3443 lines
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Entry
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- *604824 - KLOTHO; KL
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- OMIM
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<p>
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<span class="h4">*604824</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</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="#cytogenetics">Cytogenetics</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<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/604824">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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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 role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div id="mimFloatingLinksMenu">
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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=ENSG00000133116;t=ENST00000380099" 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=9365" 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=604824" 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 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="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=ENSG00000133116;t=ENST00000380099" 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_004795,XM_006719895,XM_047430775,XM_047430776" 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_004795" 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=604824" 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=05316&isoform_id=05316_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/KL" 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/2618596,2924561,2924562,16116612,16116628,24497614,77416517,119628930,119628931,193783545,209985371,349500965,578825086,2217295448,2217295450,2462538432,2462538434,2462538436" 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/Q9UEF7" 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=9365" 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=ENSG00000133116;t=ENST00000380099" 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=KL" 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=KL" 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+9365" 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/KL" 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:9365" 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/9365" 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=chr13&hgg_gene=ENST00000380099.4&hgg_start=33016243&hgg_end=33066143&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 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://medlineplus.gov/genetics/gene/kl" 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=604824[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=604824[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/ENSG00000133116" 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=KL" 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=KL" 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=KL" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://lovd.bx.psu.edu/home.php?select_db=KL" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=KL&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/PA30130" 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:6344" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0036659.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1101771" 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/KL#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:1101771" 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/9365/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=9365" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00016848;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00016848 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00017103;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00017103 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-110221-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:9365" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=KL&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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604824
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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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KLOTHO; KL
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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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ALPHA-KLOTHO
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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=KL" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">KL</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/13/87?start=-3&limit=10&highlight=87">13q13.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr13:33016243-33066143&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'})">13:33,016,243-33,066,143</a> </span>
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
|
|
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">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/13/87?start=-3&limit=10&highlight=87">
|
|
13q13.1
|
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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">
|
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?Tumoral calcinosis, hyperphosphatemic, familial, 3
|
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<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
|
|
<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
|
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</span>
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|
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</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/617994"> 617994 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</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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<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">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/604824" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/604824" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</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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<p><a href="#13" class="mim-tip-reference" title="Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., Iwasaki, H., Iida, A., Shiraki-Iida, T., Nishikawa, S., Nagai, R., Nabeshima, Y. <strong>Mutation of the mouse klotho gene leads to a syndrome resembling ageing.</strong> Nature 390: 45-51, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9363890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9363890</a>] [<a href="https://doi.org/10.1038/36285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9363890">Kuro-o et al. (1997)</a> cloned a mouse gene, which they called klotho (Kl), from a transgenic mouse model with several age-related disorders. The name of the gene, Klotho, is that of the Fate in Greek mythology who spins the thread of life. By screening human kidney and hippocampus cDNA libraries with a mouse Kl cDNA fragment at low stringency, <a href="#17" class="mim-tip-reference" title="Matsumura, Y., Aizawa, H., Shiraki-Iida, T., Nagai, R., Kuro-o, M., Nabeshima, Y. <strong>Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein.</strong> Biochem. Biophys. Res. Commun. 242: 626-630, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9464267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9464267</a>] [<a href="https://doi.org/10.1006/bbrc.1997.8019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9464267">Matsumura et al. (1998)</a> isolated cDNA clones for human klotho. Sequence analysis of the cDNAs revealed that they encode 2 different transcripts. One transcript encodes a putative 1,012-amino acid single-pass membrane protein with an N-terminal signal sequence, an extracellular domain with 2 internal repeats, and a short intracellular domain, as found in the mouse klotho protein by <a href="#13" class="mim-tip-reference" title="Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., Iwasaki, H., Iida, A., Shiraki-Iida, T., Nishikawa, S., Nagai, R., Nabeshima, Y. <strong>Mutation of the mouse klotho gene leads to a syndrome resembling ageing.</strong> Nature 390: 45-51, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9363890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9363890</a>] [<a href="https://doi.org/10.1038/36285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9363890">Kuro-o et al. (1997)</a>. Northern blot analysis revealed expression of a single 5.2-kb transcript in kidney, placenta, small intestine, and prostate. The other transcript contains a 50-bp insertion encoding a truncated putative secreted protein of 549 amino acids that lacks the second internal repeat, the transmembrane domain, and the intracellular domain. Genomic sequence analysis showed that the 2 transcripts arise by alternative RNA splicing. By RNase protection analysis, the secreted form predominated in all tissues examined, i.e., brain, hippocampus, placenta, kidney, prostate, and small intestine. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9464267+9363890" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#17" class="mim-tip-reference" title="Matsumura, Y., Aizawa, H., Shiraki-Iida, T., Nagai, R., Kuro-o, M., Nabeshima, Y. <strong>Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein.</strong> Biochem. Biophys. Res. Commun. 242: 626-630, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9464267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9464267</a>] [<a href="https://doi.org/10.1006/bbrc.1997.8019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9464267">Matsumura et al. (1998)</a> determined that the KL gene contains 5 exons and spans approximately 50 kb of genomic DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9464267" 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="#13" class="mim-tip-reference" title="Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., Iwasaki, H., Iida, A., Shiraki-Iida, T., Nishikawa, S., Nagai, R., Nabeshima, Y. <strong>Mutation of the mouse klotho gene leads to a syndrome resembling ageing.</strong> Nature 390: 45-51, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9363890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9363890</a>] [<a href="https://doi.org/10.1038/36285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9363890">Kuro-o et al. (1997)</a> mapped the human KL gene to chromosome 13q12 by FISH and by inclusion within a BAC contig. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9363890" 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="#7" class="mim-tip-reference" title="Chen, G., Liu, Y., Goetz, R., Fu, L., Jayaraman, S., Hu, MC., Moe, O. W., Liang, G., Li, X., Mohammadi, M. <strong>Alpha-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling.</strong> Nature 553: 461-466, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29342138/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29342138</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29342138[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature25451" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29342138">Chen et al. (2018)</a> presented the atomic structure of a 1:1:1 ternary complex that consists of the shed extracellular domain of alpha-klotho, the FGFR1c (see <a href="/entry/136350">136350</a>) ligand-binding domain, and FGF23 (<a href="/entry/605380">605380</a>). In this complex, alpha-klotho simultaneously tethers FGFR1c by its D3 domain and FGF23 by its C-terminal tail, thus implementing FGF23-FGFR1c proximity and conferring stability. Dimerization of the stabilized ternary complexes and receptor activation remain dependent on the binding of heparan sulfate, a mandatory cofactor of paracrine FGF signaling. The structure of alpha-klotho is incompatible with its purported glycosidase activity. Thus, <a href="#7" class="mim-tip-reference" title="Chen, G., Liu, Y., Goetz, R., Fu, L., Jayaraman, S., Hu, MC., Moe, O. W., Liang, G., Li, X., Mohammadi, M. <strong>Alpha-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling.</strong> Nature 553: 461-466, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29342138/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29342138</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29342138[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature25451" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29342138">Chen et al. (2018)</a> concluded that shed alpha-klotho functions as an on-demand nonenzymatic scaffold protein that promotes FGF23 signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29342138" 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>Patients with chronic renal failure (CRF) develop multiple complications reminiscent of the phenotype observed in Kl mutant mice. By RNase protection, immunoblot, and immunohistochemical analyses, <a href="#12" class="mim-tip-reference" title="Koh, N., Fujimori, T., Nishiguchi, S., Tamori, A., Shiomi, S., Nakatani, T., Sugimura, K., Kishimoto, T., Kinoshita, S., Kuroki, T., Nabeshima, Y. <strong>Severely reduced production of Klotho in human chronic renal failure kidney.</strong> Biochem. Biophys. Res. Commun. 280: 1015-1020, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11162628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11162628</a>] [<a href="https://doi.org/10.1006/bbrc.2000.4226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11162628">Koh et al. (2001)</a> observed severely reduced KL mRNA expression and protein production in kidneys of CRF patients. They proposed that decreased KL expression may be one of the factors underlying the degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CRF. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11162628" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Chang, Q., Hoefs, S., van der Kemp, A. W., Topala, C. N., Bindels, R. J., Hoenderop, J. G. <strong>The beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel.</strong> Science 310: 490-493, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16239475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16239475</a>] [<a href="https://doi.org/10.1126/science.1114245" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16239475">Chang et al. (2005)</a> reported that the transient receptor potential ion channel TRPV5 (<a href="/entry/606679">606679</a>) is stimulated by the mammalian hormone klotho. Klotho, a beta-glucuronidase, hydrolyzes extracellular sugar residues on TRPV5, entrapping the channel in the plasma membrane. This maintains durable calcium channel activity and membrane calcium permeability in kidney. Thus, <a href="#5" class="mim-tip-reference" title="Chang, Q., Hoefs, S., van der Kemp, A. W., Topala, C. N., Bindels, R. J., Hoenderop, J. G. <strong>The beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel.</strong> Science 310: 490-493, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16239475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16239475</a>] [<a href="https://doi.org/10.1126/science.1114245" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16239475">Chang et al. (2005)</a> concluded that klotho activates a cell surface channel by hydrolysis of its extracellular N-linked oligosaccharides. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16239475" 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="#22" class="mim-tip-reference" title="Urakawa, I., Yamazaki, Y., Shimada, T., Iijima, K., Hasegawa, H., Okawa, K., Fujita, T., Fukumoto, S., Yamashita, T. <strong>Klotho converts canonical FGF receptor into a specific receptor for FGF23.</strong> Nature 444: 770-774, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17086194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17086194</a>] [<a href="https://doi.org/10.1038/nature05315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17086194">Urakawa et al. (2006)</a> demonstrated that a previously undescribed receptor conversion by Klotho generates the FGF23 (<a href="/entry/605380">605380</a>) receptor. Using a renal homogenate, <a href="#22" class="mim-tip-reference" title="Urakawa, I., Yamazaki, Y., Shimada, T., Iijima, K., Hasegawa, H., Okawa, K., Fujita, T., Fukumoto, S., Yamashita, T. <strong>Klotho converts canonical FGF receptor into a specific receptor for FGF23.</strong> Nature 444: 770-774, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17086194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17086194</a>] [<a href="https://doi.org/10.1038/nature05315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17086194">Urakawa et al. (2006)</a> found that Klotho binds to FGF23. Forced expression of Klotho enabled the high affinity binding of FGF23 to the cell surface and restored the ability of a renal cell line to respond to FGF23 treatment. Moreover, FGF23 incompetence was induced by injecting wildtype mice with an anti-Klotho monoclonal antibody. Thus, Klotho is essential for endogenous FGF23 function. Because Klotho alone seemed to be incapable of intracellular signaling, <a href="#22" class="mim-tip-reference" title="Urakawa, I., Yamazaki, Y., Shimada, T., Iijima, K., Hasegawa, H., Okawa, K., Fujita, T., Fukumoto, S., Yamashita, T. <strong>Klotho converts canonical FGF receptor into a specific receptor for FGF23.</strong> Nature 444: 770-774, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17086194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17086194</a>] [<a href="https://doi.org/10.1038/nature05315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17086194">Urakawa et al. (2006)</a> searched for other components of the FGF23 receptor and found FGFR1(IIIc) (see <a href="/entry/136350">136350</a>), which was directly converted by Klotho into the FGF23 receptor. Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. The FGF23 receptor shows a strong affinity, one that is sufficient for interacting with physiologic concentrations of FGF23. Moreover, the tissue-specific unique biologic activity of FGF23 is likely to be regulated by a limited local distribution of Klotho. <a href="#22" class="mim-tip-reference" title="Urakawa, I., Yamazaki, Y., Shimada, T., Iijima, K., Hasegawa, H., Okawa, K., Fujita, T., Fukumoto, S., Yamashita, T. <strong>Klotho converts canonical FGF receptor into a specific receptor for FGF23.</strong> Nature 444: 770-774, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17086194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17086194</a>] [<a href="https://doi.org/10.1038/nature05315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17086194">Urakawa et al. (2006)</a> suggested that given that Klotho, with its homologs beta-klotho (KLB; <a href="/entry/611135">611135</a>) and KLPH, forms a family, other FGF-FGFR systems may be subject to similar conversions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17086194" 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="#22" class="mim-tip-reference" title="Urakawa, I., Yamazaki, Y., Shimada, T., Iijima, K., Hasegawa, H., Okawa, K., Fujita, T., Fukumoto, S., Yamashita, T. <strong>Klotho converts canonical FGF receptor into a specific receptor for FGF23.</strong> Nature 444: 770-774, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17086194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17086194</a>] [<a href="https://doi.org/10.1038/nature05315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17086194">Urakawa et al. (2006)</a> suggested that Klotho may convert other members of the FGF/FGFR receptor system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17086194" 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="#11" class="mim-tip-reference" title="Imura, A., Tsuji, Y., Murata, M., Maeda, R., Kubota, K., Iwano, A., Obuse, C., Togashi, K., Tominaga, M., Kita, N., Tomiyama, K., Iijima, J., and 13 others. <strong>Alpha-Klotho as a regulator of calcium homeostasis.</strong> Science 316: 1615-1618, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17569864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17569864</a>] [<a href="https://doi.org/10.1126/science.1135901" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17569864">Imura et al. (2007)</a> found the molecular association of Klotho (referred to as alpha-Klotho) and Na+,K+ ATPase and provided evidence for an increase of abundance of Na+,K+ ATPase at the plasma membrane. Low concentrations of extracellular free calcium rapidly induced regulated parathyroid hormone (<a href="/entry/168450">168450</a>) secretion in an alpha-Klotho-Na+,K+ ATPase-dependent manner. The authors suggested that the increased sodium ion gradient created by Na+,K+ ATPase activity might drive the transepithelial transport of calcium in cooperation with ion channels and transporters in the choroid plexus and kidney. <a href="#11" class="mim-tip-reference" title="Imura, A., Tsuji, Y., Murata, M., Maeda, R., Kubota, K., Iwano, A., Obuse, C., Togashi, K., Tominaga, M., Kita, N., Tomiyama, K., Iijima, J., and 13 others. <strong>Alpha-Klotho as a regulator of calcium homeostasis.</strong> Science 316: 1615-1618, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17569864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17569864</a>] [<a href="https://doi.org/10.1126/science.1135901" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17569864">Imura et al. (2007)</a> concluded that their findings revealed fundamental roles of alpha-Klotho in the regulation of calcium metabolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17569864" 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="Chen, C.-D., Podvin, S., Gillespie, E., Leeman, S. E., Abraham, C. R. <strong>Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17.</strong> Proc. Nat. Acad. Sci. 104: 19796-19801, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18056631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18056631</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18056631[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/10.1073/pnas.0709805104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18056631">Chen et al. (2007)</a> found that ADAM10 (<a href="/entry/602192">602192</a>) and ADAM17 (<a href="/entry/603639">603639</a>) mediated shedding of Klotho from cell membranes of Klotho-transfected COS-7 cells, a model system they validated by studies in rat kidney slices. Insulin enhanced Klotho shedding, and this effect was abolished by silencing of ADAM10 or ADAM17. Insulin appeared to stimulate ADAM10 and ADAM17 proteolytic activity toward Klotho, but did not increase their mRNA or protein levels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18056631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The CD28 gene (<a href="/entry/186760">186760</a>) is downregulated in CD4 (<a href="/entry/186940">186940</a>)-positive lymphocytes from both healthy elderly people and patients with rheumatoid arthritis (RA; <a href="/entry/180300">180300</a>) due to impaired protein binding activity of the alpha sequence in its promoter region. By database analysis, <a href="#21" class="mim-tip-reference" title="Soroczynska-Cybula, M., Bryl, E., Smolenska, Z., Witkowski, J. M. <strong>Varying expression of four genes sharing a common regulatory sequence may differentiate rheumatoid arthritis from ageing effects on the CD4(+) lymphocytes.</strong> Immunology 132: 78-86, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20738421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20738421</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20738421[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/10.1111/j.1365-2567.2010.03341.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20738421">Soroczynska-Cybula et al. (2011)</a> identified ZNF334 (<a href="/entry/621017">621017</a>), Klotho, RAR-beta-2 (<a href="/entry/180220">180220</a>), and GRAP2 (<a href="/entry/604518">604518</a>) as genes containing alpha-homologous sequences near their promoter regions. RT-PCR analysis showed that these genes were transcribed in human CD4-positive lymphocytes, but expression of RAR-beta-2, Klotho, and ZNF334 was significantly decreased in a correlated manner in cells of RA patients compared with those of healthy individuals. In RA patients, reduced expression of ZNF334 did not depend on the age of the individual, suggesting that it constitutes a disease-related phenomenon. In contrast, reduced expression of RAR-beta-2 and Klotho occurred mostly in cells of relatively younger RA patients, making them similar to lymphocytes of healthy elderly individuals. Further analysis demonstrated that the alpha-homologous sites in ZNF334 and GRAP2, but not RAR-beta-2, bound protein complexes similar to those bound by the CD28 alpha sequence in CD4-positive T-cell nuclei. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20738421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 23-year-old woman with hypophosphatemic rickets and hyperparathyroidism (<a href="/entry/612089">612089</a>), <a href="#4" class="mim-tip-reference" title="Brownstein, C. A., Adler, F., Nelson-Williams, C., Iijima, J., Li, P., Imura, A., Nabeshima, Y., Reyes-Mugica, M., Carpenter, T. O., Lifton, R. P. <strong>A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism.</strong> Proc. Nat. Acad. Sci. 105: 3455-3460, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18308935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18308935</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18308935[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/10.1073/pnas.0712361105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18308935">Brownstein et al. (2008)</a> identified a de novo balanced translocation t(9;13)(q21.13;q13.1). The authors mapped the translocation breakpoints and found that the 5-prime end of the KLOTHO gene was -49 kb distal to the breakpoint on chromosome 13. Plasma alpha-klotho levels and beta-glucuronidase activity were markedly increased in the patient, as was circulating FGF23. <a href="#4" class="mim-tip-reference" title="Brownstein, C. A., Adler, F., Nelson-Williams, C., Iijima, J., Li, P., Imura, A., Nabeshima, Y., Reyes-Mugica, M., Carpenter, T. O., Lifton, R. P. <strong>A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism.</strong> Proc. Nat. Acad. Sci. 105: 3455-3460, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18308935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18308935</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18308935[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/10.1073/pnas.0712361105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18308935">Brownstein et al. (2008)</a> concluded that the patient's novel phenotype was caused by a positional effect of the translocation, causing increased levels of alpha-klotho. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18308935" 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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In a 13-year-old girl with hyperphosphatemic tumoral calcinosis (HFTC3; <a href="/entry/617994">617994</a>), <a href="#10" class="mim-tip-reference" title="Ichikawa, S., Imel, E. A., Kreiter, M. L., Yu, X., Mackenzie, D. S., Sorenson, A. H., Goetz, R., Mohammadi, M., White, K. E., Econs, M. J. <strong>A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis.</strong> J. Clin. Invest. 117: 2684-2691, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17710231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17710231</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17710231[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/10.1172/JCI31330" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17710231">Ichikawa et al. (2007)</a> identified a homozygous mutation in the KL gene (<a href="#0002">604824.0002</a>). In vitro functional expression studies showed that the mutation led to decreased complex formation with FGF23 and to decreased FGF23 signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17710231" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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In a population-based association study, <a href="#2" class="mim-tip-reference" title="Arking, D. E., Krebsova, A., Macek, M., Sr., Macek, M., Jr., Arking, A., Mian, I. S., Fried, L., Hamosh, A., Dey, S., McIntosh, I., Dietz, H. C. <strong>Association of human aging with a functional variant of klotho.</strong> Proc. Nat. Acad. Sci. 99: 856-861, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11792841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11792841</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11792841[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/10.1073/pnas.022484299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11792841">Arking et al. (2002)</a> determined that allele 17 of microsatellite marker 1, which is 11 kb 3-prime of the last exon of the KL gene, is significantly more prevalent in Bohemian Czech newborns than in individuals more than 75 years old, independent of sex and health status. SSCP analysis identified another KL allele, which the authors termed KL-VS, defined by the presence of 6 single-nucleotide polymorphisms (SNPs) in an 800-bp region spanning exon 2 and flanking sequence. Allele-specific oligonucleotide hybridization analysis showed complete linkage disequilibrium for the coding region mutations. Of the 3 mutations in exon 2, 1 is silent and 2 encode amino acid changes, phe352 to val (F352V) and cys370 to ser (C370S). The F352V mutation occurs at a completely conserved amino acid. Genotype analysis indicated that heterozygosity for F352V is significantly more prevalent in elderly Bohemians than in newborns, while homozygosity for V352, which is rare, is more prevalent in newborns. Kaplan-Meier survival analysis revealed that the heterozygote advantage promotes not only survival but also longevity (<a href="/entry/152430">152430</a>) in elderly individuals more than 80 years old. Analysis of Caucasians and African Americans in Baltimore did not detect a heterozygote advantage for F352V, but did find decreased V352 homozygosity in the elderly. Western blot analysis of expression of the V352, S370, V352/S370, and wildtype alleles in HeLa cells or fibroblasts showed enhanced secretion of S370 mutant and decreased secretion of V352 variant compared with the 65-kD wildtype protein. The double mutant was secreted at intermediate levels, and the V352 mutant was most abundant intracellularly, suggesting a KL secretion defect. Functional analysis of a KL paralog, cytosolic beta-glucosidase (CBGL1; <a href="/entry/606619">606619</a>), which has a known substrate, p-nitrophenyl-beta-D-glucoside, established that a mutation (F289V) at the position in CBGL1 corresponding to KL F352V results in a complete loss of ability to cleave the substrate. <a href="#2" class="mim-tip-reference" title="Arking, D. E., Krebsova, A., Macek, M., Sr., Macek, M., Jr., Arking, A., Mian, I. S., Fried, L., Hamosh, A., Dey, S., McIntosh, I., Dietz, H. C. <strong>Association of human aging with a functional variant of klotho.</strong> Proc. Nat. Acad. Sci. 99: 856-861, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11792841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11792841</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11792841[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/10.1073/pnas.022484299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11792841">Arking et al. (2002)</a> concluded that the KL-VS mutation impairs the trafficking and catalytic activity of KL, which may in turn contribute to differences in the onset and severity of age-related phenotypes. They also suggested that additional deleterious mutations remained to be identified, since KL-VS is found on multiple marker allele haplotypes and is negatively associated with marker 1 allele 17. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11792841" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., Iwasaki, H., Iida, A., Shiraki-Iida, T., Nishikawa, S., Nagai, R., Nabeshima, Y. <strong>Mutation of the mouse klotho gene leads to a syndrome resembling ageing.</strong> Nature 390: 45-51, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9363890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9363890</a>] [<a href="https://doi.org/10.1038/36285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9363890">Kuro-o et al. (1997)</a> found that klotho-deficient mice display extensive and accelerated arteriosclerosis in association with medial calcification of the aorta and both medial calcification and intimal thickening of medium-sized muscular arteries. To determine whether klotho influences atherosclerotic risk in humans, <a href="#1" class="mim-tip-reference" title="Arking, D. E., Becker, D. M., Yanek, L. R., Fallin, D., Judge, D. P., Moy, T. F., Becker, L. C., Dietz, H. C. <strong>Klotho allele status and the risk of early-onset occult coronary artery disease.</strong> Am. J. Hum. Genet. 72: 1154-1161, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12669274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12669274</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12669274[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/375035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12669274">Arking et al. (2003)</a> performed cross-sectional studies to assess the association between the KL-VS allele and adult coronary artery disease (CAD) in 2 independent samples of apparently healthy sibs of individuals with onset of CAD under the age of 60 years. Analysis incorporating known CAD risk factors demonstrated that the KL-VS allele is an independent risk factor and that the imposed risk of KL-VS allele status is influenced by modifiable risk factors. Hypertension and increasing high-density lipoprotein cholesterol levels masked or reduced the risk conferred by the KL-VS allele, respectively, whereas current smoking increased the risk. The results demonstrated that the KL-VS allele is an independent risk factor for occult CAD in 2 independent high-risk samples. Modifiable risk factors, including hypertension, smoking status, and HDL cholesterol level, appear to influence the risk imposed by this allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12669274+9363890" 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>Priapism, a vasoocclusive manifestation of sickle cell disease (<a href="/entry/603903">603903</a>), affects more than 30% of males with the disorder. In sickle cell anemia patients, 148 with priapism and 529 without, <a href="#19" class="mim-tip-reference" title="Nolan, V. G., Baldwin, C., Ma, Q., Wyszynski, D. F., Amirault, Y., Farrell, J. J., Bisbee, A., Embury, S. H., Farrer, L. A., Steinberg, M. H. <strong>Association of single nucleotide polymorphisms in klotho with priapism in sickle cell anaemia.</strong> Brit. J. Haemat. 128: 266-272, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15638863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15638863</a>] [<a href="https://doi.org/10.1111/j.1365-2141.2004.05295.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15638863">Nolan et al. (2005)</a> searched SNPs from 44 genes of different functional classes for an association with priapism. By genotypic and haplotype analysis, they found an association between SNPs in the KL gene and priapism (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2249358;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2249358</a> and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs211239;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs211239</a>; adjusted odds ratio of 2.6 and 1.7, respectively). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15638863" 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="#13" class="mim-tip-reference" title="Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., Iwasaki, H., Iida, A., Shiraki-Iida, T., Nishikawa, S., Nagai, R., Nabeshima, Y. <strong>Mutation of the mouse klotho gene leads to a syndrome resembling ageing.</strong> Nature 390: 45-51, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9363890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9363890</a>] [<a href="https://doi.org/10.1038/36285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9363890">Kuro-o et al. (1997)</a> described a transgenic mouse with several age-related disorders: infertility, genital and thymus atrophy, skin atrophy as revealed by a reduction in hair follicle number, arteriosclerosis, hypokinesis, gait disturbance, ectopic calcification, osteoporosis, emphysema, pituitary abnormalities, and increases in serum calcium and phosphorus. The phenotypes appeared only in mice homozygous for the mutant Kl transgene and only after at least 2 weeks of age. The average life span of the mice was approximately 60 days with no mice surviving more than 100 days. Mice with the normal Kl gene did not express the age-related disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9363890" 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="Manya, H., Inomata, M., Fujimori, T., Dohmae, N., Sato, Y., Takio, K., Nabeshima, Y., Endo, T. <strong>Klotho protein deficiency leads to overactivation of mu-calpain.</strong> J. Biol. Chem. 277: 35503-35508, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12119304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12119304</a>] [<a href="https://doi.org/10.1074/jbc.M206033200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12119304">Manya et al. (2002)</a> showed that, while calpain-1 (<a href="/entry/114220">114220</a>) activity was unchanged in kidneys of klotho-null mice, the activity of calpain-2 (<a href="/entry/114230">114230</a>) was elevated, and the activity of its endogenous inhibitor, calpastatin (<a href="/entry/114090">114090</a>), was significantly decreased. Proteolysis of alpha-II spectrin (<a href="/entry/182860">182860</a>) also increased with decreasing levels of klotho protein. <a href="#16" class="mim-tip-reference" title="Manya, H., Inomata, M., Fujimori, T., Dohmae, N., Sato, Y., Takio, K., Nabeshima, Y., Endo, T. <strong>Klotho protein deficiency leads to overactivation of mu-calpain.</strong> J. Biol. Chem. 277: 35503-35508, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12119304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12119304</a>] [<a href="https://doi.org/10.1074/jbc.M206033200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12119304">Manya et al. (2002)</a> observed similar phenomena in normal aged mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12119304" 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 the Otsuka Long-Evans Tokushima Fatty (OLETF) rat model of atherosclerotic disease, <a href="#20" class="mim-tip-reference" title="Saito, Y., Nakamura, T., Ohyama, Y, Suzuki, T., Iida, A., Shiraki-Iida, T., Kuro-o, M., Nabeshima, Y., Kurabayashi, M., Nagai, R. <strong>In vivo klotho gene delivery protects against endothelial dysfunction in multiple risk factor syndrome.</strong> Biochem. Biophys. Res. Commun. 276: 767-772, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11027545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11027545</a>] [<a href="https://doi.org/10.1006/bbrc.2000.3470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11027545">Saito et al. (2000)</a> observed significantly reduced levels of klotho mRNA in the kidneys of these animals. <a href="#20" class="mim-tip-reference" title="Saito, Y., Nakamura, T., Ohyama, Y, Suzuki, T., Iida, A., Shiraki-Iida, T., Kuro-o, M., Nabeshima, Y., Kurabayashi, M., Nagai, R. <strong>In vivo klotho gene delivery protects against endothelial dysfunction in multiple risk factor syndrome.</strong> Biochem. Biophys. Res. Commun. 276: 767-772, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11027545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11027545</a>] [<a href="https://doi.org/10.1006/bbrc.2000.3470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11027545">Saito et al. (2000)</a> established that adenovirus-mediated klotho gene delivery improves endothelial dysfunction, increases nitric oxide production, and reduces elevated blood pressure to control rat levels, but does not have a detectable effect on weight or blood glucose levels. Klotho treatment also suppresses the medial thickness of the thoracic aorta and perivascular fibrosis in the coronary artery. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11027545" 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="#18" class="mim-tip-reference" title="Mori, K., Yahata, K., Mukoyama, M., Suganami, T., Makino, H., Nagae, T., Masuzaki, H., Ogawa, Y., Sugawara, A., Nabeshima, Y., Nakao, K. <strong>Disruption of klotho gene causes an abnormal energy homeostasis in mice.</strong> Biochem. Biophys. Res. Commun. 278: 665-670, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11095966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11095966</a>] [<a href="https://doi.org/10.1006/bbrc.2000.3864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11095966">Mori et al. (2000)</a> showed that klotho mice had a barely detectable amount of white adipose tissue, whereas brown adipose tissue (BAT) was comparably preserved. Although klotho mice consumed as much food as wildtype mice when normalized for body weight, they exhibited changes in parameters for energy homeostasis similar to those found under food-restricted conditions. The klotho mice had increased glucose tolerance and insulin sensitivity, as well as increased hepatic Pepck (<a href="/entry/614168">614168</a>) expression. Levels of uncoupling protein-1 (UCP1; <a href="/entry/113730">113730</a>) and body temperature were significantly lower in klotho mice. Histologic analysis demonstrated lower glycogen, insulin, and lipid in the liver, pancreas, and BAT, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11095966" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Fukino, K., Suzuki, T., Saito, Y., Shindo, T., Amaki, T., Kurabayashi, M., Nagai, R. <strong>Regulation of angiogenesis by the aging suppressor gene klotho.</strong> Biochem. Biophys. Res. Commun. 293: 332-337, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12054604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12054604</a>] [<a href="https://doi.org/10.1016/S0006-291X(02)00216-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12054604">Fukino et al. (2002)</a> found that mice heterozygously deficient for the klotho gene showed impaired blood flow recovery and impaired angiogenesis following ischemic hindlimb injury. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12054604" 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="#3" class="mim-tip-reference" title="Bektas, A., Schurman, S. H., Sharov, A. A., Carter, M. G., Dietz, H. C., Francomano, C. A. <strong>Klotho gene variation and expression in 20 inbred mouse strains.</strong> Mammalian Genome 15: 759-767, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15520879/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15520879</a>] [<a href="https://doi.org/10.1007/s00335-004-2375-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15520879">Bektas et al. (2004)</a> sequenced the mouse klotho gene and examined renal expression of the secreted and membrane-bound klotho isoforms from 16 laboratory-derived and 4 wild-derived inbred strains. Among the laboratory-derived strains, no sequence variation was found in any of the exons or intron-exon boundaries. Among the wild-derived strains, they found 45 sequence variants with 6 resulting in amino acid substitutions. One wild-derived strain, SPRET/Ei, had 4 amino acid substitutions and higher levels of the membrane form and total klotho mRNA. These mice had longer life spans, decreased atherosclerosis risk factors, and better hearing than almost all other mouse strains. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15520879" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Kurosu, H., Yamamoto, M., Clark, J. D., Pastor, J. V., Nandi, A., Gurnani, P., McGuinness, O. P., Chikuda, H., Yamaguchi, M., Kawaguchi, H., Shimomura, I., Takayama, Y., Herz, J., Kahn, C. R., Rosenblatt, K. P., Kuro-o, M. <strong>Suppression of aging in mice by the hormone klotho.</strong> Science 309: 1829-1833, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16123266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16123266</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16123266[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1112766" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16123266">Kurosu et al. (2005)</a> showed that overexpression of klotho in mice extends life span. Klotho protein functions as a circulating hormone that binds to a cell surface receptor and represses intracellular signals of insulin and insulin-like growth factor-1 (IGF1; <a href="/entry/147440">147440</a>), an evolutionarily conserved mechanism for extending life span. Alleviation of aging-like phenotypes in klotho-deficient mice was observed by perturbing insulin and IGF1 signaling, suggesting that klotho-mediated inhibition of insulin and IGF1 signaling contributes to its anti-aging properties. <a href="#14" class="mim-tip-reference" title="Kurosu, H., Yamamoto, M., Clark, J. D., Pastor, J. V., Nandi, A., Gurnani, P., McGuinness, O. P., Chikuda, H., Yamaguchi, M., Kawaguchi, H., Shimomura, I., Takayama, Y., Herz, J., Kahn, C. R., Rosenblatt, K. P., Kuro-o, M. <strong>Suppression of aging in mice by the hormone klotho.</strong> Science 309: 1829-1833, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16123266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16123266</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16123266[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1112766" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16123266">Kurosu et al. (2005)</a> suggested that klotho protein may function as an anti-aging hormone in mammals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16123266" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a Tenc1 (<a href="/entry/607717">607717</a>)-mutant mouse model of glomerulonephritis (ICGN), <a href="#9" class="mim-tip-reference" title="Haruna, Y., Kashihara, N., Satoh, M., Tomita, N., Namikoshi, T., Sasaki, T., Fujimori, T., Xie, P., Kanwar, Y. S. <strong>Amelioration of progressive renal injury by genetic manipulation of Klotho gene.</strong> Proc. Nat. Acad. Sci. 104: 2331-2336, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17287345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17287345</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17287345[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/10.1073/pnas.0611079104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17287345">Haruna et al. (2007)</a> introduced a Klotho transgene and found that overexpression of the Klotho gene resulted in a 70% survival rate compared to 30% for ICGN mice without the Klotho transgene. Survival was associated with dramatic improvement in renal functions, morphologic lesions, and cytochrome c oxidase activity, as well reduced beta-galactosidase (see <a href="/entry/230500">230500</a>) activity, mitochondrial DNA fragmentation, superoxide anion generation, lipid peroxidation, and Bax (<a href="/entry/600004">600004</a>) protein expression and apoptosis. Improvement was seen in both the tubular and glomerular compartments of the kidney, suggesting that the Klotho gene product may serve as a renoprotective circulating hormone while mitigating mitochondrial oxidative stress. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17287345" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Liu, H., Fergusson, M. M., Castilho, R. M., Liu, J., Cao, L., Chen, J., Malide, D., Rovira, I. I., Schimel, D., Kuo, C. J., Gutkind, J. S., Hwang, P. M., Finkel, T. <strong>Augmented Wnt signaling in a mammalian model of accelerated aging.</strong> Science 317: 803-806, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17690294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17690294</a>] [<a href="https://doi.org/10.1126/science.1143578" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17690294">Liu et al. (2007)</a> explored the contribution of stem and progenitor cell dysfunction and depletion to aging in the Klotho mouse model. Analysis of various tissues and organs from young Klotho mice revealed a decrease in stem cell number and an increase in progenitor cell senescence. Because Klotho is a secreted protein, <a href="#15" class="mim-tip-reference" title="Liu, H., Fergusson, M. M., Castilho, R. M., Liu, J., Cao, L., Chen, J., Malide, D., Rovira, I. I., Schimel, D., Kuo, C. J., Gutkind, J. S., Hwang, P. M., Finkel, T. <strong>Augmented Wnt signaling in a mammalian model of accelerated aging.</strong> Science 317: 803-806, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17690294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17690294</a>] [<a href="https://doi.org/10.1126/science.1143578" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17690294">Liu et al. (2007)</a> postulated that Klotho might interact with other soluble mediators of stem cells. They found that Klotho bound to various Wnt family members. In a cell culture model, the Wnt-Klotho interaction resulted in the suppression of Wnt biologic activity. Tissues and organs from Klotho-deficient animals showed evidence of increased Wnt signaling, and ectopic expression of Klotho antagonized the activity of endogenous and exogenous Wnt. Both in vitro and in vivo, continuous Wnt exposure triggered accelerated cellular senescence. Thus, <a href="#15" class="mim-tip-reference" title="Liu, H., Fergusson, M. M., Castilho, R. M., Liu, J., Cao, L., Chen, J., Malide, D., Rovira, I. I., Schimel, D., Kuo, C. J., Gutkind, J. S., Hwang, P. M., Finkel, T. <strong>Augmented Wnt signaling in a mammalian model of accelerated aging.</strong> Science 317: 803-806, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17690294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17690294</a>] [<a href="https://doi.org/10.1126/science.1143578" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17690294">Liu et al. (2007)</a> concluded that Klotho appears to be a secreted Wnt antagonist and that Wnt proteins have an unexpected role in mammalian aging. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17690294" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs7997728 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs7997728;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/rs7997728?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=rs7997728" 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=rs7997728" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs9527025 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs9527025;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/rs9527025?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=rs9527025" 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=rs9527025" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs9527026 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs9527026;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/rs9527026?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=rs9527026" 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=rs9527026" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs9536312 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs9536312;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/rs9536312?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=rs9536312" 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=rs9536312" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs9536313 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs9536313;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/rs9536313?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=rs9536313" 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=rs9536313" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs9536314 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs9536314;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/rs9536314?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=rs9536314" 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=rs9536314" 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=RCV000005674 OR RCV000265097 OR RCV000323675 OR RCV000362065 OR RCV001538558 OR RCV001539287 OR RCV001609847 OR RCV001653529 OR RCV001693290 OR RCV001723894" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005674, RCV000265097, RCV000323675, RCV000362065, RCV001538558, RCV001539287, RCV001609847, RCV001653529, RCV001693290, RCV001723894" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005674...</a>
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<a href="#2" class="mim-tip-reference" title="Arking, D. E., Krebsova, A., Macek, M., Sr., Macek, M., Jr., Arking, A., Mian, I. S., Fried, L., Hamosh, A., Dey, S., McIntosh, I., Dietz, H. C. <strong>Association of human aging with a functional variant of klotho.</strong> Proc. Nat. Acad. Sci. 99: 856-861, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11792841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11792841</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11792841[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/10.1073/pnas.022484299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11792841">Arking et al. (2002)</a> identified a functional variant of klotho, a haplotype termed KL-VS, which is defined by the presence of 6 single-nucleotide polymorphisms (SNPs) in an 800-bp region spanning exon 2 and flanking sequence. Allele-specific oligonucleotide hybridization analysis showed complete linkage disequilibrium for the coding region mutations. Of the 3 mutations in exon 2, 1 is silent and 2 encode amino acid changes, phe352 to val (F352V) and cys370 to ser (C370S). The variant was associated with reduced human longevity when in homozygosity. The prevalence of the variant in the general population was estimated to be 0.157. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11792841" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Coronary Artery Disease, Susceptibility to</em></strong></p><p>
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<a href="#1" class="mim-tip-reference" title="Arking, D. E., Becker, D. M., Yanek, L. R., Fallin, D., Judge, D. P., Moy, T. F., Becker, L. C., Dietz, H. C. <strong>Klotho allele status and the risk of early-onset occult coronary artery disease.</strong> Am. J. Hum. Genet. 72: 1154-1161, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12669274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12669274</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12669274[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/375035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12669274">Arking et al. (2003)</a> demonstrated an association between the variant allele and susceptibility to coronary artery disease that proved to be a risk factor independent of known risk factors. The authors found, however, that the risk imposed by KL-VS was influenced by other risk factors, including hypertension, smoking status, and HDL cholesterol level. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12669274" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 TUMORAL CALCINOSIS, FAMILIAL, HYPERPHOSPHATEMIC, 3 (1 patient)</strong>
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KL, HIS193ARG
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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> rs121908423 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908423;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/rs121908423?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=rs121908423" 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=rs121908423" 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=RCV000005675 OR RCV000758698 OR RCV003555927" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005675, RCV000758698, RCV003555927" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005675...</a>
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<p>In a 13-year-old girl with hyperphosphatemic tumoral calcinosis (HFTC3; <a href="/entry/617994">617994</a>), <a href="#10" class="mim-tip-reference" title="Ichikawa, S., Imel, E. A., Kreiter, M. L., Yu, X., Mackenzie, D. S., Sorenson, A. H., Goetz, R., Mohammadi, M., White, K. E., Econs, M. J. <strong>A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis.</strong> J. Clin. Invest. 117: 2684-2691, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17710231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17710231</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17710231[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/10.1172/JCI31330" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17710231">Ichikawa et al. (2007)</a> identified a homozygous 578A-G transition in exon 1 of the KL gene, resulting in a his193-to-arg (H193R) substitution in the first of 2 tandem putative glycosidase domains. The substitution was predicted to destabilize the tertiary fold of the glycosidase domain, leading to decreased expression and secretion of the protein. In vitro functional expression studies indicated that the H193R mutant protein was not fully glycosylated, was not fully secreted, and had decreased stability compared to wildtype. In addition, the mutation led to decreased complex formation with FGF23 (<a href="/entry/605380">605380</a>) and to decreased FGF23 signaling. The patient had hyperphosphatemia, increased serum vitamin D, tumoral calcinosis in the dura, and osteopenia. She also had hyperparathyroidism due to hyperplastic glands; the relationship of this feature to the KL mutation was unclear. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17710231" 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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Arking, D. E., Becker, D. M., Yanek, L. R., Fallin, D., Judge, D. P., Moy, T. F., Becker, L. C., Dietz, H. C.
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<strong>Klotho allele status and the risk of early-onset occult coronary artery disease.</strong>
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Am. J. Hum. Genet. 72: 1154-1161, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12669274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12669274</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12669274[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=12669274" 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/10.1086/375035" target="_blank">Full Text</a>]
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Arking, D. E., Krebsova, A., Macek, M., Sr., Macek, M., Jr., Arking, A., Mian, I. S., Fried, L., Hamosh, A., Dey, S., McIntosh, I., Dietz, H. C.
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<strong>Association of human aging with a functional variant of klotho.</strong>
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Proc. Nat. Acad. Sci. 99: 856-861, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11792841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11792841</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11792841[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=11792841" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.022484299" target="_blank">Full Text</a>]
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Bektas, A., Schurman, S. H., Sharov, A. A., Carter, M. G., Dietz, H. C., Francomano, C. A.
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<strong>Klotho gene variation and expression in 20 inbred mouse strains.</strong>
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Mammalian Genome 15: 759-767, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15520879/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15520879</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15520879" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00335-004-2375-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0712361105" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1114245" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0709805104" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature25451" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/S0006-291X(02)00216-4" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0611079104" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI31330" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1135901" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15638863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15638863</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15638863" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1365-2141.2004.05295.x" 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="20" class="mim-anchor"></a>
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<a id="Saito2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Saito, Y., Nakamura, T., Ohyama, Y, Suzuki, T., Iida, A., Shiraki-Iida, T., Kuro-o, M., Nabeshima, Y., Kurabayashi, M., Nagai, R.
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<strong>In vivo klotho gene delivery protects against endothelial dysfunction in multiple risk factor syndrome.</strong>
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Biochem. Biophys. Res. Commun. 276: 767-772, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11027545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11027545</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11027545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/bbrc.2000.3470" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="21" class="mim-anchor"></a>
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<a id="Soroczynska-Cybula2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Soroczynska-Cybula, M., Bryl, E., Smolenska, Z., Witkowski, J. M.
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<strong>Varying expression of four genes sharing a common regulatory sequence may differentiate rheumatoid arthritis from ageing effects on the CD4(+) lymphocytes.</strong>
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Immunology 132: 78-86, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20738421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20738421</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20738421[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=20738421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1365-2567.2010.03341.x" 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="22" class="mim-anchor"></a>
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<a id="Urakawa2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Urakawa, I., Yamazaki, Y., Shimada, T., Iijima, K., Hasegawa, H., Okawa, K., Fujita, T., Fukumoto, S., Yamashita, T.
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<strong>Klotho converts canonical FGF receptor into a specific receptor for FGF23.</strong>
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Nature 444: 770-774, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17086194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17086194</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17086194" 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/nature05315" target="_blank">Full Text</a>]
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</p>
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</ol>
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<br />
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</div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div 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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Bao Lige - updated : 11/21/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 08/21/2018<br>Marla J. F. O'Neill - updated : 5/29/2008<br>Patricia A. Hartz - updated : 1/29/2008<br>Cassandra L. Kniffin - updated : 11/13/2007<br>Ada Hamosh - updated : 8/29/2007<br>Ada Hamosh - updated : 6/26/2007<br>Marla J. F. O'Neill - updated : 4/19/2007<br>Ada Hamosh - updated : 1/23/2007<br>Ada Hamosh - updated : 11/14/2005<br>Victor A. McKusick - updated : 5/12/2005<br>Victor A. McKusick - updated : 12/20/2004<br>Patricia A. Hartz - updated : 7/8/2003<br>Victor A. McKusick - updated : 6/4/2003<br>Patricia A. Hartz - updated : 11/7/2002<br>Paul J. Converse - updated : 5/28/2002<br>Victor A. McKusick - updated : 2/6/2002<br>Paul J. Converse - updated : 1/17/2002<br>Paul J. Converse - updated : 4/6/2001<br>Paul J. Converse - updated : 2/1/2001
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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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Paul J. Converse : 4/11/2000
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</span>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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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 class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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mgross : 11/21/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 08/21/2018<br>carol : 05/23/2018<br>carol : 03/03/2017<br>carol : 07/08/2014<br>joanna : 1/22/2013<br>carol : 5/29/2008<br>mgross : 2/7/2008<br>terry : 1/29/2008<br>wwang : 12/12/2007<br>ckniffin : 11/13/2007<br>carol : 10/10/2007<br>carol : 10/10/2007<br>alopez : 9/6/2007<br>terry : 8/29/2007<br>alopez : 6/29/2007<br>terry : 6/26/2007<br>mgross : 6/26/2007<br>mgross : 6/14/2007<br>terry : 6/11/2007<br>wwang : 4/19/2007<br>wwang : 4/19/2007<br>alopez : 1/24/2007<br>alopez : 1/24/2007<br>terry : 1/23/2007<br>alopez : 3/28/2006<br>alopez : 11/16/2005<br>alopez : 11/15/2005<br>terry : 11/14/2005<br>wwang : 6/7/2005<br>wwang : 5/12/2005<br>carol : 12/28/2004<br>terry : 12/20/2004<br>carol : 7/6/2004<br>carol : 7/6/2004<br>carol : 7/6/2004<br>mgross : 7/8/2003<br>cwells : 6/10/2003<br>terry : 6/4/2003<br>tkritzer : 11/14/2002<br>tkritzer : 11/7/2002<br>tkritzer : 11/7/2002<br>mgross : 5/28/2002<br>terry : 4/23/2002<br>terry : 2/6/2002<br>mgross : 1/17/2002<br>mgross : 1/17/2002<br>mgross : 4/6/2001<br>cwells : 2/6/2001<br>cwells : 2/1/2001<br>carol : 4/11/2000
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</span>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 604824
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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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KLOTHO; KL
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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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ALPHA-KLOTHO
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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: KL</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: 13q13.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 13:33,016,243-33,066,143 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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13q13.1
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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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?Tumoral calcinosis, hyperphosphatemic, familial, 3
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</span>
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</td>
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<td>
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<span class="mim-font">
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617994
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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3
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>Kuro-o et al. (1997) cloned a mouse gene, which they called klotho (Kl), from a transgenic mouse model with several age-related disorders. The name of the gene, Klotho, is that of the Fate in Greek mythology who spins the thread of life. By screening human kidney and hippocampus cDNA libraries with a mouse Kl cDNA fragment at low stringency, Matsumura et al. (1998) isolated cDNA clones for human klotho. Sequence analysis of the cDNAs revealed that they encode 2 different transcripts. One transcript encodes a putative 1,012-amino acid single-pass membrane protein with an N-terminal signal sequence, an extracellular domain with 2 internal repeats, and a short intracellular domain, as found in the mouse klotho protein by Kuro-o et al. (1997). Northern blot analysis revealed expression of a single 5.2-kb transcript in kidney, placenta, small intestine, and prostate. The other transcript contains a 50-bp insertion encoding a truncated putative secreted protein of 549 amino acids that lacks the second internal repeat, the transmembrane domain, and the intracellular domain. Genomic sequence analysis showed that the 2 transcripts arise by alternative RNA splicing. By RNase protection analysis, the secreted form predominated in all tissues examined, i.e., brain, hippocampus, placenta, kidney, prostate, and small intestine. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene Structure</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Matsumura et al. (1998) determined that the KL gene contains 5 exons and spans approximately 50 kb of genomic DNA. </p>
|
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</span>
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<div>
|
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Mapping</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Kuro-o et al. (1997) mapped the human KL gene to chromosome 13q12 by FISH and by inclusion within a BAC contig. </p>
|
|
</span>
|
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<div>
|
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<br />
|
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Biochemical Features</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><strong><em>Crystal Structure</em></strong></p><p>
|
|
Chen et al. (2018) presented the atomic structure of a 1:1:1 ternary complex that consists of the shed extracellular domain of alpha-klotho, the FGFR1c (see 136350) ligand-binding domain, and FGF23 (605380). In this complex, alpha-klotho simultaneously tethers FGFR1c by its D3 domain and FGF23 by its C-terminal tail, thus implementing FGF23-FGFR1c proximity and conferring stability. Dimerization of the stabilized ternary complexes and receptor activation remain dependent on the binding of heparan sulfate, a mandatory cofactor of paracrine FGF signaling. The structure of alpha-klotho is incompatible with its purported glycosidase activity. Thus, Chen et al. (2018) concluded that shed alpha-klotho functions as an on-demand nonenzymatic scaffold protein that promotes FGF23 signaling. </p>
|
|
</span>
|
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<div>
|
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<br />
|
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Patients with chronic renal failure (CRF) develop multiple complications reminiscent of the phenotype observed in Kl mutant mice. By RNase protection, immunoblot, and immunohistochemical analyses, Koh et al. (2001) observed severely reduced KL mRNA expression and protein production in kidneys of CRF patients. They proposed that decreased KL expression may be one of the factors underlying the degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CRF. </p><p>Chang et al. (2005) reported that the transient receptor potential ion channel TRPV5 (606679) is stimulated by the mammalian hormone klotho. Klotho, a beta-glucuronidase, hydrolyzes extracellular sugar residues on TRPV5, entrapping the channel in the plasma membrane. This maintains durable calcium channel activity and membrane calcium permeability in kidney. Thus, Chang et al. (2005) concluded that klotho activates a cell surface channel by hydrolysis of its extracellular N-linked oligosaccharides. </p><p>Urakawa et al. (2006) demonstrated that a previously undescribed receptor conversion by Klotho generates the FGF23 (605380) receptor. Using a renal homogenate, Urakawa et al. (2006) found that Klotho binds to FGF23. Forced expression of Klotho enabled the high affinity binding of FGF23 to the cell surface and restored the ability of a renal cell line to respond to FGF23 treatment. Moreover, FGF23 incompetence was induced by injecting wildtype mice with an anti-Klotho monoclonal antibody. Thus, Klotho is essential for endogenous FGF23 function. Because Klotho alone seemed to be incapable of intracellular signaling, Urakawa et al. (2006) searched for other components of the FGF23 receptor and found FGFR1(IIIc) (see 136350), which was directly converted by Klotho into the FGF23 receptor. Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. The FGF23 receptor shows a strong affinity, one that is sufficient for interacting with physiologic concentrations of FGF23. Moreover, the tissue-specific unique biologic activity of FGF23 is likely to be regulated by a limited local distribution of Klotho. Urakawa et al. (2006) suggested that given that Klotho, with its homologs beta-klotho (KLB; 611135) and KLPH, forms a family, other FGF-FGFR systems may be subject to similar conversions. </p><p>Urakawa et al. (2006) suggested that Klotho may convert other members of the FGF/FGFR receptor system. </p><p>Imura et al. (2007) found the molecular association of Klotho (referred to as alpha-Klotho) and Na+,K+ ATPase and provided evidence for an increase of abundance of Na+,K+ ATPase at the plasma membrane. Low concentrations of extracellular free calcium rapidly induced regulated parathyroid hormone (168450) secretion in an alpha-Klotho-Na+,K+ ATPase-dependent manner. The authors suggested that the increased sodium ion gradient created by Na+,K+ ATPase activity might drive the transepithelial transport of calcium in cooperation with ion channels and transporters in the choroid plexus and kidney. Imura et al. (2007) concluded that their findings revealed fundamental roles of alpha-Klotho in the regulation of calcium metabolism. </p><p>Chen et al. (2007) found that ADAM10 (602192) and ADAM17 (603639) mediated shedding of Klotho from cell membranes of Klotho-transfected COS-7 cells, a model system they validated by studies in rat kidney slices. Insulin enhanced Klotho shedding, and this effect was abolished by silencing of ADAM10 or ADAM17. Insulin appeared to stimulate ADAM10 and ADAM17 proteolytic activity toward Klotho, but did not increase their mRNA or protein levels. </p><p>The CD28 gene (186760) is downregulated in CD4 (186940)-positive lymphocytes from both healthy elderly people and patients with rheumatoid arthritis (RA; 180300) due to impaired protein binding activity of the alpha sequence in its promoter region. By database analysis, Soroczynska-Cybula et al. (2011) identified ZNF334 (621017), Klotho, RAR-beta-2 (180220), and GRAP2 (604518) as genes containing alpha-homologous sequences near their promoter regions. RT-PCR analysis showed that these genes were transcribed in human CD4-positive lymphocytes, but expression of RAR-beta-2, Klotho, and ZNF334 was significantly decreased in a correlated manner in cells of RA patients compared with those of healthy individuals. In RA patients, reduced expression of ZNF334 did not depend on the age of the individual, suggesting that it constitutes a disease-related phenomenon. In contrast, reduced expression of RAR-beta-2 and Klotho occurred mostly in cells of relatively younger RA patients, making them similar to lymphocytes of healthy elderly individuals. Further analysis demonstrated that the alpha-homologous sites in ZNF334 and GRAP2, but not RAR-beta-2, bound protein complexes similar to those bound by the CD28 alpha sequence in CD4-positive T-cell nuclei. </p>
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<h4>
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<span class="mim-font">
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<strong>Cytogenetics</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>In a 23-year-old woman with hypophosphatemic rickets and hyperparathyroidism (612089), Brownstein et al. (2008) identified a de novo balanced translocation t(9;13)(q21.13;q13.1). The authors mapped the translocation breakpoints and found that the 5-prime end of the KLOTHO gene was -49 kb distal to the breakpoint on chromosome 13. Plasma alpha-klotho levels and beta-glucuronidase activity were markedly increased in the patient, as was circulating FGF23. Brownstein et al. (2008) concluded that the patient's novel phenotype was caused by a positional effect of the translocation, causing increased levels of alpha-klotho. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p><strong><em>Hyperphosphatemic Familial Tumoral Calcinosis 3</em></strong></p><p>
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In a 13-year-old girl with hyperphosphatemic tumoral calcinosis (HFTC3; 617994), Ichikawa et al. (2007) identified a homozygous mutation in the KL gene (604824.0002). In vitro functional expression studies showed that the mutation led to decreased complex formation with FGF23 and to decreased FGF23 signaling. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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In a population-based association study, Arking et al. (2002) determined that allele 17 of microsatellite marker 1, which is 11 kb 3-prime of the last exon of the KL gene, is significantly more prevalent in Bohemian Czech newborns than in individuals more than 75 years old, independent of sex and health status. SSCP analysis identified another KL allele, which the authors termed KL-VS, defined by the presence of 6 single-nucleotide polymorphisms (SNPs) in an 800-bp region spanning exon 2 and flanking sequence. Allele-specific oligonucleotide hybridization analysis showed complete linkage disequilibrium for the coding region mutations. Of the 3 mutations in exon 2, 1 is silent and 2 encode amino acid changes, phe352 to val (F352V) and cys370 to ser (C370S). The F352V mutation occurs at a completely conserved amino acid. Genotype analysis indicated that heterozygosity for F352V is significantly more prevalent in elderly Bohemians than in newborns, while homozygosity for V352, which is rare, is more prevalent in newborns. Kaplan-Meier survival analysis revealed that the heterozygote advantage promotes not only survival but also longevity (152430) in elderly individuals more than 80 years old. Analysis of Caucasians and African Americans in Baltimore did not detect a heterozygote advantage for F352V, but did find decreased V352 homozygosity in the elderly. Western blot analysis of expression of the V352, S370, V352/S370, and wildtype alleles in HeLa cells or fibroblasts showed enhanced secretion of S370 mutant and decreased secretion of V352 variant compared with the 65-kD wildtype protein. The double mutant was secreted at intermediate levels, and the V352 mutant was most abundant intracellularly, suggesting a KL secretion defect. Functional analysis of a KL paralog, cytosolic beta-glucosidase (CBGL1; 606619), which has a known substrate, p-nitrophenyl-beta-D-glucoside, established that a mutation (F289V) at the position in CBGL1 corresponding to KL F352V results in a complete loss of ability to cleave the substrate. Arking et al. (2002) concluded that the KL-VS mutation impairs the trafficking and catalytic activity of KL, which may in turn contribute to differences in the onset and severity of age-related phenotypes. They also suggested that additional deleterious mutations remained to be identified, since KL-VS is found on multiple marker allele haplotypes and is negatively associated with marker 1 allele 17. </p><p>Kuro-o et al. (1997) found that klotho-deficient mice display extensive and accelerated arteriosclerosis in association with medial calcification of the aorta and both medial calcification and intimal thickening of medium-sized muscular arteries. To determine whether klotho influences atherosclerotic risk in humans, Arking et al. (2003) performed cross-sectional studies to assess the association between the KL-VS allele and adult coronary artery disease (CAD) in 2 independent samples of apparently healthy sibs of individuals with onset of CAD under the age of 60 years. Analysis incorporating known CAD risk factors demonstrated that the KL-VS allele is an independent risk factor and that the imposed risk of KL-VS allele status is influenced by modifiable risk factors. Hypertension and increasing high-density lipoprotein cholesterol levels masked or reduced the risk conferred by the KL-VS allele, respectively, whereas current smoking increased the risk. The results demonstrated that the KL-VS allele is an independent risk factor for occult CAD in 2 independent high-risk samples. Modifiable risk factors, including hypertension, smoking status, and HDL cholesterol level, appear to influence the risk imposed by this allele. </p><p>Priapism, a vasoocclusive manifestation of sickle cell disease (603903), affects more than 30% of males with the disorder. In sickle cell anemia patients, 148 with priapism and 529 without, Nolan et al. (2005) searched SNPs from 44 genes of different functional classes for an association with priapism. By genotypic and haplotype analysis, they found an association between SNPs in the KL gene and priapism (rs2249358 and rs211239; adjusted odds ratio of 2.6 and 1.7, respectively). </p>
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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>Kuro-o et al. (1997) described a transgenic mouse with several age-related disorders: infertility, genital and thymus atrophy, skin atrophy as revealed by a reduction in hair follicle number, arteriosclerosis, hypokinesis, gait disturbance, ectopic calcification, osteoporosis, emphysema, pituitary abnormalities, and increases in serum calcium and phosphorus. The phenotypes appeared only in mice homozygous for the mutant Kl transgene and only after at least 2 weeks of age. The average life span of the mice was approximately 60 days with no mice surviving more than 100 days. Mice with the normal Kl gene did not express the age-related disorders. </p><p>Manya et al. (2002) showed that, while calpain-1 (114220) activity was unchanged in kidneys of klotho-null mice, the activity of calpain-2 (114230) was elevated, and the activity of its endogenous inhibitor, calpastatin (114090), was significantly decreased. Proteolysis of alpha-II spectrin (182860) also increased with decreasing levels of klotho protein. Manya et al. (2002) observed similar phenomena in normal aged mice. </p><p>Using the Otsuka Long-Evans Tokushima Fatty (OLETF) rat model of atherosclerotic disease, Saito et al. (2000) observed significantly reduced levels of klotho mRNA in the kidneys of these animals. Saito et al. (2000) established that adenovirus-mediated klotho gene delivery improves endothelial dysfunction, increases nitric oxide production, and reduces elevated blood pressure to control rat levels, but does not have a detectable effect on weight or blood glucose levels. Klotho treatment also suppresses the medial thickness of the thoracic aorta and perivascular fibrosis in the coronary artery. </p><p>Mori et al. (2000) showed that klotho mice had a barely detectable amount of white adipose tissue, whereas brown adipose tissue (BAT) was comparably preserved. Although klotho mice consumed as much food as wildtype mice when normalized for body weight, they exhibited changes in parameters for energy homeostasis similar to those found under food-restricted conditions. The klotho mice had increased glucose tolerance and insulin sensitivity, as well as increased hepatic Pepck (614168) expression. Levels of uncoupling protein-1 (UCP1; 113730) and body temperature were significantly lower in klotho mice. Histologic analysis demonstrated lower glycogen, insulin, and lipid in the liver, pancreas, and BAT, respectively. </p><p>Fukino et al. (2002) found that mice heterozygously deficient for the klotho gene showed impaired blood flow recovery and impaired angiogenesis following ischemic hindlimb injury. </p><p>Bektas et al. (2004) sequenced the mouse klotho gene and examined renal expression of the secreted and membrane-bound klotho isoforms from 16 laboratory-derived and 4 wild-derived inbred strains. Among the laboratory-derived strains, no sequence variation was found in any of the exons or intron-exon boundaries. Among the wild-derived strains, they found 45 sequence variants with 6 resulting in amino acid substitutions. One wild-derived strain, SPRET/Ei, had 4 amino acid substitutions and higher levels of the membrane form and total klotho mRNA. These mice had longer life spans, decreased atherosclerosis risk factors, and better hearing than almost all other mouse strains. </p><p>Kurosu et al. (2005) showed that overexpression of klotho in mice extends life span. Klotho protein functions as a circulating hormone that binds to a cell surface receptor and represses intracellular signals of insulin and insulin-like growth factor-1 (IGF1; 147440), an evolutionarily conserved mechanism for extending life span. Alleviation of aging-like phenotypes in klotho-deficient mice was observed by perturbing insulin and IGF1 signaling, suggesting that klotho-mediated inhibition of insulin and IGF1 signaling contributes to its anti-aging properties. Kurosu et al. (2005) suggested that klotho protein may function as an anti-aging hormone in mammals. </p><p>In a Tenc1 (607717)-mutant mouse model of glomerulonephritis (ICGN), Haruna et al. (2007) introduced a Klotho transgene and found that overexpression of the Klotho gene resulted in a 70% survival rate compared to 30% for ICGN mice without the Klotho transgene. Survival was associated with dramatic improvement in renal functions, morphologic lesions, and cytochrome c oxidase activity, as well reduced beta-galactosidase (see 230500) activity, mitochondrial DNA fragmentation, superoxide anion generation, lipid peroxidation, and Bax (600004) protein expression and apoptosis. Improvement was seen in both the tubular and glomerular compartments of the kidney, suggesting that the Klotho gene product may serve as a renoprotective circulating hormone while mitigating mitochondrial oxidative stress. </p><p>Liu et al. (2007) explored the contribution of stem and progenitor cell dysfunction and depletion to aging in the Klotho mouse model. Analysis of various tissues and organs from young Klotho mice revealed a decrease in stem cell number and an increase in progenitor cell senescence. Because Klotho is a secreted protein, Liu et al. (2007) postulated that Klotho might interact with other soluble mediators of stem cells. They found that Klotho bound to various Wnt family members. In a cell culture model, the Wnt-Klotho interaction resulted in the suppression of Wnt biologic activity. Tissues and organs from Klotho-deficient animals showed evidence of increased Wnt signaling, and ectopic expression of Klotho antagonized the activity of endogenous and exogenous Wnt. Both in vitro and in vivo, continuous Wnt exposure triggered accelerated cellular senescence. Thus, Liu et al. (2007) concluded that Klotho appears to be a secreted Wnt antagonist and that Wnt proteins have an unexpected role in mammalian aging. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>2 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 KLOTHO POLYMORPHISM</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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KL, KL-VS HAPLOTYPE
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<br />
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SNP: rs7997728, rs9527025, rs9527026, rs9536312, rs9536313, rs9536314,
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gnomAD: rs7997728, rs9527025, rs9527026, rs9536312, rs9536313, rs9536314,
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ClinVar: RCV000005674, RCV000265097, RCV000323675, RCV000362065, RCV001538558, RCV001539287, RCV001609847, RCV001653529, RCV001693290, RCV001723894
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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 />
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<p><strong><em>Longevity</em></strong></p><p>
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Arking et al. (2002) identified a functional variant of klotho, a haplotype termed KL-VS, which is defined by the presence of 6 single-nucleotide polymorphisms (SNPs) in an 800-bp region spanning exon 2 and flanking sequence. Allele-specific oligonucleotide hybridization analysis showed complete linkage disequilibrium for the coding region mutations. Of the 3 mutations in exon 2, 1 is silent and 2 encode amino acid changes, phe352 to val (F352V) and cys370 to ser (C370S). The variant was associated with reduced human longevity when in homozygosity. The prevalence of the variant in the general population was estimated to be 0.157. </p><p><strong><em>Coronary Artery Disease, Susceptibility to</em></strong></p><p>
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Arking et al. (2003) demonstrated an association between the variant allele and susceptibility to coronary artery disease that proved to be a risk factor independent of known risk factors. The authors found, however, that the risk imposed by KL-VS was influenced by other risk factors, including hypertension, smoking status, and HDL cholesterol level. </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 TUMORAL CALCINOSIS, FAMILIAL, HYPERPHOSPHATEMIC, 3 (1 patient)</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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KL, HIS193ARG
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<br />
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SNP: rs121908423,
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gnomAD: rs121908423,
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ClinVar: RCV000005675, RCV000758698, RCV003555927
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 13-year-old girl with hyperphosphatemic tumoral calcinosis (HFTC3; 617994), Ichikawa et al. (2007) identified a homozygous 578A-G transition in exon 1 of the KL gene, resulting in a his193-to-arg (H193R) substitution in the first of 2 tandem putative glycosidase domains. The substitution was predicted to destabilize the tertiary fold of the glycosidase domain, leading to decreased expression and secretion of the protein. In vitro functional expression studies indicated that the H193R mutant protein was not fully glycosylated, was not fully secreted, and had decreased stability compared to wildtype. In addition, the mutation led to decreased complex formation with FGF23 (605380) and to decreased FGF23 signaling. The patient had hyperphosphatemia, increased serum vitamin D, tumoral calcinosis in the dura, and osteopenia. She also had hyperparathyroidism due to hyperplastic glands; the relationship of this feature to the KL mutation was unclear. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Arking, D. E., Becker, D. M., Yanek, L. R., Fallin, D., Judge, D. P., Moy, T. F., Becker, L. C., Dietz, H. C.
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<strong>Klotho allele status and the risk of early-onset occult coronary artery disease.</strong>
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Am. J. Hum. Genet. 72: 1154-1161, 2003.
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[PubMed: 12669274]
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[Full Text: https://doi.org/10.1086/375035]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Arking, D. E., Krebsova, A., Macek, M., Sr., Macek, M., Jr., Arking, A., Mian, I. S., Fried, L., Hamosh, A., Dey, S., McIntosh, I., Dietz, H. C.
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<strong>Association of human aging with a functional variant of klotho.</strong>
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Proc. Nat. Acad. Sci. 99: 856-861, 2002.
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[PubMed: 11792841]
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[Full Text: https://doi.org/10.1073/pnas.022484299]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Bektas, A., Schurman, S. H., Sharov, A. A., Carter, M. G., Dietz, H. C., Francomano, C. A.
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<strong>Klotho gene variation and expression in 20 inbred mouse strains.</strong>
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Mammalian Genome 15: 759-767, 2004.
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[PubMed: 15520879]
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[Full Text: https://doi.org/10.1007/s00335-004-2375-3]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Brownstein, C. A., Adler, F., Nelson-Williams, C., Iijima, J., Li, P., Imura, A., Nabeshima, Y., Reyes-Mugica, M., Carpenter, T. O., Lifton, R. P.
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<strong>A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism.</strong>
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Proc. Nat. Acad. Sci. 105: 3455-3460, 2008.
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[PubMed: 18308935]
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[Full Text: https://doi.org/10.1073/pnas.0712361105]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Chang, Q., Hoefs, S., van der Kemp, A. W., Topala, C. N., Bindels, R. J., Hoenderop, J. G.
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<strong>The beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel.</strong>
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Science 310: 490-493, 2005.
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[PubMed: 16239475]
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[Full Text: https://doi.org/10.1126/science.1114245]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Chen, C.-D., Podvin, S., Gillespie, E., Leeman, S. E., Abraham, C. R.
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<strong>Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17.</strong>
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Proc. Nat. Acad. Sci. 104: 19796-19801, 2007.
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[PubMed: 18056631]
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[Full Text: https://doi.org/10.1073/pnas.0709805104]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Chen, G., Liu, Y., Goetz, R., Fu, L., Jayaraman, S., Hu, MC., Moe, O. W., Liang, G., Li, X., Mohammadi, M.
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<strong>Alpha-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling.</strong>
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Nature 553: 461-466, 2018.
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[PubMed: 29342138]
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[Full Text: https://doi.org/10.1038/nature25451]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Fukino, K., Suzuki, T., Saito, Y., Shindo, T., Amaki, T., Kurabayashi, M., Nagai, R.
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<strong>Regulation of angiogenesis by the aging suppressor gene klotho.</strong>
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Biochem. Biophys. Res. Commun. 293: 332-337, 2002.
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Soroczynska-Cybula, M., Bryl, E., Smolenska, Z., Witkowski, J. M.
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<strong>Varying expression of four genes sharing a common regulatory sequence may differentiate rheumatoid arthritis from ageing effects on the CD4(+) lymphocytes.</strong>
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