkova, B., Majewski, J., Hodanova, K., Ondrova, L., Jerabkova, M., Zikanova, M., Vylet'al, P., Sebesta, I., Marinaki, A., Simmonds, A., Matthijs, G., Fryns, J.-P., Torres, R., Puig, J. G., Ott, J., Kmoch, S. <strong>Familial juvenile hyperuricaemic nephropathy (FJHN): linkage analysis in 15 families, physical and transcriptional characterisation of the FJHN critical region on chromosome 16p11.2 and the analysis of seven candidate genes.</strong> Europ. J. Hum. Genet. 11: 145-154, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12634862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12634862</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200937" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12634862">Stiburkova et al., 2003</a>) (see, e.g., <a href="#0006">191845.0006</a> and <a href="#0011">191845.0011</a>). Functional studies of mutant proteins showed distinct glycosylation patterns, impaired intracellular trafficking, and decreased ability to be exposed on the plasma membrane, which correlated with observations in kidney tissue from patients. A reduction in urinary modulin excretion was found in 18 of the 19 families and was associated with case-specific differences in uromodulin immunohistochemical staining patterns in kidney tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16883323+12205338+10780922+12634862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 6 of 17 probands with ADTKD who were studied for UMOD mutations, <a href="#32" class="mim-tip-reference" title="Williams, S. E., Reed, A. A. C., Galvanovskis, J., Antignac, C., Goodship, T., Karet, F. E., Kotanko, P., Lhotta, K., Moriniere, V., Williams, P., Wong, W., Rorsman, P., Thakker, R. V. <strong>Uromodulin mutations causing familial juvenile hyperuricaemic nephropathy lead to protein maturation defects and retention in the endoplasmic reticulum.</strong> Hum. Molec. Genet. 18: 2963-2974, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19465746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19465746</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19465746[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp235" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19465746">Williams et al. (2009)</a> identified 6 different heterozygous missense mutations in the UMOD gene (see, e.g., D196N; <a href="#0016">191845.0016</a>). In vitro functional studies of some of the mutations expressed in HeLa cells showed that the mutant uromodulins had significantly delayed maturation compared to wildtype, with abnormal protein retention in the ER and reduced or absent expression at the plasma membrane. There were different effects allowing the identification of 2 mutation groups: group A (including mutants C32W, D196N, and G488R) had 50% maturation compared to wildtype with some expression at the plasma membrane, whereas group B (including mutants C126R, <a href="#0006">191845.0006</a>; N128S, <a href="#0007">191845.0007</a>; and C223R) had 25% maturation compared to wildtype and absence of expression at the plasma membrane. There were no phenotypic differences between patients with group A and group B mutations. The findings suggested that abnormal folding of the mutant proteins resulted in protein retention in the ER, which may trigger apoptosis and underlie the mechanism for disease pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19465746" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 10 unrelated families with ADTKD1, <a href="#34" class="mim-tip-reference" title="Zaucke, F., Boehnlein, J. M., Steffens, S., Polishchuk, R. S., Rampoldi, L., Fischer, A., Pasch, A., Boehm, C. W. A., Baasner, A., Attanasio, M., Hoppe, B., Hopfer, H., Beck, B. B., Sayer, J. A., Hildebrandt, F., Wolf, M. T. F. <strong>Uromodulin is expressed in renal primary cilia and UMOD mutations result in decreased ciliary uromodulin expression.</strong> Hum. Molec. Genet. 19: 1985-1997, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20172860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20172860</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20172860[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq077" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20172860">Zaucke et al. (2010)</a> identified 7 novel and 3 previously reported heterozygous missense mutations in the UMOD gene (see, e.g., <a href="#0009">191845.0009</a> and <a href="#0013">191845.0013</a>). Most of the mutations affected conserved cysteine residues. The number of UMOD-positive primary cilia in renal biopsy samples from 2 of the patients was significantly decreased compared to control samples. The authors suggested that this defect may contribute to cyst formation. The families were ascertained from a cohort of 44 families with nephropathy from western Europe and the United States who underwent direct sequencing of the UMOD gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20172860" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using transfected MDCK cells, <a href="#12" class="mim-tip-reference" title="Ma, L., Liu, Y., El-Achkar, T. M., Wu, X.-R. <strong>Molecular and cellular effects of Tamm-Horsfall protein mutations and their rescue by chemical chaperones.</strong> J. Biol. Chem. 287: 1290-1305, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22117067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22117067</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22117067[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M111.283036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22117067">Ma et al. (2012)</a> found that mutant mouse Thp with substitutions corresponding to human cys126 to arg (C126R; <a href="#0006">191845.0006</a>) or cys217 to gly (C217G; <a href="#0012">191845.0012</a>) resulted in protein misfolding, retention of mutant protein in the ER, and reduced surface Thp expression and secretion. In all measures, the C217G substitution within the D8C domain was more severe than the C126R substitution within EGF-like domain-3. Both substitutions also led to reduced expression of the chaperone protein Hsp70 (see HSPA1A; <a href="/entry/140550">140550</a>), trapped wildtype Thp in the ER in a dominant-negative manner, and induced apoptosis. Treatments that favored correct protein folding tended to reduce the effect of the mutations. Greatest rescue was obtained with exposure to sodium 4-phenylbutyrate, a chemical chaperone that increases the expression of heat-shock proteins, and probenecid, a drug used clinically to treat hyperuricemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22117067" 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>Type 1-fimbriated E. coli, which contains a mannose-sensitive lectin subunit at the fimbrial tip, binds THP, and this binding inhibits binding of E. coli to kidney epithelial cells. <a href="#17" class="mim-tip-reference" title="Mo, L., Zhu, X.-H., Huang, H.-Y., Shapiro, E., Hasty, D. L., Wu, X.-R. <strong>Ablation of the Tamm-Horsfall protein gene increases susceptibility of mice to bladder colonization by type 1-fimbriated Escherichia coli.</strong> Am. J. Physiol. Renal Physiol. 286: F795-F802, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14665435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14665435</a>] [<a href="https://doi.org/10.1152/ajprenal.00357.2003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14665435">Mo et al. (2004)</a> found that Thp -/- mice, which were obtained in the expected mendelian ratio, showed increased susceptibility to bladder infection by type 1-fimbriated E. coli. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14665435" 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="Mo, L., Huang, H.-Y., Zhu, X.-H., Shapiro, E., Hasty, D. L., Wu, X.-R. <strong>Tamm-Horsfall protein is a critical renal defense factor protecting against calcium oxalate crystal formation.</strong> Kidney Int. 66: 1159-1166, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15327412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15327412</a>] [<a href="https://doi.org/10.1111/j.1523-1755.2004.00867.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15327412">Mo et al. (2004)</a> found spontaneous formation of calcium crystals in kidneys of adult Thp -/- mice. Excessive intake of calcium and oxalate dramatically increased both the frequency and severity of renal calcium crystal formation in Thp -/- mice. High calcium/oxalate also induced Thp -/- renal epithelial cells to express osteopontin (OPN, or SPP1; <a href="/entry/166490">166490</a>), an inhibitor of bone mineralization. <a href="#16" class="mim-tip-reference" title="Mo, L., Huang, H.-Y., Zhu, X.-H., Shapiro, E., Hasty, D. L., Wu, X.-R. <strong>Tamm-Horsfall protein is a critical renal defense factor protecting against calcium oxalate crystal formation.</strong> Kidney Int. 66: 1159-1166, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15327412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15327412</a>] [<a href="https://doi.org/10.1111/j.1523-1755.2004.00867.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15327412">Mo et al. (2004)</a> hypothesized that OPN may be an inducible inhibitor of calcium crystallization, whereas THP is a constitutive inhibitor of calcium crystallization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15327412" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Bachmann, S., Mutig, K., Bates, J., Welker, P., Geist, B., Gross, V., Luft, F. C., Alenina, N., Bader, M., Thiele, B. J., Prasadan, K., Raffi, H. S., Kumar, S. <strong>Renal effects of Tamm-Horsfall protein (uromodulin) deficiency in mice.</strong> Am. J. Physiol. Renal Physiol. 288: F559-F567, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15522986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15522986</a>] [<a href="https://doi.org/10.1152/ajprenal.00143.2004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15522986">Bachmann et al. (2005)</a> found that kidneys of Thp -/- mice were anatomically normal. However, Thp -/- kidneys showed reduced creatinine clearance, impaired water reabsorption following deprivation, and altered expression of renal transporters, channels, and regulatory molecules. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15522986" 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="Bernascone, I., Janas, S., Ikehata, M., Trudu, M., Corbelli, A., Schaeffer, C., Rastaldi, M. P., Devuyst, O., Rampoldi, L. <strong>A transgenic mouse model for uromodulin-associated kidney diseases shows specific tubulo-interstitial damage, urinary concentrating defect and renal failure.</strong> Hum. Molec. Genet. 19: 2998-3010, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20472742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20472742</a>] [<a href="https://doi.org/10.1093/hmg/ddq205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20472742">Bernascone et al. (2010)</a> generated a transgenic mouse model with a Umod C147W mutation corresponding to the human UMOD C148W mutation (<a href="#0015">191845.0015</a>). The mutant mice showed tubulointerstitial fibrosis with inflammatory cell infiltration, tubule dilation, and selective damage to the epithelial cells lining the thick ascending limb of the loop of Henle (TAL), leading to mild renal failure. Umod was retained in the ER of expressing cells, leading to ER hyperplasia. The authors suggested that impaired TAL function is a consequence of a gain-of-function effect of UMOD mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20472742" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=191845[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong><div class="mim-changed mim-change">.0001 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 1</div></strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1555487528 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555487528;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=rs1555487528" 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=rs1555487528" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 36 individuals from a large multigenerational kindred (family 1) with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; <a href="/entry/162000">162000</a>), <a href="#9" class="mim-tip-reference" title="Hart, T. C., Gorry, M. C., Hart, P. S., Woodard, A. S., Shihabi, Z., Sandhu, J., Shirts, B., Xu, L., Zhu, H., Barmada, M. M., Bleyer, A. J. <strong>Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy.</strong> J. Med. Genet. 39: 882-892, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12471200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12471200</a>] [<a href="https://doi.org/10.1136/jmg.39.12.882" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12471200">Hart et al. (2002)</a> identified a heterozygous in-frame 27-bp deletion (c.529_555del) in exon 4 of the UMOD gene, resulting in the deletion of 9 amino acids (His177_Arg185del). The mutation, which was found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the family. The family contained more than 300 individuals spanning 7 generations. Four mutation carriers, who were all women, had normal serum uric acid despite low fractional excretions of uric acid; 2 had mild renal insufficiency. Functional studies of the variant and studies of patient cells were not performed. The original clinical diagnosis was familial juvenile hyperuricemic nephropathy (FJHN, HNFJ). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12471200" 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><div class="mim-changed mim-change">.0002 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 1</div></strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28934582 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28934582;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=rs28934582" 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=rs28934582" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 9 affected members of a 5-generation family (family 2) with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; <a href="/entry/162000">162000</a>), <a href="#9" class="mim-tip-reference" title="Hart, T. C., Gorry, M. C., Hart, P. S., Woodard, A. S., Shihabi, Z., Sandhu, J., Shirts, B., Xu, L., Zhu, H., Barmada, M. M., Bleyer, A. J. <strong>Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy.</strong> J. Med. Genet. 39: 882-892, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12471200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12471200</a>] [<a href="https://doi.org/10.1136/jmg.39.12.882" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12471200">Hart et al. (2002)</a> identified a heterozygous c.443G-A transition in exon 4 of the UMOD gene, resulting in a cys148-to-tyr (C148Y) substitution at a conserved residue. The mutation, which was found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. The original clinical diagnosis was familial juvenile hyperuricemic nephropathy (FJHN, HNFJ). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12471200" 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><div class="mim-changed mim-change">.0003 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 1</div></strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28934583 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28934583;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=rs28934583" 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=rs28934583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an affected individual from a family (family 4) with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; <a href="/entry/162000">162000</a>), <a href="#9" class="mim-tip-reference" title="Hart, T. C., Gorry, M. C., Hart, P. S., Woodard, A. S., Shihabi, Z., Sandhu, J., Shirts, B., Xu, L., Zhu, H., Barmada, M. M., Bleyer, A. J. <strong>Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy.</strong> J. Med. Genet. 39: 882-892, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12471200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12471200</a>] [<a href="https://doi.org/10.1136/jmg.39.12.882" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12471200">Hart et al. (2002)</a> identified a heterozygous c.649T-C transition in exon 4 of the UMOD gene, resulting in a cys217-to-arg (C217R) substitution at a conserved residue. Functional studies of the variant and studies of patient cells were not performed. The family had previously been reported by <a href="#13" class="mim-tip-reference" title="Massari, P. U., Hsu, C. H., Barnes, R. V., Fox, I. H., Gikas, P. W., Weller, J. M. <strong>Familial hyperuricemia and renal disease.</strong> Arch. Intern. Med. 140: 680-684, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7396593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7396593</a>]" pmid="7396593">Massari et al. (1980)</a> as having a clinical phenotype consistent with familial juvenile hyperuricemic nephropathy (FJHN, HNFJ). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12471200+7396593" 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="Yang, H., Wu, C., Zhao, S., Guo, J. <strong>Identification and characterization of D8C, a novel domain present in liver-specific LZP, uromodulin and glycoprotein 2, mutated in familial juvenile hyperuricaemic nephropathy.</strong> FEBS Lett. 578: 236-238, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15589826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15589826</a>] [<a href="https://doi.org/10.1016/j.febslet.2004.10.092" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15589826">Yang et al. (2004)</a> determined that cys217 is 1 of 8 cysteines within UMOD predicted to form 4 disulfide bridges. The C217R mutation likely disrupts one of these disulfide bonds. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15589826" 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><div class="mim-changed mim-change">.0004 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 1</div></strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28934584 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28934584;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/rs28934584?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=rs28934584" 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=rs28934584" 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=RCV002251320 OR RCV004528105" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002251320, RCV004528105" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002251320...</a>
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<p>In 3 affected members of a multigenerational family (family 3) with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; <a href="/entry/162000">162000</a>), <a href="#9" class="mim-tip-reference" title="Hart, T. C., Gorry, M. C., Hart, P. S., Woodard, A. S., Shihabi, Z., Sandhu, J., Shirts, B., Xu, L., Zhu, H., Barmada, M. M., Bleyer, A. J. <strong>Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy.</strong> J. Med. Genet. 39: 882-892, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12471200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12471200</a>] [<a href="https://doi.org/10.1136/jmg.39.12.882" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12471200">Hart et al. (2002)</a> identified a heterozygous c.307G-T transversion in exon 4 of the UMOD gene, resulting in a gly103-to-cys (G103C) substitution at a conserved residue. Functional studies of the variant and studies of patient cells were not performed. The patients, who had hyperuricemia and renal insufficiency, were diagnosed clinically with medullary cystic kidney disease (MCKD). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12471200" 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><div class="mim-changed mim-change">.0005 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 1</div></strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121917768 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917768;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=rs121917768" 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=rs121917768" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a family (11/00) from Austria with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; <a href="/entry/162000">162000</a>), <a href="#29" class="mim-tip-reference" title="Turner, J. J. O., Stacey, J. M., Harding, B., Kotanko, P., Lhotta, K., Puig, J. G., Roberts, I., Torres, R. J., Thakker, R. V. <strong>UROMODULIN mutations cause familial juvenile hyperuricemic nephropathy.</strong> J. Clin. Endocr. Metab. 88: 1398-1401, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12629136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12629136</a>] [<a href="https://doi.org/10.1210/jc.2002-021973" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12629136">Turner et al. (2003)</a> identified a heterozygous c.335G-A transition in the UMOD gene that was predicted to result in a cys77-to-tyr (C77Y) substitution. Functional studies of the variant and studies of patient cells were not performed. The family had previously been reported by <a href="#25" class="mim-tip-reference" title="Stacey, J. M., Turner, J. J. O., Harding, B., Nesbit, M. A., Kotanko, P., Lhotta, K., Puig, J. G., Torres, R. J., Thakker, R. V. <strong>Genetic mapping studies of familial juvenile hyperuricemic nephropathy on chromosome 16p11-p13.</strong> J. Clin. Endocr. Metab. 88: 464-470, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12519891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12519891</a>] [<a href="https://doi.org/10.1210/jc.2002-021268" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12519891">Stacey et al. (2003)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12629136+12519891" 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">rs121917769 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917769;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=rs121917769" 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=rs121917769" 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=RCV002251322" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002251322" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002251322</a>
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<p>In affected members of a family (13/00) from Austria with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; <a href="/entry/162000">162000</a>), <a href="#29" class="mim-tip-reference" title="Turner, J. J. O., Stacey, J. M., Harding, B., Kotanko, P., Lhotta, K., Puig, J. G., Roberts, I., Torres, R. J., Thakker, R. V. <strong>UROMODULIN mutations cause familial juvenile hyperuricemic nephropathy.</strong> J. Clin. Endocr. Metab. 88: 1398-1401, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12629136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12629136</a>] [<a href="https://doi.org/10.1210/jc.2002-021973" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12629136">Turner et al. (2003)</a> identified a heterozygous c.481T-C transition in the UMOD gene that was predicted to result in a cys126-to-arg (C126R) substitution. Functional studies of the variant and studies of patient cells were not performed. The family had previously been reported by <a href="#25" class="mim-tip-reference" title="Stacey, J. M., Turner, J. J. O., Harding, B., Nesbit, M. A., Kotanko, P., Lhotta, K., Puig, J. G., Torres, R. J., Thakker, R. V. <strong>Genetic mapping studies of familial juvenile hyperuricemic nephropathy on chromosome 16p11-p13.</strong> J. Clin. Endocr. Metab. 88: 464-470, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12519891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12519891</a>] [<a href="https://doi.org/10.1210/jc.2002-021268" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12519891">Stacey et al. (2003)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12629136+12519891" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a family with ADTKD1, originally reported by <a href="#5" class="mim-tip-reference" title="Fairbanks, L. D., Cameron, J. S., Venkat-Raman, G., Rigden, S. P. A., Rees, L., Van't Hoff, W., Mansell, M., Pattison, J., Goldsmith, D. J. A., Simmonds, H. A. <strong>Early treatment with allopurinol in familial juvenile hyperuricaemic nephropathy (FJHN) ameliorates the long-term progression of renal disease.</strong> Quart. J. Med. 95: 597-607, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12205338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12205338</a>] [<a href="https://doi.org/10.1093/qjmed/95.9.597" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12205338">Fairbanks et al. (2002)</a>, <a href="#30" class="mim-tip-reference" title="Vylet'al, P., Kublova, M., Kalbacova, M., Hodanova, K., Baresova, V., Stiburkova, B., Sikora, J., Hulkova, H., Zivny, J., Majewski, J., Simmonds, A., Fryns, J.-P., Venkat-Raman, G., Elleder, M., Kmoch, S. <strong>Alterations of uromodulin biology: a common denominator of the genetically heterogeneous FJHN/MCKD syndrome.</strong> Kidney Int. 70: 1155-1169, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16883323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16883323</a>] [<a href="https://doi.org/10.1038/sj.ki.5001728" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16883323">Vylet'al et al. (2006)</a> identified heterozygosity for the C126R mutation in the UMOD gene. A female patient who had onset of disease at age 31, with gout, hypertension, elevated creatinine and hyperuricemia, underwent kidney transplantation but died at 36 years of age. A 43-year-old woman and 40-year-old man, who had onset of hyperuricemia at age 19 years and 16 years, respectively, had no abnormalities on renal ultrasound and had not developed any other symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16883323+12205338" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In HeLa cells transfected with C126R mutant uromodulin, <a href="#32" class="mim-tip-reference" title="Williams, S. E., Reed, A. A. C., Galvanovskis, J., Antignac, C., Goodship, T., Karet, F. E., Kotanko, P., Lhotta, K., Moriniere, V., Williams, P., Wong, W., Rorsman, P., Thakker, R. V. <strong>Uromodulin mutations causing familial juvenile hyperuricaemic nephropathy lead to protein maturation defects and retention in the endoplasmic reticulum.</strong> Hum. Molec. Genet. 18: 2963-2974, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19465746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19465746</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19465746[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp235" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19465746">Williams et al. (2009)</a> found that the mutant protein had delayed maturation (about 25% of wildtype), was retained in the ER, and not trafficked to the plasma membrane, likely due to protein misfolding. The authors suggested that abnormal protein retention in the ER may trigger apoptosis and underlie the mechanism for the pathogenesis of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19465746" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using transfected MDCK cells, <a href="#12" class="mim-tip-reference" title="Ma, L., Liu, Y., El-Achkar, T. M., Wu, X.-R. <strong>Molecular and cellular effects of Tamm-Horsfall protein mutations and their rescue by chemical chaperones.</strong> J. Biol. Chem. 287: 1290-1305, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22117067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22117067</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22117067[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M111.283036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22117067">Ma et al. (2012)</a> found that mutant mouse Thp with substitutions corresponding to human C126R or cys217 to gly (C217G; <a href="#0012">191845.0012</a>) resulted in protein misfolding, retention of mutant protein in the ER, and reduced surface Thp expression and secretion. In all measures, the C217G substitution within the D8C domain was more severe than the C126R substitution within EGF-like domain-3. Both substitutions also led to reduced expression of the chaperone protein Hsp70 (see HSPA1A; <a href="/entry/140550">140550</a>), trapped wildtype Thp in the ER in a dominant-negative manner, and induced apoptosis. Treatments that favored correct protein folding tended to reduce the effect of the mutations. Greatest rescue was obtained with exposure to sodium 4-phenylbutyrate, a chemical chaperone that increases the expression of heat-shock proteins, and probenecid, a drug used clinically to treat hyperuricemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22117067" 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><div class="mim-changed mim-change">.0007 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 1</div></strong>
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<p>In affected members of a family from Spain (1/96) with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; <a href="/entry/162000">162000</a>), <a href="#29" class="mim-tip-reference" title="Turner, J. J. O., Stacey, J. M., Harding, B., Kotanko, P., Lhotta, K., Puig, J. G., Roberts, I., Torres, R. J., Thakker, R. V. <strong>UROMODULIN mutations cause familial juvenile hyperuricemic nephropathy.</strong> J. Clin. Endocr. Metab. 88: 1398-1401, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12629136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12629136</a>] [<a href="https://doi.org/10.1210/jc.2002-021973" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12629136">Turner et al. (2003)</a> identified a heterozygous c.488A-G transition in the UMOD gene that was predicted to result in an asn128-to-ser (N128S) substitution. Functional studies of the variant and studies of patient cells were not performed. The family had previously been reported by <a href="#25" class="mim-tip-reference" title="Stacey, J. M., Turner, J. J. O., Harding, B., Nesbit, M. A., Kotanko, P., Lhotta, K., Puig, J. G., Torres, R. J., Thakker, R. V. <strong>Genetic mapping studies of familial juvenile hyperuricemic nephropathy on chromosome 16p11-p13.</strong> J. Clin. Endocr. Metab. 88: 464-470, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12519891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12519891</a>] [<a href="https://doi.org/10.1210/jc.2002-021268" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12519891">Stacey et al. (2003)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12629136+12519891" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In HeLa cells transfected with N128S mutant uromodulin, <a href="#32" class="mim-tip-reference" title="Williams, S. E., Reed, A. A. C., Galvanovskis, J., Antignac, C., Goodship, T., Karet, F. E., Kotanko, P., Lhotta, K., Moriniere, V., Williams, P., Wong, W., Rorsman, P., Thakker, R. V. <strong>Uromodulin mutations causing familial juvenile hyperuricaemic nephropathy lead to protein maturation defects and retention in the endoplasmic reticulum.</strong> Hum. Molec. Genet. 18: 2963-2974, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19465746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19465746</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19465746[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp235" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19465746">Williams et al. (2009)</a> found that the mutant protein had delayed maturation (about 25% of wildtype), was retained in the ER, and not trafficked to the plasma membrane, likely due to protein misfolding. The authors suggested that abnormal protein retention in the ER may trigger apoptosis and underlie the mechanism for the pathogenesis of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19465746" 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">rs121917771 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917771;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=rs121917771" 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=rs121917771" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a family from Spain (13/96) with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; <a href="/entry/162000">162000</a>), <a href="#29" class="mim-tip-reference" title="Turner, J. J. O., Stacey, J. M., Harding, B., Kotanko, P., Lhotta, K., Puig, J. G., Roberts, I., Torres, R. J., Thakker, R. V. <strong>UROMODULIN mutations cause familial juvenile hyperuricemic nephropathy.</strong> J. Clin. Endocr. Metab. 88: 1398-1401, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12629136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12629136</a>] [<a href="https://doi.org/10.1210/jc.2002-021973" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12629136">Turner et al. (2003)</a> identified a heterozygous c.869G-A transition in the UMOD gene, resulting in a cys255-to-tyr (C255Y) substitution at a conserved residue. Functional studies of the variant and studies of patient cells were not performed. The family had previously been reported by <a href="#25" class="mim-tip-reference" title="Stacey, J. M., Turner, J. J. O., Harding, B., Nesbit, M. A., Kotanko, P., Lhotta, K., Puig, J. G., Torres, R. J., Thakker, R. V. <strong>Genetic mapping studies of familial juvenile hyperuricemic nephropathy on chromosome 16p11-p13.</strong> J. Clin. Endocr. Metab. 88: 464-470, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12519891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12519891</a>] [<a href="https://doi.org/10.1210/jc.2002-021268" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12519891">Stacey et al. (2003)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12629136+12519891" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 14 affected members of a large consanguineous Spanish family with ADTKD1, <a href="#22" class="mim-tip-reference" title="Rezende-Lima, W., Parreira, K. S., Garcia-Gonzalez, M., Riveira, E., Banet, J. F., Lens, X. M. <strong>Homozygosity for uromodulin disorders: FJHN and MCKD-type 2.</strong> Kidney Int. 66: 558-563, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15253706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15253706</a>] [<a href="https://doi.org/10.1111/j.1523-1755.2004.00774.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15253706">Rezende-Lima et al. (2004)</a> identified a C255Y mutation in the UMOD gene. These authors stated that the substitution resulted from a c.764G-A transition in exon 4 and that the mutation disrupted a light chain-binding domain. Eleven family members were heterozygous for the mutation, whereas 3 were homozygous. The homozygous individuals had earlier disease onset than the heterozygous individuals, but the report demonstrated that homozygosity for UMOD mutations is not lethal. The clinical phenotype was consistent with medullary cystic kidney disease (MCKD), although the authors noted that cyst formation may be nonspecific secondary effect. This family was also reported as family F4 by <a href="#11" class="mim-tip-reference" title="Lens, X. M., Banet, J. F., Outeda, P., Barrio-Lucia, V. <strong>A novel pattern of mutation in uromodulin disorders: autosomal dominant medullary cystic kidney disease type 2, familial juvenile hyperuricemic nephropathy, and autosomal dominant glomerulocystic kidney disease.</strong> Am. J. Kidney Dis. 46: 52-57, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15983957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15983957</a>] [<a href="https://doi.org/10.1053/j.ajkd.2005.04.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15983957">Lens et al. (2005)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15253706+15983957" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of a family from Spain (20/96) with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; <a href="/entry/162000">162000</a>), <a href="#29" class="mim-tip-reference" title="Turner, J. J. O., Stacey, J. M., Harding, B., Kotanko, P., Lhotta, K., Puig, J. G., Roberts, I., Torres, R. J., Thakker, R. V. <strong>UROMODULIN mutations cause familial juvenile hyperuricemic nephropathy.</strong> J. Clin. Endocr. Metab. 88: 1398-1401, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12629136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12629136</a>] [<a href="https://doi.org/10.1210/jc.2002-021973" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12629136">Turner et al. (2003)</a> identified a heterozygous c.1003T-G transversion in the UMOD gene that was predicted to result in a cys300-to-gly (C300G) substitution. Functional studies of the variant and studies of patient cells were not performed. The family had previously been reported by <a href="#25" class="mim-tip-reference" title="Stacey, J. M., Turner, J. J. O., Harding, B., Nesbit, M. A., Kotanko, P., Lhotta, K., Puig, J. G., Torres, R. J., Thakker, R. V. <strong>Genetic mapping studies of familial juvenile hyperuricemic nephropathy on chromosome 16p11-p13.</strong> J. Clin. Endocr. Metab. 88: 464-470, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12519891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12519891</a>] [<a href="https://doi.org/10.1210/jc.2002-021268" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12519891">Stacey et al. (2003)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12629136+12519891" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a Spanish family (F3) with ADTKD1, <a href="#11" class="mim-tip-reference" title="Lens, X. M., Banet, J. F., Outeda, P., Barrio-Lucia, V. <strong>A novel pattern of mutation in uromodulin disorders: autosomal dominant medullary cystic kidney disease type 2, familial juvenile hyperuricemic nephropathy, and autosomal dominant glomerulocystic kidney disease.</strong> Am. J. Kidney Dis. 46: 52-57, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15983957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15983957</a>] [<a href="https://doi.org/10.1053/j.ajkd.2005.04.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15983957">Lens et al. (2005)</a> identified heterozygosity for the C300G mutation in exon 5 of the UMOD gene. The phenotype included glomerulocystic kidney disease (GCKD), thus expanding the spectrum of manifestations associated with this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15983957" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of an Italian family (GCKD1) with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; <a href="/entry/162000">162000</a>), <a href="#21" class="mim-tip-reference" title="Rampoldi, L., Caridi, G., Santon, D., Boaretto, F., Bernascone, I., Lamorte, G., Tardanico, R., Dagnino, M., Colussi, G., Scolari, F., Ghiggeri, G. M., Amoroso, A., Casari, G. <strong>Allelism of MCKD, FJHN and GCKD caused by impairment of uromodulin export dynamics.</strong> Hum. Molec. Genet. 12: 3369-3384, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14570709/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14570709</a>] [<a href="https://doi.org/10.1093/hmg/ddg353" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14570709">Rampoldi et al. (2003)</a> identified a c.943T-C transition (c.943T-C, NM_003361) in exon 5 of the UMOD gene, predicted to result in a cys315-to-arg (C315R) substitution. The family had previously been reported by <a href="#24" class="mim-tip-reference" title="Scolari, F., Puzzer, D., Amoroso, A., Caridi, G., Ghiggeri, G. M., Maiorca, R., Aridon, P., De Fusco, M., Ballabio, A., Casari, G. <strong>Identification of a new locus for medullary cystic disease, on chromosome 16p12.</strong> Am. J. Hum. Genet. 64: 1655-1660, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10330352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10330352</a>] [<a href="https://doi.org/10.1086/302414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10330352">Scolari et al. (1999)</a> with a clinical diagnosis of glomerulocystic kidney disease (GCKD). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10330352+14570709" 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">rs121917774 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917774;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=rs121917774" 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=rs121917774" 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=RCV001566754 OR RCV002251327" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001566754, RCV002251327" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001566754...</a>
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<p>In 3 Belgian brothers with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; <a href="/entry/162000">162000</a>), originally reported as family BE2 by <a href="#26" class="mim-tip-reference" title="Stiburkova, B., Majewski, J., Hodanova, K., Ondrova, L., Jerabkova, M., Zikanova, M., Vylet'al, P., Sebesta, I., Marinaki, A., Simmonds, A., Matthijs, G., Fryns, J.-P., Torres, R., Puig, J. G., Ott, J., Kmoch, S. <strong>Familial juvenile hyperuricaemic nephropathy (FJHN): linkage analysis in 15 families, physical and transcriptional characterisation of the FJHN critical region on chromosome 16p11.2 and the analysis of seven candidate genes.</strong> Europ. J. Hum. Genet. 11: 145-154, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12634862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12634862</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200937" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12634862">Stiburkova et al. (2003)</a>, <a href="#30" class="mim-tip-reference" title="Vylet'al, P., Kublova, M., Kalbacova, M., Hodanova, K., Baresova, V., Stiburkova, B., Sikora, J., Hulkova, H., Zivny, J., Majewski, J., Simmonds, A., Fryns, J.-P., Venkat-Raman, G., Elleder, M., Kmoch, S. <strong>Alterations of uromodulin biology: a common denominator of the genetically heterogeneous FJHN/MCKD syndrome.</strong> Kidney Int. 70: 1155-1169, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16883323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16883323</a>] [<a href="https://doi.org/10.1038/sj.ki.5001728" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16883323">Vylet'al et al. (2006)</a> identified a heterozygous mutation in the UMOD gene resulting in a val273-to-phe (V273F) substitution. Functional studies showed that the V273F-mutant protein was retained in the endoplasmic reticulum and did not reach the plasma membrane. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16883323+12634862" 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">rs28934583 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28934583;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=rs28934583" 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=rs28934583" 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=RCV002251328" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002251328" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002251328</a>
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<p>In a 36-year-old Belgian woman with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; <a href="/entry/162000">162000</a>), <a href="#3" class="mim-tip-reference" title="Dahan, K., Devuyst, O., Smaers, M., Vertommen, D., Loute, G., Poux, J. M., Viron, B., Jacquot, C., Gagnadoux, M. F., Chauveau, D., Buchler, M., Cochat, P., Cosyns, J. P., Mougenot, B., Rider, M. H., Antignac, C., Verellen-Dumoulin, C., Pirson, Y. <strong>A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin.</strong> J. Am. Soc. Nephrol. 14: 2883-2893, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14569098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14569098</a>] [<a href="https://doi.org/10.1097/01.asn.0000092147.83480.b5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14569098">Dahan et al. (2003)</a> identified a heterozygous c.754T-G transversion in exon 4 of the UMOD gene, resulting in a cys217-to-gly (C217G) substitution. The patient was in end-stage renal failure, and she had a history of gout, with onset at age 21 years. Her father, grandmother, and 1 sister were also affected. <a href="#3" class="mim-tip-reference" title="Dahan, K., Devuyst, O., Smaers, M., Vertommen, D., Loute, G., Poux, J. M., Viron, B., Jacquot, C., Gagnadoux, M. F., Chauveau, D., Buchler, M., Cochat, P., Cosyns, J. P., Mougenot, B., Rider, M. H., Antignac, C., Verellen-Dumoulin, C., Pirson, Y. <strong>A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin.</strong> J. Am. Soc. Nephrol. 14: 2883-2893, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14569098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14569098</a>] [<a href="https://doi.org/10.1097/01.asn.0000092147.83480.b5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14569098">Dahan et al. (2003)</a> erroneously reported this mutation as 794T-G, instead of 754T-G, in their paper. In addition, their numbering of the UMOD sequence began at nucleotide 1, rather than at the ATG start codon at nucleotide 106. Following the convention of numbering from the start codon, this mutation should be referred to as c.649T-G (<a href="#8" class="mim-tip-reference" title="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 2/11/2013."None>Gross, 2013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14569098" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using transfected MCKD cells, <a href="#12" class="mim-tip-reference" title="Ma, L., Liu, Y., El-Achkar, T. M., Wu, X.-R. <strong>Molecular and cellular effects of Tamm-Horsfall protein mutations and their rescue by chemical chaperones.</strong> J. Biol. Chem. 287: 1290-1305, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22117067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22117067</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22117067[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M111.283036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22117067">Ma et al. (2012)</a> found that mutant mouse Thp with substitutions corresponding to human cys126 to arg (C126R; <a href="#0006">191845.0006</a>) or C217G resulted in protein misfolding, retention of mutant protein in the ER, and reduced surface Thp expression and secretion. In all measures, the C217G substitution within the D8C domain was more severe than the C126R substitution within EGF-like domain-3. Both substitutions also led to reduced expression of the chaperone protein Hsp70 (see HSPA1A; <a href="/entry/140550">140550</a>), trapped wildtype Thp in the ER in a dominant-negative manner, and induced apoptosis. Treatments that favored correct protein folding tended to reduce the effect of the mutations. Greatest rescue was obtained with exposure to sodium 4-phenylbutyrate, a chemical chaperone that increases the expression of heat-shock proteins, and probenecid, a drug used clinically to treat hyperuricemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22117067" 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><div class="mim-changed mim-change">.0013 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 1</div></strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122388 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122388;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=rs398122388" 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=rs398122388" 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=RCV002251329" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002251329" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002251329</a>
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<p>In 3 members of a 2-generation family (F6) with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; <a href="/entry/162000">162000</a>), <a href="#34" class="mim-tip-reference" title="Zaucke, F., Boehnlein, J. M., Steffens, S., Polishchuk, R. S., Rampoldi, L., Fischer, A., Pasch, A., Boehm, C. W. A., Baasner, A., Attanasio, M., Hoppe, B., Hopfer, H., Beck, B. B., Sayer, J. A., Hildebrandt, F., Wolf, M. T. F. <strong>Uromodulin is expressed in renal primary cilia and UMOD mutations result in decreased ciliary uromodulin expression.</strong> Hum. Molec. Genet. 19: 1985-1997, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20172860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20172860</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20172860[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq077" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20172860">Zaucke et al. (2010)</a> identified a heterozygous c.743G-C transversion in the UMOD gene, resulting in a cys248-to-ser substitution (C248S) at a conserved residue in the D8C domain. The father exhibited hypertension, gout, congestive heart failure, varices, and an aortic aneurysm. Renal biopsy showed tubular atrophy, tubulointerstitial fibrosis, and a thickened tubular basement membrane. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20172860" 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">rs1555487318 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555487318;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=rs1555487318" 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=rs1555487318" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of 2 apparently unrelated Spanish families (F1 and F2) with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; <a href="/entry/162000">162000</a>), <a href="#11" class="mim-tip-reference" title="Lens, X. M., Banet, J. F., Outeda, P., Barrio-Lucia, V. <strong>A novel pattern of mutation in uromodulin disorders: autosomal dominant medullary cystic kidney disease type 2, familial juvenile hyperuricemic nephropathy, and autosomal dominant glomerulocystic kidney disease.</strong> Am. J. Kidney Dis. 46: 52-57, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15983957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15983957</a>] [<a href="https://doi.org/10.1053/j.ajkd.2005.04.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15983957">Lens et al. (2005)</a> identified a heterozygous c.947A-C transversion in exon 5 of the UMOD gene, resulting in a gln316-to-pro (Q316P) substitution at a conserved residue. The mutation segregated with the phenotype in the families and was not found in 100 control chromosomes. The clinical phenotype in family 1 was consistent with medullary cystic kidney disease (MCKD), whereas the clinical phenotype in family 2 was consistent with familial juvenile hyperuricemic nephropathy (FJHN). The results demonstrated that these variable clinical manifestations are part of the same disease entity, referred to as ADTKD1. Although functional studies of the variant were not performed, the authors suggested that the mutation could alter the tertiary structure of UMOD, leading to defects in vesicular transport in the thick ascending loop of Henle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15983957" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV002251407" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002251407" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002251407</a>
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<p>In affected members of an Italian family (MCKD9) with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; <a href="/entry/162000">162000</a>), <a href="#21" class="mim-tip-reference" title="Rampoldi, L., Caridi, G., Santon, D., Boaretto, F., Bernascone, I., Lamorte, G., Tardanico, R., Dagnino, M., Colussi, G., Scolari, F., Ghiggeri, G. M., Amoroso, A., Casari, G. <strong>Allelism of MCKD, FJHN and GCKD caused by impairment of uromodulin export dynamics.</strong> Hum. Molec. Genet. 12: 3369-3384, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14570709/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14570709</a>] [<a href="https://doi.org/10.1093/hmg/ddg353" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14570709">Rampoldi et al. (2003)</a> identified a heterozygous c.444T-G transversion (c.444T-G, NM_003361) in exon 4 of the UMOD gene, resulting in a cys148-to-trp (C148W) substitution at a conserved residue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14570709" 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="Bernascone, I., Janas, S., Ikehata, M., Trudu, M., Corbelli, A., Schaeffer, C., Rastaldi, M. P., Devuyst, O., Rampoldi, L. <strong>A transgenic mouse model for uromodulin-associated kidney diseases shows specific tubulo-interstitial damage, urinary concentrating defect and renal failure.</strong> Hum. Molec. Genet. 19: 2998-3010, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20472742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20472742</a>] [<a href="https://doi.org/10.1093/hmg/ddq205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20472742">Bernascone et al. (2010)</a> generated a transgenic mouse model with a Umod C147W mutation corresponding to the human UMOD C148W mutation. The mutant mice showed tubulointerstitial fibrosis with inflammatory cell infiltration, tubule dilation, and selective damage to the epithelial cells lining the thick ascending limb of the loop of Henle (TAL), leading to mild renal failure. Umod was retained in the ER of expressing cells, leading to ER hyperplasia. The authors suggested that impaired TAL function is a consequence of a gain-of-function effect of UMOD mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20472742" 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><div class="mim-changed mim-change">.0016 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 1</div></strong>
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UMOD, ASP196ASN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1965729129 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1965729129;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=rs1965729129" 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=rs1965729129" 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=RCV002251408" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002251408" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002251408</a>
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<p>In 3 affected members of a family (family 5) with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; <a href="/entry/162000">162000</a>), <a href="#32" class="mim-tip-reference" title="Williams, S. E., Reed, A. A. C., Galvanovskis, J., Antignac, C., Goodship, T., Karet, F. E., Kotanko, P., Lhotta, K., Moriniere, V., Williams, P., Wong, W., Rorsman, P., Thakker, R. V. <strong>Uromodulin mutations causing familial juvenile hyperuricaemic nephropathy lead to protein maturation defects and retention in the endoplasmic reticulum.</strong> Hum. Molec. Genet. 18: 2963-2974, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19465746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19465746</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19465746[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp235" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19465746">Williams et al. (2009)</a> identified a heterozygous c.586G-A transition in exon 3 of the UMOD gene, resulting in an asp196-to-asn (D196N) substitution in the cysteine-rich domain. In vitro functional expression studies in HeLa cells transfected with the mutation showed that it caused a 50% delay in maturation compared to wildtype. The mutant protein was retained in the ER and showed decreased expression at the plasma membrane. The findings suggested that abnormal protein retention in the ER may trigger apoptosis and underlie the mechanism for disease pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19465746" 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="Bachmann2005" class="mim-anchor"></a>
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<strong>Renal effects of Tamm-Horsfall protein (uromodulin) deficiency in mice.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15522986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15522986</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15522986" 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/10.1152/ajprenal.00143.2004" target="_blank">Full Text</a>]
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Bernascone, I., Janas, S., Ikehata, M., Trudu, M., Corbelli, A., Schaeffer, C., Rastaldi, M. P., Devuyst, O., Rampoldi, L.
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<strong>A transgenic mouse model for uromodulin-associated kidney diseases shows specific tubulo-interstitial damage, urinary concentrating defect and renal failure.</strong>
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Hum. Molec. Genet. 19: 2998-3010, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20472742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20472742</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20472742" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddq205" target="_blank">Full Text</a>]
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Dahan, K., Devuyst, O., Smaers, M., Vertommen, D., Loute, G., Poux, J. M., Viron, B., Jacquot, C., Gagnadoux, M. F., Chauveau, D., Buchler, M., Cochat, P., Cosyns, J. P., Mougenot, B., Rider, M. H., Antignac, C., Verellen-Dumoulin, C., Pirson, Y.
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<strong>A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin.</strong>
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J. Am. Soc. Nephrol. 14: 2883-2893, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14569098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14569098</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14569098" 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/10.1097/01.asn.0000092147.83480.b5" target="_blank">Full Text</a>]
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Deng, Z., Johnson, K., Engleward, B. P., Lane, S., Callen, D. F., Samson, L. D., Davisson, M. T., Siciliano, M. J.
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<strong>New regions of conserved synteny and linkage between human chromosome 16p12-p13 and mouse chromosomes 16 and 11. (Abstract)</strong>
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Cytogenet. Cell Genet. 68: 180 only, 1995.
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Fairbanks, L. D., Cameron, J. S., Venkat-Raman, G., Rigden, S. P. A., Rees, L., Van't Hoff, W., Mansell, M., Pattison, J., Goldsmith, D. J. A., Simmonds, H. A.
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<strong>Early treatment with allopurinol in familial juvenile hyperuricaemic nephropathy (FJHN) ameliorates the long-term progression of renal disease.</strong>
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Quart. J. Med. 95: 597-607, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12205338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12205338</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12205338" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/qjmed/95.9.597" target="_blank">Full Text</a>]
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Fukuoka, S.-I., Matsuda, Y.
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<strong>Assignment of the Tamm-Horsfall protein/uromodulin gene (Umod) to mouse chromosome bands 7F1-F2 and rat chromosome bands 1q36-q37 by in situ hybridization.</strong>
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Cytogenet. Cell Genet. 79: 241-242, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9605864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9605864</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9605864" 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/10.1159/000134735" target="_blank">Full Text</a>]
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Greimel, P., Jabs, S., Storch, S., Cherif, S., Honke, K., Braulke, T., Thiem, J.
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<strong>In vitro sulfation of N-acetyllactosaminide by soluble recombinant human beta-Gal-3-prime-sulfotransferase.</strong>
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Carbohydr. Res. 341: 918-924, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16516177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16516177</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16516177" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.carres.2006.02.006" target="_blank">Full Text</a>]
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Gross, M. B.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 2/11/2013.
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Hart, T. C., Gorry, M. C., Hart, P. S., Woodard, A. S., Shihabi, Z., Sandhu, J., Shirts, B., Xu, L., Zhu, H., Barmada, M. M., Bleyer, A. J.
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<strong>Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy.</strong>
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J. Med. Genet. 39: 882-892, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12471200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12471200</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12471200" 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/10.1136/jmg.39.12.882" target="_blank">Full Text</a>]
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Jeanpierre, C., Whitmore, S. A., Austruy, E., Cohen-Salmon, M., Callen, D. F., Junien, C.
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<strong>Chromosomal assignment of the uromodulin gene (UMOD) to 16p13.11.</strong>
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Cytogenet. Cell Genet. 62: 185-187, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8382593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8382593</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8382593" 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/10.1159/000133470" target="_blank">Full Text</a>]
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Lens, X. M., Banet, J. F., Outeda, P., Barrio-Lucia, V.
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<strong>A novel pattern of mutation in uromodulin disorders: autosomal dominant medullary cystic kidney disease type 2, familial juvenile hyperuricemic nephropathy, and autosomal dominant glomerulocystic kidney disease.</strong>
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Am. J. Kidney Dis. 46: 52-57, 2005.
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[<a href="https://doi.org/10.1074/jbc.M111.283036" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jcp.22.3.334" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14907962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14907962</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14907962" 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/10.1084/jem.95.1.71" 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="29" class="mim-anchor"></a>
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<a id="Turner2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Turner, J. J. O., Stacey, J. M., Harding, B., Kotanko, P., Lhotta, K., Puig, J. G., Roberts, I., Torres, R. J., Thakker, R. V.
|
|
<strong>UROMODULIN mutations cause familial juvenile hyperuricemic nephropathy.</strong>
|
|
J. Clin. Endocr. Metab. 88: 1398-1401, 2003.
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|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12629136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12629136</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12629136" 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/10.1210/jc.2002-021973" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="30" class="mim-anchor"></a>
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<a id="Vylet'al2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vylet'al, P., Kublova, M., Kalbacova, M., Hodanova, K., Baresova, V., Stiburkova, B., Sikora, J., Hulkova, H., Zivny, J., Majewski, J., Simmonds, A., Fryns, J.-P., Venkat-Raman, G., Elleder, M., Kmoch, S.
|
|
<strong>Alterations of uromodulin biology: a common denominator of the genetically heterogeneous FJHN/MCKD syndrome.</strong>
|
|
Kidney Int. 70: 1155-1169, 2006.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16883323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16883323</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16883323" 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/sj.ki.5001728" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="31" class="mim-anchor"></a>
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<a id="Weiss2020" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Weiss, G. L., Stanisich, J. J., Sauer, M. M., Lin, C.-W., Eras, J., Zyla, D. S., Truck, J., Devuyst, O., Aebi, M., Pilhofer, M., Glockshuber, R.
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|
<strong>Architecture and function of human uromodulin filaments in urinary tract infections.</strong>
|
|
Science 369: 1005-1010, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32616672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32616672</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32616672" 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.aaz9866" 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="32" class="mim-anchor"></a>
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<a id="Williams2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Williams, S. E., Reed, A. A. C., Galvanovskis, J., Antignac, C., Goodship, T., Karet, F. E., Kotanko, P., Lhotta, K., Moriniere, V., Williams, P., Wong, W., Rorsman, P., Thakker, R. V.
|
|
<strong>Uromodulin mutations causing familial juvenile hyperuricaemic nephropathy lead to protein maturation defects and retention in the endoplasmic reticulum.</strong>
|
|
Hum. Molec. Genet. 18: 2963-2974, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19465746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19465746</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19465746[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19465746" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp235" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="33" class="mim-anchor"></a>
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<a id="Yang2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yang, H., Wu, C., Zhao, S., Guo, J.
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<strong>Identification and characterization of D8C, a novel domain present in liver-specific LZP, uromodulin and glycoprotein 2, mutated in familial juvenile hyperuricaemic nephropathy.</strong>
|
|
FEBS Lett. 578: 236-238, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15589826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15589826</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15589826" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.febslet.2004.10.092" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="34" class="mim-anchor"></a>
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<a id="Zaucke2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zaucke, F., Boehnlein, J. M., Steffens, S., Polishchuk, R. S., Rampoldi, L., Fischer, A., Pasch, A., Boehm, C. W. A., Baasner, A., Attanasio, M., Hoppe, B., Hopfer, H., Beck, B. B., Sayer, J. A., Hildebrandt, F., Wolf, M. T. F.
|
|
<strong>Uromodulin is expressed in renal primary cilia and UMOD mutations result in decreased ciliary uromodulin expression.</strong>
|
|
Hum. Molec. Genet. 19: 1985-1997, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20172860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20172860</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20172860[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20172860" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddq077" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 01/26/2021
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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 : 12/04/2020<br>Carol A. Bocchini - updated : 10/18/2017<br>George E. Tiller - updated : 9/9/2013<br>Cassandra L. Kniffin - updated : 2/13/2013<br>Matthew B. Gross - updated : 2/11/2013<br>Patricia A. Hartz - updated : 2/8/2013<br>George E. Tiller - updated : 6/25/2010<br>Marla J. F. O'Neill - updated : 10/15/2009<br>George E. Tiller - updated : 1/10/2006<br>Patricia A. Hartz - updated : 4/19/2005<br>John A. Phillips, III - updated : 3/29/2004<br>Victor A. McKusick - updated : 6/30/2003<br>Victor A. McKusick - updated : 5/28/1998
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/6/1994
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 02/26/2025
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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 : 02/09/2021<br>ckniffin : 01/26/2021<br>mgross : 12/04/2020<br>carol : 10/19/2017<br>carol : 10/18/2017<br>alopez : 09/09/2013<br>alopez : 9/9/2013<br>tpirozzi : 9/5/2013<br>tpirozzi : 9/5/2013<br>carol : 3/4/2013<br>ckniffin : 2/13/2013<br>mgross : 2/11/2013<br>mgross : 2/11/2013<br>terry : 2/8/2013<br>mgross : 8/3/2011<br>carol : 12/10/2010<br>wwang : 7/15/2010<br>terry : 6/25/2010<br>alopez : 1/6/2010<br>terry : 10/21/2009<br>wwang : 10/16/2009<br>terry : 10/15/2009<br>carol : 6/18/2008<br>terry : 12/17/2007<br>wwang : 2/10/2006<br>terry : 1/10/2006<br>mgross : 4/25/2005<br>terry : 4/19/2005<br>alopez : 3/29/2004<br>tkritzer : 7/15/2003<br>tkritzer : 7/7/2003<br>terry : 6/30/2003<br>terry : 6/1/1998<br>terry : 5/28/1998<br>jason : 6/6/1994
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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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> 191845
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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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UROMODULIN; UMOD
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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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TAMM-HORSFALL GLYCOPROTEIN; THP; THGP
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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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<p>
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: UMOD</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: 16p12.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 16:20,333,051-20,356,301 </span>
|
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</em>
|
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</strong>
|
|
<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>
|
|
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>
|
|
Inheritance
|
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</th>
|
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<th>
|
|
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">
|
|
16p12.3
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Tubulointerstitial kidney disease, autosomal dominant, 1
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
162000
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Autosomal dominant
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
3
|
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</span>
|
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>TEXT</strong>
|
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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">
|
|
<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">
|
|
<p>The Tamm-Horsfall glycoprotein (Tamm and Horsfall, 1952), also referred to as uromodulin (Muchmore and Decker, 1985), is a GPI-anchored glycoprotein and the most abundant protein in normal urine. Uromodulin, uropontin, and nephrocalcin are the 3 known urinary glycoproteins that affect the formation of calcium-containing kidney stones (167030). Uromodulin is synthesized by kidney and localizes in cells lining the ascending limb of Henle and distal convoluted tubule (McKenzie and McQueen, 1969; Schenk et al., 1971). </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">
|
|
<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>Pennica et al. (1987) cloned uromodulin from human kidney total RNA. The deduced 639-amino acid protein contains an N-terminal signal peptide and regions of similarity with LDL receptor (LDLR; 606945) and the EGF precursor protein (131530). Uromodulin has 48 cysteines and 8 potential N-glycosylation sites. Northern blot analysis of about 150 different epithelial, connective, and hematopoietic tissues and tumor-derived cell lines detected a 2.6-kb transcript in adult kidney only. </p><p>Yang et al. (2004) described the domain structure of the UMOD protein. It has an N-terminal signal sequence, followed by 3 EGF-like repeats, a domain with 8 conserved cysteines (D8C), and a C-terminal zona pellucida (ZP) domain. The D8C domain is about 130 amino acids long, and the 8 cysteines are predicted to form 4 pairs of disulfide bridges. The secondary structure is composed mainly of beta strands. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Pennica et al. (1987) reported that UMOD gene contains 11 exons. </p><p>Hart et al. (2002) subsequently determined that the UMOD gene contains 12 exons, with the novel exon being exon 2. Exons 1 and 2 are noncoding; the ATG translation initiation site is located in exon 3. </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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<p>Jeanpierre et al. (1993) mapped the UMOD gene to chromosome 16p13.11 by somatic cell hybrid analysis. By study of a different mapping panel, Pook et al. (1993) mapped the gene to chromosome 16p12.3-qter. Combining the results of the 2 studies suggested that the gene is located in the region 16p13.11-p12.3. </p><p>Fukuoka and Matsuda (1997) assigned the Umod gene to mouse chromosome 7F1-F2 and rat chromosome 1q36-q37 by fluorescence in situ hybridization. The result was discordant with the previous localization of the gene to mouse chromosome 17 by somatic cell hybrid analysis (Deng et al., 1995). </p>
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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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<span class="mim-text-font">
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<p>Muchmore and Decker (1985) purified 85-kD uromodulin from urine of pregnant women and found that it showed immunoregulatory potential. Uromodulin had a broad dose-response curve in inhibition of antigen-specific T-cell proliferation. It also inhibited monocyte reactivity in vitro and spontaneous monocyte cytotoxicity. It had no effect on B-cell function or cell viability. </p><p>Greimel et al. (2006) stated that approximately 30% of the mass of THP consists of sulfated N-linked glycans. They showed that both membrane-bound and soluble recombinant human GP3ST (GAL3ST2; 608237) incorporated radiolabeled SO4 into purified human urine THP in a concentration-dependent manner. </p><p>Using immunohistochemical studies, Dahan et al. (2003) found that uromodulin is distributed primarily at the apical membrane of the thick ascending loop and distal convoluted tubule in the human kidney. Uromodulin is a GPI-anchor-linked protein. It has putative roles in cell adhesion, signal transduction, inhibition of calcium oxalate crystal aggregation, defense against urinary tract infection, and modulation of urine-concentrating ability. It may also act as a potential nephritogenic antigen. </p><p>Zaucke et al. (2010) demonstrated that UMOD was expressed in the primary cilia of renal tubules. Immunofluorescent and ultrastructural studies confirmed ciliary expression of UMOD, with localization to the mitotic spindle poles and colocalization with ciliary proteins nephrocystin-1 (NPHP1; 607100) and kinesin family member 3A (KIF3A; 604683). </p><p>Using cryoelectron tomography, Weiss et al. (2020) showed that the human uromodulin filament consisted of a zigzag-shaped backbone with laterally protruding arms. N-glycosylation mapping and biophysical assays revealed that uromodulin acted as a multivalent ligand for the bacterial type-1 pilus adhesin, presenting specific epitopes on the regularly spaced arms. Imaging of uromodulin-uropathogen interactions in vitro and in patient urine showed that uromodulin filaments associated with uropathogens and mediated bacterial aggregation, likely preventing adhesion and allowing clearance by micturition. </p>
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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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</h4>
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<span class="mim-text-font">
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<p>In affected members of 4 unrelated families with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; 162000), Hart et al. (2002) identified 4 different heterozygous mutations in exon 4 of the UMOD gene (191845.0001-191845.0004). The mutations, which were found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the families. Three families had a clinical diagnosis of familial juvenile hyperuricemic nephropathy (FJHN, HNFJ), whereas the fourth family was diagnosed clinically with medullary cystic kidney disease (MCKD). In all families, the phenotype was characterized mainly by juvenile onset of hyperuricemia, polyuria, gout, and progressive renal insufficiency that was tubulointerstitial in origin. Renal biopsies showed tubular atrophy and interstitial fibrosis. Global glomerulosclerosis was also observed, although there was no evidence of glomerulonephritis. Necroscopy showed sheathing of the renal tubules by dense acellular hyaline fibrous tissue that likely represented abnormal deposition of the UMOD protein. Medullary cysts were present in 1 family. The authors noted that the disorder is associated with impaired urinary concentrating ability, which likely causes increased proximal tubular reabsorption of uric acid and hyperuricemia. Functional studies of the variants and studies of patient cells were not performed, but the authors postulated that the mutations caused tertiary structural changes in the uromodulin protein that could alter cytokine binding and ultimately lead to fibrosis and progressive renal failure. The report established that the clinical entities of FJHN and MCKD not only share clinical features, but are also either allelic or variable manifestations of the same disease. Noting that hyperuricemia and medullary cysts are variable features and that the conditions result from mutations in the same gene, the authors suggested the designation 'uromodulin-associated kidney disease.' </p><p>In 5 unrelated kindreds with ADTKD1, 2 from Austria and 3 from Spain, Turner et al. (2003) identified 5 heterozygous missense mutations in the UMOD gene (191845.0005-191845.0009) that altered evolutionary conserved residues. These mutations were not found in 110 alleles from 55 unrelated normal individuals. Functional studies of the variants were not performed, but the authors postulated a loss-of-function effect. The families had previously been reported by Stacey et al. (2003). </p><p>In affected members of 4 unrelated Italian families with variable manifestations of ADTKD1, Rampoldi et al. (2003) identified heterozygous missense mutations in the UMOD gene (see, e.g., C315R, 191845.0010 and C148W, 191845.0015). All mutations affected highly conserved cysteine residues and were predicted to affect protein structure. Immunohistochemistry of kidney biopsies revealed dense intracellular accumulation of uromodulin in tubular epithelia of the thick ascending limb of Henle loop. Electron microscopy showed accumulation of dense fibrillar material within the endoplasmic reticulum (ER), and patient urine samples consistently showed a severe reduction of excreted uromodulin. Experiments in transfected cells showed that all 4 mutations caused a delay in protein export to the plasma membrane due to a longer retention time in the ER. The protein maturation impairment and retention in the ER, which may trigger ubiquitination and ER stress, suggested a pathogenetic mechanism leading to these kidney diseases. Rampoldi et al. (2003) postulated that hyperuricemia is a secondary effect of volume contraction resulting from UMOD dysfunction in the thick ascending loop of Henle. Three families had a clinical diagnosis of MCKD/FJHN (including a family previously reported by Scolari et al., 1999), and 1 family had a clinical diagnosis of glomerulocystic kidney disease (GCKD), thus demonstrating that these clinical entities are allelic and are different manifestations of the same disorder. </p><p>In patients from 11 families with ADTKD1, Dahan et al. (2003) identified 11 different heterozygous UMOD mutations, including 10 novel ones (see, e.g., 191845.0012). All of the mutations occurred at highly conserved residues in exon 4, and 5 of the mutations affected a conserved cysteine residue. The families were ascertained from a larger group of 25 families with a similar phenotype; thus, UMOD mutations were found in 44% of families. Patient kidney samples showed abnormal uromodulin immunostaining within enlarged or cystic profiles within tubules in the thick ascending loop, and not at the apical membrane as observed in controls. Mutant UMOD was not found in proximal tubules. Patients also showed decreased urinary excretion of wildtype uromodulin. The findings indicated that mutant uromodulin accumulates within renal tubular cells in patients with UMOD mutations. </p><p>In affected members of 4 unrelated Spanish families with variable clinical manifestations of ADTKD1, Lens et al. (2005) identified heterozygous missense mutations in the UMOD gene (see, e.g., C300G, 191845.0009 and Q316P, 191845.0014). The mutations, which were found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in available family members. Two families (F1 and F2) with the same mutation (Q316P) had clinical phenotypes consistent with MCKD (F1) and FJHN (F2). Family 4 had a phenotype consistent with FJHN, and F3, with the C300G mutation, had a phenotype consistent with GCKD. These genetic findings further supported the idea that MCKD, FJHN, and GCKD represent the same disease entity. </p><p>Vylet'al et al. (2006) sequenced the UMOD gene in 19 families with variable manifestations of ADTKD1 and identified heterozygous mutations in 6 families, 5 of which had been previously reported (kindred 6 from McBride et al., 1998; kindreds A and B from Stiburkova et al., 2000; Fairbanks et al., 2002; and family BE2 from Stiburkova et al., 2003) (see, e.g., 191845.0006 and 191845.0011). Functional studies of mutant proteins showed distinct glycosylation patterns, impaired intracellular trafficking, and decreased ability to be exposed on the plasma membrane, which correlated with observations in kidney tissue from patients. A reduction in urinary modulin excretion was found in 18 of the 19 families and was associated with case-specific differences in uromodulin immunohistochemical staining patterns in kidney tissues. </p><p>In 6 of 17 probands with ADTKD who were studied for UMOD mutations, Williams et al. (2009) identified 6 different heterozygous missense mutations in the UMOD gene (see, e.g., D196N; 191845.0016). In vitro functional studies of some of the mutations expressed in HeLa cells showed that the mutant uromodulins had significantly delayed maturation compared to wildtype, with abnormal protein retention in the ER and reduced or absent expression at the plasma membrane. There were different effects allowing the identification of 2 mutation groups: group A (including mutants C32W, D196N, and G488R) had 50% maturation compared to wildtype with some expression at the plasma membrane, whereas group B (including mutants C126R, 191845.0006; N128S, 191845.0007; and C223R) had 25% maturation compared to wildtype and absence of expression at the plasma membrane. There were no phenotypic differences between patients with group A and group B mutations. The findings suggested that abnormal folding of the mutant proteins resulted in protein retention in the ER, which may trigger apoptosis and underlie the mechanism for disease pathogenesis. </p><p>In affected members of 10 unrelated families with ADTKD1, Zaucke et al. (2010) identified 7 novel and 3 previously reported heterozygous missense mutations in the UMOD gene (see, e.g., 191845.0009 and 191845.0013). Most of the mutations affected conserved cysteine residues. The number of UMOD-positive primary cilia in renal biopsy samples from 2 of the patients was significantly decreased compared to control samples. The authors suggested that this defect may contribute to cyst formation. The families were ascertained from a cohort of 44 families with nephropathy from western Europe and the United States who underwent direct sequencing of the UMOD gene. </p><p>Using transfected MDCK cells, Ma et al. (2012) found that mutant mouse Thp with substitutions corresponding to human cys126 to arg (C126R; 191845.0006) or cys217 to gly (C217G; 191845.0012) resulted in protein misfolding, retention of mutant protein in the ER, and reduced surface Thp expression and secretion. In all measures, the C217G substitution within the D8C domain was more severe than the C126R substitution within EGF-like domain-3. Both substitutions also led to reduced expression of the chaperone protein Hsp70 (see HSPA1A; 140550), trapped wildtype Thp in the ER in a dominant-negative manner, and induced apoptosis. Treatments that favored correct protein folding tended to reduce the effect of the mutations. Greatest rescue was obtained with exposure to sodium 4-phenylbutyrate, a chemical chaperone that increases the expression of heat-shock proteins, and probenecid, a drug used clinically to treat hyperuricemia. </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>Type 1-fimbriated E. coli, which contains a mannose-sensitive lectin subunit at the fimbrial tip, binds THP, and this binding inhibits binding of E. coli to kidney epithelial cells. Mo et al. (2004) found that Thp -/- mice, which were obtained in the expected mendelian ratio, showed increased susceptibility to bladder infection by type 1-fimbriated E. coli. </p><p>Mo et al. (2004) found spontaneous formation of calcium crystals in kidneys of adult Thp -/- mice. Excessive intake of calcium and oxalate dramatically increased both the frequency and severity of renal calcium crystal formation in Thp -/- mice. High calcium/oxalate also induced Thp -/- renal epithelial cells to express osteopontin (OPN, or SPP1; 166490), an inhibitor of bone mineralization. Mo et al. (2004) hypothesized that OPN may be an inducible inhibitor of calcium crystallization, whereas THP is a constitutive inhibitor of calcium crystallization. </p><p>Bachmann et al. (2005) found that kidneys of Thp -/- mice were anatomically normal. However, Thp -/- kidneys showed reduced creatinine clearance, impaired water reabsorption following deprivation, and altered expression of renal transporters, channels, and regulatory molecules. </p><p>Bernascone et al. (2010) generated a transgenic mouse model with a Umod C147W mutation corresponding to the human UMOD C148W mutation (191845.0015). The mutant mice showed tubulointerstitial fibrosis with inflammatory cell infiltration, tubule dilation, and selective damage to the epithelial cells lining the thick ascending limb of the loop of Henle (TAL), leading to mild renal failure. Umod was retained in the ER of expressing cells, leading to ER hyperplasia. The authors suggested that impaired TAL function is a consequence of a gain-of-function effect of UMOD mutations. </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>16 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 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 1</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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UMOD, 27-BP DEL, NT529
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<br />
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SNP: rs1555487528,
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ClinVar: RCV000518183, RCV002251317, RCV004739301
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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 36 individuals from a large multigenerational kindred (family 1) with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; 162000), Hart et al. (2002) identified a heterozygous in-frame 27-bp deletion (c.529_555del) in exon 4 of the UMOD gene, resulting in the deletion of 9 amino acids (His177_Arg185del). The mutation, which was found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the family. The family contained more than 300 individuals spanning 7 generations. Four mutation carriers, who were all women, had normal serum uric acid despite low fractional excretions of uric acid; 2 had mild renal insufficiency. Functional studies of the variant and studies of patient cells were not performed. The original clinical diagnosis was familial juvenile hyperuricemic nephropathy (FJHN, HNFJ). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 1</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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UMOD, CYS148TYR
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<br />
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SNP: rs28934582,
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ClinVar: RCV002251318, RCV002513003
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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 9 affected members of a 5-generation family (family 2) with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; 162000), Hart et al. (2002) identified a heterozygous c.443G-A transition in exon 4 of the UMOD gene, resulting in a cys148-to-tyr (C148Y) substitution at a conserved residue. The mutation, which was found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. The original clinical diagnosis was familial juvenile hyperuricemic nephropathy (FJHN, HNFJ). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 1</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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UMOD, CYS217ARG
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<br />
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SNP: rs28934583,
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ClinVar: RCV002251319
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an affected individual from a family (family 4) with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; 162000), Hart et al. (2002) identified a heterozygous c.649T-C transition in exon 4 of the UMOD gene, resulting in a cys217-to-arg (C217R) substitution at a conserved residue. Functional studies of the variant and studies of patient cells were not performed. The family had previously been reported by Massari et al. (1980) as having a clinical phenotype consistent with familial juvenile hyperuricemic nephropathy (FJHN, HNFJ). </p><p>Yang et al. (2004) determined that cys217 is 1 of 8 cysteines within UMOD predicted to form 4 disulfide bridges. The C217R mutation likely disrupts one of these disulfide bonds. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 1</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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UMOD, GLY103CYS
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<br />
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SNP: rs28934584,
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gnomAD: rs28934584,
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ClinVar: RCV002251320, RCV004528105
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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 3 affected members of a multigenerational family (family 3) with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; 162000), Hart et al. (2002) identified a heterozygous c.307G-T transversion in exon 4 of the UMOD gene, resulting in a gly103-to-cys (G103C) substitution at a conserved residue. Functional studies of the variant and studies of patient cells were not performed. The patients, who had hyperuricemia and renal insufficiency, were diagnosed clinically with medullary cystic kidney disease (MCKD). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0005 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 1</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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UMOD, CYS77TYR
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<br />
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SNP: rs121917768,
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ClinVar: RCV002251321
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family (11/00) from Austria with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; 162000), Turner et al. (2003) identified a heterozygous c.335G-A transition in the UMOD gene that was predicted to result in a cys77-to-tyr (C77Y) substitution. Functional studies of the variant and studies of patient cells were not performed. The family had previously been reported by Stacey et al. (2003). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0006 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 1</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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UMOD, CYS126ARG
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<br />
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SNP: rs121917769,
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ClinVar: RCV002251322
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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 affected members of a family (13/00) from Austria with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; 162000), Turner et al. (2003) identified a heterozygous c.481T-C transition in the UMOD gene that was predicted to result in a cys126-to-arg (C126R) substitution. Functional studies of the variant and studies of patient cells were not performed. The family had previously been reported by Stacey et al. (2003). </p><p>In affected members of a family with ADTKD1, originally reported by Fairbanks et al. (2002), Vylet'al et al. (2006) identified heterozygosity for the C126R mutation in the UMOD gene. A female patient who had onset of disease at age 31, with gout, hypertension, elevated creatinine and hyperuricemia, underwent kidney transplantation but died at 36 years of age. A 43-year-old woman and 40-year-old man, who had onset of hyperuricemia at age 19 years and 16 years, respectively, had no abnormalities on renal ultrasound and had not developed any other symptoms. </p><p>In HeLa cells transfected with C126R mutant uromodulin, Williams et al. (2009) found that the mutant protein had delayed maturation (about 25% of wildtype), was retained in the ER, and not trafficked to the plasma membrane, likely due to protein misfolding. The authors suggested that abnormal protein retention in the ER may trigger apoptosis and underlie the mechanism for the pathogenesis of the disorder. </p><p>Using transfected MDCK cells, Ma et al. (2012) found that mutant mouse Thp with substitutions corresponding to human C126R or cys217 to gly (C217G; 191845.0012) resulted in protein misfolding, retention of mutant protein in the ER, and reduced surface Thp expression and secretion. In all measures, the C217G substitution within the D8C domain was more severe than the C126R substitution within EGF-like domain-3. Both substitutions also led to reduced expression of the chaperone protein Hsp70 (see HSPA1A; 140550), trapped wildtype Thp in the ER in a dominant-negative manner, and induced apoptosis. Treatments that favored correct protein folding tended to reduce the effect of the mutations. Greatest rescue was obtained with exposure to sodium 4-phenylbutyrate, a chemical chaperone that increases the expression of heat-shock proteins, and probenecid, a drug used clinically to treat hyperuricemia. </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>.0007 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 1</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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UMOD, ASN128SER
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<br />
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SNP: rs121917770,
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|
|
ClinVar: RCV002251323
|
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In affected members of a family from Spain (1/96) with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; 162000), Turner et al. (2003) identified a heterozygous c.488A-G transition in the UMOD gene that was predicted to result in an asn128-to-ser (N128S) substitution. Functional studies of the variant and studies of patient cells were not performed. The family had previously been reported by Stacey et al. (2003). </p><p>In HeLa cells transfected with N128S mutant uromodulin, Williams et al. (2009) found that the mutant protein had delayed maturation (about 25% of wildtype), was retained in the ER, and not trafficked to the plasma membrane, likely due to protein misfolding. The authors suggested that abnormal protein retention in the ER may trigger apoptosis and underlie the mechanism for the pathogenesis of the disorder. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0008 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 1</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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UMOD, CYS255TYR
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<br />
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SNP: rs121917771,
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ClinVar: RCV002251324
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In affected members of a family from Spain (13/96) with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; 162000), Turner et al. (2003) identified a heterozygous c.869G-A transition in the UMOD gene, resulting in a cys255-to-tyr (C255Y) substitution at a conserved residue. Functional studies of the variant and studies of patient cells were not performed. The family had previously been reported by Stacey et al. (2003). </p><p>In 14 affected members of a large consanguineous Spanish family with ADTKD1, Rezende-Lima et al. (2004) identified a C255Y mutation in the UMOD gene. These authors stated that the substitution resulted from a c.764G-A transition in exon 4 and that the mutation disrupted a light chain-binding domain. Eleven family members were heterozygous for the mutation, whereas 3 were homozygous. The homozygous individuals had earlier disease onset than the heterozygous individuals, but the report demonstrated that homozygosity for UMOD mutations is not lethal. The clinical phenotype was consistent with medullary cystic kidney disease (MCKD), although the authors noted that cyst formation may be nonspecific secondary effect. This family was also reported as family F4 by Lens et al. (2005). </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>.0009 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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UMOD, CYS300GLY
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<br />
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SNP: rs121917772,
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ClinVar: RCV002251325
|
|
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family from Spain (20/96) with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; 162000), Turner et al. (2003) identified a heterozygous c.1003T-G transversion in the UMOD gene that was predicted to result in a cys300-to-gly (C300G) substitution. Functional studies of the variant and studies of patient cells were not performed. The family had previously been reported by Stacey et al. (2003). </p><p>In affected members of a Spanish family (F3) with ADTKD1, Lens et al. (2005) identified heterozygosity for the C300G mutation in exon 5 of the UMOD gene. The phenotype included glomerulocystic kidney disease (GCKD), thus expanding the spectrum of manifestations associated with this mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
UMOD, CYS315ARG
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|
|
<br />
|
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|
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SNP: rs121917773,
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|
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|
|
|
ClinVar: RCV002251326
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of an Italian family (GCKD1) with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; 162000), Rampoldi et al. (2003) identified a c.943T-C transition (c.943T-C, NM_003361) in exon 5 of the UMOD gene, predicted to result in a cys315-to-arg (C315R) substitution. The family had previously been reported by Scolari et al. (1999) with a clinical diagnosis of glomerulocystic kidney disease (GCKD). </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
UMOD, VAL273PHE
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs121917774,
|
|
|
|
|
|
|
|
ClinVar: RCV001566754, RCV002251327
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 Belgian brothers with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; 162000), originally reported as family BE2 by Stiburkova et al. (2003), Vylet'al et al. (2006) identified a heterozygous mutation in the UMOD gene resulting in a val273-to-phe (V273F) substitution. Functional studies showed that the V273F-mutant protein was retained in the endoplasmic reticulum and did not reach the plasma membrane. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
UMOD, CYS217GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28934583,
|
|
|
|
|
|
|
|
ClinVar: RCV002251328
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 36-year-old Belgian woman with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; 162000), Dahan et al. (2003) identified a heterozygous c.754T-G transversion in exon 4 of the UMOD gene, resulting in a cys217-to-gly (C217G) substitution. The patient was in end-stage renal failure, and she had a history of gout, with onset at age 21 years. Her father, grandmother, and 1 sister were also affected. Dahan et al. (2003) erroneously reported this mutation as 794T-G, instead of 754T-G, in their paper. In addition, their numbering of the UMOD sequence began at nucleotide 1, rather than at the ATG start codon at nucleotide 106. Following the convention of numbering from the start codon, this mutation should be referred to as c.649T-G (Gross, 2013). </p><p>Using transfected MCKD cells, Ma et al. (2012) found that mutant mouse Thp with substitutions corresponding to human cys126 to arg (C126R; 191845.0006) or C217G resulted in protein misfolding, retention of mutant protein in the ER, and reduced surface Thp expression and secretion. In all measures, the C217G substitution within the D8C domain was more severe than the C126R substitution within EGF-like domain-3. Both substitutions also led to reduced expression of the chaperone protein Hsp70 (see HSPA1A; 140550), trapped wildtype Thp in the ER in a dominant-negative manner, and induced apoptosis. Treatments that favored correct protein folding tended to reduce the effect of the mutations. Greatest rescue was obtained with exposure to sodium 4-phenylbutyrate, a chemical chaperone that increases the expression of heat-shock proteins, and probenecid, a drug used clinically to treat hyperuricemia. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
UMOD, CYS248SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs398122388,
|
|
|
|
|
|
|
|
ClinVar: RCV002251329
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 members of a 2-generation family (F6) with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; 162000), Zaucke et al. (2010) identified a heterozygous c.743G-C transversion in the UMOD gene, resulting in a cys248-to-ser substitution (C248S) at a conserved residue in the D8C domain. The father exhibited hypertension, gout, congestive heart failure, varices, and an aortic aneurysm. Renal biopsy showed tubular atrophy, tubulointerstitial fibrosis, and a thickened tubular basement membrane. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
UMOD, GLN316PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1555487318,
|
|
|
|
|
|
|
|
ClinVar: RCV002251372
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 2 apparently unrelated Spanish families (F1 and F2) with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; 162000), Lens et al. (2005) identified a heterozygous c.947A-C transversion in exon 5 of the UMOD gene, resulting in a gln316-to-pro (Q316P) substitution at a conserved residue. The mutation segregated with the phenotype in the families and was not found in 100 control chromosomes. The clinical phenotype in family 1 was consistent with medullary cystic kidney disease (MCKD), whereas the clinical phenotype in family 2 was consistent with familial juvenile hyperuricemic nephropathy (FJHN). The results demonstrated that these variable clinical manifestations are part of the same disease entity, referred to as ADTKD1. Although functional studies of the variant were not performed, the authors suggested that the mutation could alter the tertiary structure of UMOD, leading to defects in vesicular transport in the thick ascending loop of Henle. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
UMOD, CYS148TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1965741911,
|
|
|
|
|
|
|
|
ClinVar: RCV002251407
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of an Italian family (MCKD9) with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; 162000), Rampoldi et al. (2003) identified a heterozygous c.444T-G transversion (c.444T-G, NM_003361) in exon 4 of the UMOD gene, resulting in a cys148-to-trp (C148W) substitution at a conserved residue. </p><p>Bernascone et al. (2010) generated a transgenic mouse model with a Umod C147W mutation corresponding to the human UMOD C148W mutation. The mutant mice showed tubulointerstitial fibrosis with inflammatory cell infiltration, tubule dilation, and selective damage to the epithelial cells lining the thick ascending limb of the loop of Henle (TAL), leading to mild renal failure. Umod was retained in the ER of expressing cells, leading to ER hyperplasia. The authors suggested that impaired TAL function is a consequence of a gain-of-function effect of UMOD mutations. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
UMOD, ASP196ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1965729129,
|
|
|
|
|
|
|
|
ClinVar: RCV002251408
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 affected members of a family (family 5) with autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1; 162000), Williams et al. (2009) identified a heterozygous c.586G-A transition in exon 3 of the UMOD gene, resulting in an asp196-to-asn (D196N) substitution in the cysteine-rich domain. In vitro functional expression studies in HeLa cells transfected with the mutation showed that it caused a 50% delay in maturation compared to wildtype. The mutant protein was retained in the ER and showed decreased expression at the plasma membrane. The findings suggested that abnormal protein retention in the ER may trigger apoptosis and underlie the mechanism for disease pathogenesis. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bachmann, S., Mutig, K., Bates, J., Welker, P., Geist, B., Gross, V., Luft, F. C., Alenina, N., Bader, M., Thiele, B. J., Prasadan, K., Raffi, H. S., Kumar, S.
|
|
<strong>Renal effects of Tamm-Horsfall protein (uromodulin) deficiency in mice.</strong>
|
|
Am. J. Physiol. Renal Physiol. 288: F559-F567, 2005.
|
|
|
|
|
|
[PubMed: 15522986]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1152/ajprenal.00143.2004]
|
|
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|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bernascone, I., Janas, S., Ikehata, M., Trudu, M., Corbelli, A., Schaeffer, C., Rastaldi, M. P., Devuyst, O., Rampoldi, L.
|
|
<strong>A transgenic mouse model for uromodulin-associated kidney diseases shows specific tubulo-interstitial damage, urinary concentrating defect and renal failure.</strong>
|
|
Hum. Molec. Genet. 19: 2998-3010, 2010.
|
|
|
|
|
|
[PubMed: 20472742]
|
|
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|
|
[Full Text: https://doi.org/10.1093/hmg/ddq205]
|
|
|
|
|
|
</p>
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Cassandra L. Kniffin - updated : 01/26/2021<br>Ada Hamosh - updated : 12/04/2020<br>Carol A. Bocchini - updated : 10/18/2017<br>George E. Tiller - updated : 9/9/2013<br>Cassandra L. Kniffin - updated : 2/13/2013<br>Matthew B. Gross - updated : 2/11/2013<br>Patricia A. Hartz - updated : 2/8/2013<br>George E. Tiller - updated : 6/25/2010<br>Marla J. F. O'Neill - updated : 10/15/2009<br>George E. Tiller - updated : 1/10/2006<br>Patricia A. Hartz - updated : 4/19/2005<br>John A. Phillips, III - updated : 3/29/2004<br>Victor A. McKusick - updated : 6/30/2003<br>Victor A. McKusick - updated : 5/28/1998
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Victor A. McKusick : 6/6/1994
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carol : 02/26/2025<br>alopez : 02/09/2021<br>ckniffin : 01/26/2021<br>mgross : 12/04/2020<br>carol : 10/19/2017<br>carol : 10/18/2017<br>alopez : 09/09/2013<br>alopez : 9/9/2013<br>tpirozzi : 9/5/2013<br>tpirozzi : 9/5/2013<br>carol : 3/4/2013<br>ckniffin : 2/13/2013<br>mgross : 2/11/2013<br>mgross : 2/11/2013<br>terry : 2/8/2013<br>mgross : 8/3/2011<br>carol : 12/10/2010<br>wwang : 7/15/2010<br>terry : 6/25/2010<br>alopez : 1/6/2010<br>terry : 10/21/2009<br>wwang : 10/16/2009<br>terry : 10/15/2009<br>carol : 6/18/2008<br>terry : 12/17/2007<br>wwang : 2/10/2006<br>terry : 1/10/2006<br>mgross : 4/25/2005<br>terry : 4/19/2005<br>alopez : 3/29/2004<br>tkritzer : 7/15/2003<br>tkritzer : 7/7/2003<br>terry : 6/30/2003<br>terry : 6/1/1998<br>terry : 5/28/1998<br>jason : 6/6/1994
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