3615 lines
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Entry
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- *605380 - FIBROBLAST GROWTH FACTOR 23; FGF23
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- OMIM
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<p>
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<span class="h4">*605380</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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<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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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/605380">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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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000118972;t=ENST00000237837" 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=8074" 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=605380" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000118972;t=ENST00000237837" 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_020638" 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_020638" 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=605380" 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=05648&isoform_id=05648_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/FGF23" 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/9964292,10119774,10190674,13626688,14196227,33151107,37181765,45359885,46854342,63089578,66794650,66990036,67514227,119609254,218051910,218090770,308906994" 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/Q9GZV9" 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=8074" 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=ENSG00000118972;t=ENST00000237837" 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=FGF23" 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=FGF23" 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+8074" 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/FGF23" 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:8074" 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/8074" 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=chr12&hgg_gene=ENST00000237837.2&hgg_start=4368227&hgg_end=4379712&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://medlineplus.gov/genetics/gene/fgf23" 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=605380[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=605380[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/ENSG00000118972" 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=FGF23" 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=FGF23" 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=FGF23" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=FGF23&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/PA28119" 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:3680" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1891427" 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/FGF23#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:1891427" 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/8074/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=8074" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-050201-4" 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:8074" 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=FGF23&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 237889002<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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605380
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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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FIBROBLAST GROWTH FACTOR 23; FGF23
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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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<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=FGF23" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FGF23</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/12/32?start=-3&limit=10&highlight=32">12p13.32</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr12:4368227-4379712&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'})">12:4,368,227-4,379,712</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>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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<span class="hidden-sm hidden-xs pull-right">
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<a href="/clinicalSynopsis/table?mimNumber=193100,617993" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
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View Clinical Synopses
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</a>
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</span>
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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="2">
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<span class="mim-font">
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<a href="/geneMap/12/32?start=-3&limit=10&highlight=32">
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12p13.32
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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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Hypophosphatemic rickets, autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/193100"> 193100 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<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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<tr>
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<td>
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<span class="mim-font">
|
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Tumoral calcinosis, hyperphosphatemic, familial, 2
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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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<a href="/entry/617993"> 617993 </a>
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal 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">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/605380" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/605380" 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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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
|
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
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<strong>TEXT</strong>
|
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</span>
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</span>
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</h4>
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<div>
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<a id="cloning" class="mim-anchor"></a>
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<p>Using the mouse Fgf23 sequence as query, <a href="#18" class="mim-tip-reference" title="Yamashita, T., Yoshioka, M., Itoh, N. <strong>Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain.</strong> Biochem. Biophys. Res. Commun. 277: 494-498, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11032749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11032749</a>] [<a href="https://doi.org/10.1006/bbrc.2000.3696" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11032749">Yamashita et al. (2000)</a> identified FGF23 in a genomic database. They cloned the full-length cDNA from a placenta library. The deduced 251-amino acid protein contains an N-terminal 24-amino acid signal sequence. FGF23 shares 72% sequence identity with mouse Fgf23, and 24% and 22% identity with human FGF21 (<a href="/entry/609436">609436</a>) and FGF19 (<a href="/entry/603891">603891</a>), respectively. By quantitative PCR, <a href="#18" class="mim-tip-reference" title="Yamashita, T., Yoshioka, M., Itoh, N. <strong>Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain.</strong> Biochem. Biophys. Res. Commun. 277: 494-498, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11032749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11032749</a>] [<a href="https://doi.org/10.1006/bbrc.2000.3696" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11032749">Yamashita et al. (2000)</a> found highest expression of Fgf23 in mouse brain and lower expression in thymus. In situ hybridization of mouse brain revealed discrete specific labeling only in the ventrolateral thalamic nucleus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11032749" 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 <a href="#1" class="mim-tip-reference" title="ADHR Consortium. <strong>Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23.</strong> Nature Genet. 26: 345-348, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11062477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11062477</a>] [<a href="https://doi.org/10.1038/81664" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11062477">ADHR Consortium (2000)</a> described a positional cloning approach used to identify the gene mutated in patients with autosomal dominant hypophosphatemic rickets (ADHR; <a href="/entry/193100">193100</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11062477" 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>The <a href="#1" class="mim-tip-reference" title="ADHR Consortium. <strong>Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23.</strong> Nature Genet. 26: 345-348, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11062477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11062477</a>] [<a href="https://doi.org/10.1038/81664" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11062477">ADHR Consortium (2000)</a> demonstrated that the FGF23 gene is composed of 3 exons, spanning 10 kb of genomic sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11062477" 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 (<a href="/entry/604824">604824</a>), the FGFR1c (see <a href="/entry/136350">136350</a>) ligand-binding domain, and FGF23. 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>The <a href="#1" class="mim-tip-reference" title="ADHR Consortium. <strong>Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23.</strong> Nature Genet. 26: 345-348, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11062477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11062477</a>] [<a href="https://doi.org/10.1038/81664" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11062477">ADHR Consortium (2000)</a> found that the FGF23 gene lies 54 kb telomeric of FGF6 (<a href="/entry/134921">134921</a>) on 12p13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11062477" 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>Tumor-induced osteomalacia is one of the paraneoplastic disorders characterized by hypophosphatemia caused by renal phosphate wasting. The fact that removal of responsible tumors normalizes phosphate metabolism is evidence that a humoral phosphaturic factor, sometimes called phosphatonin (<a href="#15" class="mim-tip-reference" title="Strewler, G. J. <strong>FGF23, hypophosphatemia, and rickets: has phosphorylation been found? (Commentary)</strong> Proc. Nat. Acad. Sci. 98: 5945-5946, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11371627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11371627</a>] [<a href="https://doi.org/10.1073/pnas.111154898" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11371627">Strewler, 2001</a>), is the basis of tumor-induced osteomalacia. <a href="#13" class="mim-tip-reference" title="Shimada, T., Mizutani, S., Muto, T., Yoneya, T., Hino, R., Takeda, S., Takeuchi, Y., Fujita, T., Fukumoto, S., Yamashita, T. <strong>Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia.</strong> Proc. Nat. Acad. Sci. 98: 6500-6505, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11344269/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11344269</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11344269[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.101545198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11344269">Shimada et al. (2001)</a> cloned and characterized FGF23 as a causative factor of tumor-induced osteomalacia. They found that administration of recombinant FGF23 decreased serum phosphate in mice within 12 hours. When Chinese hamster ovary cells stably expressing FGF23 were subcutaneously implanted into nude mice, hypophosphatemia with increased renal phosphate clearance was observed. Continuous production of FGF23 in these animals reproduced the clinical, biochemical, and histologic features of tumor-induced osteomalacia in vivo. Thus, overproduction of FGF23 causes tumor-induced osteomalacia, whereas mutations in the FGF23 gene result in autosomal hypophosphatemic rickets possibly by preventing proteolytic cleavage, which enhances the biologic activity of FGF23. The mutations in FGF23 found in autosomal dominant hypophosphatemic rickets lie within 3 nucleotides of each other in the proprotein convertase cleavage site. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11371627+11344269" 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="#17" class="mim-tip-reference" title="White, K. E., Jonsson, K. B., Carn, G., Hampson, G., Spector, T. D., Mannstadt, M., Lorenz-Depiereux, B., Miyauchi, A., Yang, I. M., Ljunggren, O., Meitinger, T., Strom, T. M., Juppner, H., Econs, M. J. <strong>The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting.</strong> J. Clin. Endocr. Metab. 86: 497-500, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11157998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11157998</a>] [<a href="https://doi.org/10.1210/jcem.86.2.7408" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11157998">White et al. (2001)</a> investigated whether FGF23 is a secreted factor and whether it is abundantly expressed in oncogenic hypophosphatemic osteomalacia (OHO) tumors. After transient transfection of OK-E, COS-7, and HEK293 cells with a plasmid encoding full-length FGF23, all 3 cell lines efficiently secreted 2 protein species that were approximately 32 and 12 kD upon SDS-PAGE analysis and subsequent Western blot analysis using an affinity-purified polyclonal antibody to FGF23. Northern blot analysis using total RNA from 5 OHO tumors revealed high levels of FGF23 mRNA, and Western blot analysis of extracts from a sixth tumor detected the 32-kD FGF23 protein. The authors concluded that FGF23 is a secreted protein, that its mRNA is abundantly expressed by several different OHO tumors, and that it may be the candidate phosphate wasting factor phosphatonin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11157998" 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="Bowe, A. E., Finnegan, R., Jan de Beur, S. M., Cho, J., Levine, M. A., Kumar, R., Schiavi, S. C. <strong>FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate.</strong> Biochem. Biophys. Res. Commun. 284: 977-981, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11409890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11409890</a>] [<a href="https://doi.org/10.1006/bbrc.2001.5084" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11409890">Bowe et al. (2001)</a> found that conditioned medium from COS-7 cells, transfected with either wildtype FGF23 or the FGF23 R179Q mutation (<a href="#0001">605380.0001</a>), inhibited sodium-dependent phosphate uptake in opossum kidney cells. The R179Q mutant was resistant to degradation by the endopeptidase PHEX (<a href="/entry/300550">300550</a>), a member of the neutral endopeptidase family of proteins that is mutated in X-linked hypophosphatasia (<a href="/entry/307800">307800</a>). By RT-PCR, FGF23 was found to be overexpressed in oncogenic osteomalacia but not in other mesenchymal tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11409890" 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="Shimada, T., Muto, T., Urakawa, I., Yoneya, T., Yamazaki, Y., Okawa, K., Takeuchi, Y., Fujita, T., Fukumoto, S., Yamashita, T. <strong>Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo.</strong> Endocrinology 143: 3179-3182, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12130585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12130585</a>] [<a href="https://doi.org/10.1210/endo.143.8.8795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12130585">Shimada et al. (2002)</a> showed that FGF23 is cleaved between arg179 and ser180, and that this processing abolished biologic activity of FGF23 to induce hypophosphatemia. <a href="#19" class="mim-tip-reference" title="Yamazaki, Y., Okazaki, R., Shibata, M., Hasegawa, Y., Satoh, K., Tajima, T., Takeuchi, Y., Fujita, T., Nakahara, K., Yamashita, T., Fukumoto, S. <strong>Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia.</strong> J. Clin. Endocr. Metab. 87: 4957-4960, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12414858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12414858</a>] [<a href="https://doi.org/10.1210/jc.2002-021105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12414858">Yamazaki et al. (2002)</a> developed sandwich ELISA for human FGF23, using 2 monoclonal antibodies to FGF23. The results indicated that biologically active uncleaved FGF23 is present in normal circulation. In addition, the circulatory level of FGF23 was increased in a patient with tumor-induced rickets/osteomalacia and returned to normal soon after resection of the tumor. The serum level of FGF23 was high in patients with X-linked hypophosphatemic rickets/osteomalacia (<a href="/entry/307800">307800</a>). The authors suggested that hypophosphatemic rickets/osteomalacia may be caused by excess activity of full-length FGF23. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12414858+12130585" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Jonsson, K. B., Zahradnik, R., Larsson, T., White, K. E., Sugimoto, T., Imanishi, Y., Yamamoto, T., Hampson, G., Koshiyama, H., Ljunggren, O., Oba, K., Yang, I. M., Miyauchi, A., Econs, M. J., Lavigne, J., Juppner, H. <strong>Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia.</strong> New Eng. J. Med. 348: 1656-1663, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12711740/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12711740</a>] [<a href="https://doi.org/10.1056/NEJMoa020881" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12711740">Jonsson et al. (2003)</a> showed that FGF23 is readily detectable in the plasma or serum of healthy persons and can be markedly elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, suggesting that this growth factor has a role in phosphate homeostasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12711740" 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="#10" class="mim-tip-reference" title="Kato, K., Jeanneau, C., Tarp, M. A., Benet-Pages, A., Lorenz-Depiereux, B., Bennett, E. P., Mandel, U., Strom, T. M., Clausen, H. <strong>Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation.</strong> J. Biol. Chem. 281: 18370-18377, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16638743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16638743</a>] [<a href="https://doi.org/10.1074/jbc.M602469200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16638743">Kato et al. (2006)</a> identified GALNT3 (<a href="/entry/601756">601756</a>) as an enzyme that protects intact FGF23 from proteolytic processing. FGF23 is a phosphaturic protein whose secretion as an intact active form requires O-glycosylation by GALNT3. GALNT3 selectively directs O-glycosylation of FGF23 in a subtilisin-like proprotein convertase (SPC) recognition sequence motif at thr178, which blocks proteolytic processing of FGF23. The findings suggested a novel posttranslational regulatory model of FGF23 involving competing O-glycosylation by GALNT3 and protease processing to produce intact FGF23. Mutations in GALNT3 result in a cleavage of intact FGF23 before secretion, leading to an accumulation of fragmented FGF23 and reduced intact active FGF23. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16638743" 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="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 (<a href="/entry/604824">604824</a>) generates the FGF23 receptor. Using a renal homogenate, <a href="#16" 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="#16" 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. <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>
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The <a href="#1" class="mim-tip-reference" title="ADHR Consortium. <strong>Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23.</strong> Nature Genet. 26: 345-348, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11062477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11062477</a>] [<a href="https://doi.org/10.1038/81664" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11062477">ADHR Consortium (2000)</a> identified 3 missense mutations in the FGF23 (see, e.g., <a href="#0001">605380.0001</a>-<a href="#0002">605380.0002</a>) in affected members of 4 unrelated families with autosomal dominant hypophosphatemic rickets (<a href="/entry/193100">193100</a>). These mutations, which represented the first found in a human FGF gene causing disease, affected 2 arginines that lie only 3 amino acids apart. This finding supported the speculation that the ADHR phenotype is caused by a gain-of-function mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11062477" 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>Hyperphosphatemic Familial Tumoral Calcinosis 2</em></strong></p><p>
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In an individual with familial hyperphosphatemic tumoral calcinosis (HFTC2; <a href="/entry/617933">617933</a>), an autosomal recessive disorder characterized by ectopic calcifications and elevated serum phosphate levels, <a href="#3" class="mim-tip-reference" title="Benet-Pages, A., Orlik, P., Strom, T. M., Lorenz-Depiereux, B. <strong>An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia.</strong> Hum. Molec. Genet. 14: 385-390, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15590700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15590700</a>] [<a href="https://doi.org/10.1093/hmg/ddi034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15590700">Benet-Pages et al. (2005)</a> identified a homozygous ser71-to-gly (S71G) substitution in the FGF23 gene (<a href="#0003">605380.0003</a>). Whereas wildtype FGF23 is secreted as an intact protein as well as processed N-terminal and C-terminal fragments, transfection experiments revealed that the mutated protein was only secreted as the C-terminal fragment; the intact protein was retained in the Golgi complex. <a href="#3" class="mim-tip-reference" title="Benet-Pages, A., Orlik, P., Strom, T. M., Lorenz-Depiereux, B. <strong>An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia.</strong> Hum. Molec. Genet. 14: 385-390, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15590700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15590700</a>] [<a href="https://doi.org/10.1093/hmg/ddi034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15590700">Benet-Pages et al. (2005)</a> suggested that FGF23 function is decreased by absent or extremely reduced secretion of intact FGF23 and that FGF23 mutations in hypophosphatemic rickets and familial tumoral calcinosis have opposite effects on phosphate homeostasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15590700" 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 patient with hyperphosphatemic tumoral calcinosis, <a href="#6" class="mim-tip-reference" title="Chefetz, I., Heller, R., Galli-Tsinopoulou, A., Richard, G., Wollnik, B., Indelman, M., Koerber, F., Topaz, O., Bergman, R., Sprecher, E., Schoenau, E. <strong>A novel homozygous missense mutation in FGF23 causes familial tumoral calcinosis associated with disseminated visceral calcification.</strong> Hum. Genet. 118: 261-266, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16151858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16151858</a>] [<a href="https://doi.org/10.1007/s00439-005-0026-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16151858">Chefetz et al. (2005)</a> identified a homozygous missense mutation (M6T; <a href="#0004">605380.0004</a>) in the FGF23 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16151858" 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 2 affected members of a consanguineous Arabian family with hyperphosphatemic tumoral calcinosis, <a href="#2" class="mim-tip-reference" title="Araya, K., Fukumoto, S., Backenroth, R., Takeuchi, Y., Nakayama, K., Ito, N., Yoshii, N., Yamazaki, Y., Yamashita, T., Silver, J., Igarashi, T., Fujita, T. <strong>A novel mutation in fibroblast growth factor 23 gene as a cause of tumoral calcinosis.</strong> J. Clin. Endocr. Metab. 90: 5523-5527, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16030159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16030159</a>] [<a href="https://doi.org/10.1210/jc.2005-0301" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16030159">Araya et al. (2005)</a> identified a homozygous missense mutation (S129F; <a href="#0005">605380.0005</a>) in the FGF23 gene. Two other members of the family were affected, but were unavailable for testing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16030159" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#12" class="mim-tip-reference" title="Shimada, T., Kakitani, M., Yamazaki, Y., Hasegawa, H., Takeuchi, Y., Fujita, T., Fukumoto, S., Tomizuka, K., Yamashita, T. <strong>Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism.</strong> J. Clin. Invest. 113: 561-568, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14966565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14966565</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14966565[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/JCI19081" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14966565">Shimada et al. (2004)</a> generated Fgf23 -/- mice which exhibited severe growth retardation with an abnormal bone phenotype and markedly short life span, as well as severe hyperphosphatemia, enhanced renal phosphate reabsorption. They also showed high serum 1,25-dihydroxyvitamin D due to increased expression of renal 25-hydroxyvitamin D-1-alpha-hydroxylase. Heterozygotes showed no abnormality in any of the parameters examined, including serum FGF23. Because these phenotypes could not be explained by known regulators of mineral homeostasis, <a href="#12" class="mim-tip-reference" title="Shimada, T., Kakitani, M., Yamazaki, Y., Hasegawa, H., Takeuchi, Y., Fujita, T., Fukumoto, S., Tomizuka, K., Yamashita, T. <strong>Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism.</strong> J. Clin. Invest. 113: 561-568, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14966565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14966565</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14966565[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/JCI19081" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14966565">Shimada et al. (2004)</a> concluded that FGF23 is essential for normal phosphate and vitamin D metabolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14966565" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of 2 unrelated families with autosomal dominant hypophosphatemic rickets (<a href="/entry/193100">193100</a>), the <a href="#1" class="mim-tip-reference" title="ADHR Consortium. <strong>Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23.</strong> Nature Genet. 26: 345-348, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11062477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11062477</a>] [<a href="https://doi.org/10.1038/81664" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11062477">ADHR Consortium (2000)</a> identified a heterozygous 527G-A transition in the FGF23 gene, resulting in an arg176-to-gln (R176Q) substitution. The families had been reported by <a href="#4" class="mim-tip-reference" title="Bianchine, J. W., Stambler, A. A., Harrison, H. E. <strong>Familial hypophosphatemic rickets showing autosomal dominant inheritance.</strong> Birth Defects Orig. Art. Ser. VII(6): 287-294, 1971.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5173181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5173181</a>]" pmid="5173181">Bianchine et al. (1971)</a> and <a href="#8" class="mim-tip-reference" title="Econs, M. J., McEnery, P. T. <strong>Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder.</strong> J. Clin. Endocr. Metab. 82: 674-681, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9024275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9024275</a>] [<a href="https://doi.org/10.1210/jcem.82.2.3765" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9024275">Econs and McEnery (1997)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5173181+9024275+11062477" 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> rs28937882 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28937882;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/rs28937882?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=rs28937882" 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=rs28937882" 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=RCV000005329 OR RCV000424624" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005329, RCV000424624" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005329...</a>
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<p>In affected members of a family with autosomal dominant hypophosphatemic rickets (<a href="/entry/193100">193100</a>) reported by <a href="#11" class="mim-tip-reference" title="Rowe, P. S. N., Read, A. P., Mountford, R., Benham, F., Kruse, T. A., Camerino, G., Davies, K. E., O'Riordan, J. L. H. <strong>Three DNA markers for hypophosphataemic rickets.</strong> Hum. Genet. 89: 539-542, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1353055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1353055</a>] [<a href="https://doi.org/10.1007/BF00219180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1353055">Rowe et al. (1992)</a>, the <a href="#1" class="mim-tip-reference" title="ADHR Consortium. <strong>Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23.</strong> Nature Genet. 26: 345-348, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11062477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11062477</a>] [<a href="https://doi.org/10.1038/81664" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11062477">ADHR Consortium (2000)</a> identified a 535C-T transition in the FGF23 gene, resulting in an arg179-to-trp (R179W) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1353055+11062477" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 TUMORAL CALCINOSIS, FAMILIAL, HYPERPHOSPHATEMIC, 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs104894342 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894342;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/rs104894342?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=rs104894342" 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=rs104894342" 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=RCV000005330 OR RCV000412723 OR RCV000662354 OR RCV000984806 OR RCV005007825" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005330, RCV000412723, RCV000662354, RCV000984806, RCV005007825" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005330...</a>
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<p>In an individual with tumoral calcinosis with hyperphosphatemia (HFTC2; <a href="/entry/617993">617993</a>), <a href="#3" class="mim-tip-reference" title="Benet-Pages, A., Orlik, P., Strom, T. M., Lorenz-Depiereux, B. <strong>An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia.</strong> Hum. Molec. Genet. 14: 385-390, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15590700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15590700</a>] [<a href="https://doi.org/10.1093/hmg/ddi034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15590700">Benet-Pages et al. (2005)</a> identified a homozygous 211A-G transition in the FGF23 gene, resulting in a ser71-to-gly (S71G) substitution at an evolutionarily conserved residue. Expression of the mutated protein in HEK293 cells showed that only the C-terminal fragment was secreted, whereas the intact protein was retained in the Golgi complex. Circulating FGF23 in the patient showed a marked increase in the C-terminal fragment. <a href="#3" class="mim-tip-reference" title="Benet-Pages, A., Orlik, P., Strom, T. M., Lorenz-Depiereux, B. <strong>An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia.</strong> Hum. Molec. Genet. 14: 385-390, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15590700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15590700</a>] [<a href="https://doi.org/10.1093/hmg/ddi034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15590700">Benet-Pages et al. (2005)</a> suggested that FGF23 function is decreased by absent or extremely reduced secretion of intact FGF23. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15590700" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 TUMORAL CALCINOSIS, FAMILIAL, HYPERPHOSPHATEMIC, 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894343 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894343;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104894343" 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=rs104894343" 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=RCV000005331 OR RCV001528527" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005331, RCV001528527" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005331...</a>
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<p>In a severe case of tumoral calcinosis (HFTC2; <a href="/entry/617993">617993</a>) displaying calcifications of cutaneous and numerous extracutaneous tissues, <a href="#6" class="mim-tip-reference" title="Chefetz, I., Heller, R., Galli-Tsinopoulou, A., Richard, G., Wollnik, B., Indelman, M., Koerber, F., Topaz, O., Bergman, R., Sprecher, E., Schoenau, E. <strong>A novel homozygous missense mutation in FGF23 causes familial tumoral calcinosis associated with disseminated visceral calcification.</strong> Hum. Genet. 118: 261-266, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16151858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16151858</a>] [<a href="https://doi.org/10.1007/s00439-005-0026-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16151858">Chefetz et al. (2005)</a> identified a homozygous T-to-C transition at position 287 of the FGF23 gene that resulted in a met96-to-thr (M96T) amino acid substitution. The M96T mutation affected a highly conserved methionine residue. No direct familial relationship between the parents of the index patient could be established, although they both originated from the same Greek village located near the Turkish border. The patient was first seen at 5 years of age for surgical removal of calcified foci from the oral mucosa. Subsequently, he developed large subcutaneous tumors around his wrists, knees, and ankles. Small calcified deposits were visible at the external border of the lower eyelids. He showed persistent hyperphosphatemia at the age of 13 years. There was sonographic evidence of calcinosis of the renal medullae, and disseminated foci of vascular calcifications including aortic valve and arch. Eruption of permanent teeth was delayed, with 8 primary teeth still in place at the age of 12 years and 4 months. The patient suffered a left-sided facial nerve palsy at 13 years of age that was thought possibly to be caused by bony compression. Hearing was not impaired. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16151858" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 TUMORAL CALCINOSIS, FAMILIAL, HYPERPHOSPHATEMIC, 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894344 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894344;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104894344" 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=rs104894344" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In the proband of a consanguineous Arabian family with hyperphosphatemic tumoral calcinosis (HFTC2; <a href="/entry/617993">617993</a>), <a href="#2" class="mim-tip-reference" title="Araya, K., Fukumoto, S., Backenroth, R., Takeuchi, Y., Nakayama, K., Ito, N., Yoshii, N., Yamazaki, Y., Yamashita, T., Silver, J., Igarashi, T., Fujita, T. <strong>A novel mutation in fibroblast growth factor 23 gene as a cause of tumoral calcinosis.</strong> J. Clin. Endocr. Metab. 90: 5523-5527, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16030159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16030159</a>] [<a href="https://doi.org/10.1210/jc.2005-0301" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16030159">Araya et al. (2005)</a> detected homozygosity for a C-to-T transition at codon 129 of FGF23 that resulted in substitution of phenylalanine for serine (S129F). The same mutation was found in the proband's brother; 2 other members of the family who were unavailable for analysis were also affected. Serum FGF23 in the proband was extremely high when measured by C-terminal assay. In contrast, it was low normal by full-length assay. When the mutant FGF23 was expressed in vitro, full-length and N-terminal fragments were barely detectable by Western blotting, whereas a C-terminal fragment with the same molecular weight as that from wildtype FGF23 could be detected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16030159" 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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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11062477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11062477</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11062477" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Araya, K., Fukumoto, S., Backenroth, R., Takeuchi, Y., Nakayama, K., Ito, N., Yoshii, N., Yamazaki, Y., Yamashita, T., Silver, J., Igarashi, T., Fujita, T.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16030159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16030159</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16030159" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia.</strong>
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Hum. Molec. Genet. 14: 385-390, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12414858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12414858</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12414858" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jc.2002-021105" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 08/21/2018
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Cassandra L. Kniffin - updated : 11/11/2010<br>John A. Phillips, III - updated : 5/15/2007<br>Ada Hamosh - updated : 1/23/2007<br>Victor A. McKusick - updated : 2/14/2006<br>Cassandra L. Kniffin - updated : 8/15/2005<br>George E. Tiller - updated : 5/19/2005<br>Marla J. F. O'Neill - updated : 3/4/2004<br>Victor A. McKusick - updated : 5/28/2003<br>John A. Phillips, III - updated : 4/8/2003<br>Patricia A. Hartz - updated : 7/2/2002<br>John A. Phillips, III - updated : 7/27/2001<br>Victor A. McKusick - updated : 6/27/2001
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 10/31/2000
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alopez : 08/21/2018
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carol : 07/11/2018<br>carol : 07/25/2014<br>carol : 7/24/2014<br>carol : 7/23/2014<br>wwang : 11/16/2010<br>ckniffin : 11/11/2010<br>terry : 1/20/2010<br>alopez : 5/15/2007<br>alopez : 1/24/2007<br>terry : 1/23/2007<br>ckniffin : 7/7/2006<br>alopez : 2/28/2006<br>terry : 2/14/2006<br>carol : 9/1/2005<br>carol : 9/1/2005<br>ckniffin : 8/15/2005<br>mgross : 6/23/2005<br>tkritzer : 5/20/2005<br>terry : 5/19/2005<br>tkritzer : 3/8/2004<br>terry : 3/4/2004<br>cwells : 6/5/2003<br>terry : 5/28/2003<br>terry : 5/16/2003<br>carol : 4/14/2003<br>terry : 4/8/2003<br>carol : 10/22/2002<br>tkritzer : 10/18/2002<br>terry : 10/8/2002<br>tkritzer : 9/27/2002<br>carol : 7/2/2002<br>alopez : 3/21/2002<br>terry : 2/4/2002<br>cwells : 10/30/2001<br>alopez : 10/30/2001<br>mgross : 7/27/2001<br>mgross : 7/27/2001<br>cwells : 7/12/2001<br>cwells : 7/9/2001<br>terry : 6/27/2001<br>alopez : 11/1/2000<br>alopez : 10/31/2000
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<span class="mim-font">
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<strong>*</strong> 605380
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FIBROBLAST GROWTH FACTOR 23; FGF23
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<strong><em>HGNC Approved Gene Symbol: FGF23</em></strong>
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<strong>SNOMEDCT:</strong> 237889002;
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Cytogenetic location: 12p13.32
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Genomic coordinates <span class="small">(GRCh38)</span> : 12:4,368,227-4,379,712 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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12p13.32
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Hypophosphatemic rickets, autosomal dominant
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<span class="mim-font">
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193100
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Autosomal dominant
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3
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Tumoral calcinosis, hyperphosphatemic, familial, 2
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617993
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Autosomal recessive
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<span class="mim-font">
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3
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<span class="mim-font">
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<strong>TEXT</strong>
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<h4>
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<strong>Cloning and Expression</strong>
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<p>Using the mouse Fgf23 sequence as query, Yamashita et al. (2000) identified FGF23 in a genomic database. They cloned the full-length cDNA from a placenta library. The deduced 251-amino acid protein contains an N-terminal 24-amino acid signal sequence. FGF23 shares 72% sequence identity with mouse Fgf23, and 24% and 22% identity with human FGF21 (609436) and FGF19 (603891), respectively. By quantitative PCR, Yamashita et al. (2000) found highest expression of Fgf23 in mouse brain and lower expression in thymus. In situ hybridization of mouse brain revealed discrete specific labeling only in the ventrolateral thalamic nucleus. </p><p>The ADHR Consortium (2000) described a positional cloning approach used to identify the gene mutated in patients with autosomal dominant hypophosphatemic rickets (ADHR; 193100). </p>
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<strong>Gene Structure</strong>
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<span class="mim-text-font">
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<p>The ADHR Consortium (2000) demonstrated that the FGF23 gene is composed of 3 exons, spanning 10 kb of genomic sequence. </p>
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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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<span class="mim-text-font">
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<p><strong><em>Crystal Structure</em></strong></p><p>
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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 (604824), the FGFR1c (see 136350) ligand-binding domain, and FGF23. 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>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The ADHR Consortium (2000) found that the FGF23 gene lies 54 kb telomeric of FGF6 (134921) on 12p13. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</div>
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<span class="mim-text-font">
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<p>Tumor-induced osteomalacia is one of the paraneoplastic disorders characterized by hypophosphatemia caused by renal phosphate wasting. The fact that removal of responsible tumors normalizes phosphate metabolism is evidence that a humoral phosphaturic factor, sometimes called phosphatonin (Strewler, 2001), is the basis of tumor-induced osteomalacia. Shimada et al. (2001) cloned and characterized FGF23 as a causative factor of tumor-induced osteomalacia. They found that administration of recombinant FGF23 decreased serum phosphate in mice within 12 hours. When Chinese hamster ovary cells stably expressing FGF23 were subcutaneously implanted into nude mice, hypophosphatemia with increased renal phosphate clearance was observed. Continuous production of FGF23 in these animals reproduced the clinical, biochemical, and histologic features of tumor-induced osteomalacia in vivo. Thus, overproduction of FGF23 causes tumor-induced osteomalacia, whereas mutations in the FGF23 gene result in autosomal hypophosphatemic rickets possibly by preventing proteolytic cleavage, which enhances the biologic activity of FGF23. The mutations in FGF23 found in autosomal dominant hypophosphatemic rickets lie within 3 nucleotides of each other in the proprotein convertase cleavage site. </p><p>White et al. (2001) investigated whether FGF23 is a secreted factor and whether it is abundantly expressed in oncogenic hypophosphatemic osteomalacia (OHO) tumors. After transient transfection of OK-E, COS-7, and HEK293 cells with a plasmid encoding full-length FGF23, all 3 cell lines efficiently secreted 2 protein species that were approximately 32 and 12 kD upon SDS-PAGE analysis and subsequent Western blot analysis using an affinity-purified polyclonal antibody to FGF23. Northern blot analysis using total RNA from 5 OHO tumors revealed high levels of FGF23 mRNA, and Western blot analysis of extracts from a sixth tumor detected the 32-kD FGF23 protein. The authors concluded that FGF23 is a secreted protein, that its mRNA is abundantly expressed by several different OHO tumors, and that it may be the candidate phosphate wasting factor phosphatonin. </p><p>Bowe et al. (2001) found that conditioned medium from COS-7 cells, transfected with either wildtype FGF23 or the FGF23 R179Q mutation (605380.0001), inhibited sodium-dependent phosphate uptake in opossum kidney cells. The R179Q mutant was resistant to degradation by the endopeptidase PHEX (300550), a member of the neutral endopeptidase family of proteins that is mutated in X-linked hypophosphatasia (307800). By RT-PCR, FGF23 was found to be overexpressed in oncogenic osteomalacia but not in other mesenchymal tumors. </p><p>Shimada et al. (2002) showed that FGF23 is cleaved between arg179 and ser180, and that this processing abolished biologic activity of FGF23 to induce hypophosphatemia. Yamazaki et al. (2002) developed sandwich ELISA for human FGF23, using 2 monoclonal antibodies to FGF23. The results indicated that biologically active uncleaved FGF23 is present in normal circulation. In addition, the circulatory level of FGF23 was increased in a patient with tumor-induced rickets/osteomalacia and returned to normal soon after resection of the tumor. The serum level of FGF23 was high in patients with X-linked hypophosphatemic rickets/osteomalacia (307800). The authors suggested that hypophosphatemic rickets/osteomalacia may be caused by excess activity of full-length FGF23. </p><p>Jonsson et al. (2003) showed that FGF23 is readily detectable in the plasma or serum of healthy persons and can be markedly elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, suggesting that this growth factor has a role in phosphate homeostasis. </p><p>Kato et al. (2006) identified GALNT3 (601756) as an enzyme that protects intact FGF23 from proteolytic processing. FGF23 is a phosphaturic protein whose secretion as an intact active form requires O-glycosylation by GALNT3. GALNT3 selectively directs O-glycosylation of FGF23 in a subtilisin-like proprotein convertase (SPC) recognition sequence motif at thr178, which blocks proteolytic processing of FGF23. The findings suggested a novel posttranslational regulatory model of FGF23 involving competing O-glycosylation by GALNT3 and protease processing to produce intact FGF23. Mutations in GALNT3 result in a cleavage of intact FGF23 before secretion, leading to an accumulation of fragmented FGF23 and reduced intact active FGF23. </p><p>Urakawa et al. (2006) demonstrated that a previously undescribed receptor conversion by Klotho (604824) generates the FGF23 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. </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>Molecular Genetics</strong>
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</span>
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<span class="mim-text-font">
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<p><strong><em>Hypophosphatemic Rickets, Autosomal Dominant</em></strong></p><p>
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The ADHR Consortium (2000) identified 3 missense mutations in the FGF23 (see, e.g., 605380.0001-605380.0002) in affected members of 4 unrelated families with autosomal dominant hypophosphatemic rickets (193100). These mutations, which represented the first found in a human FGF gene causing disease, affected 2 arginines that lie only 3 amino acids apart. This finding supported the speculation that the ADHR phenotype is caused by a gain-of-function mechanism. </p><p><strong><em>Hyperphosphatemic Familial Tumoral Calcinosis 2</em></strong></p><p>
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In an individual with familial hyperphosphatemic tumoral calcinosis (HFTC2; 617933), an autosomal recessive disorder characterized by ectopic calcifications and elevated serum phosphate levels, Benet-Pages et al. (2005) identified a homozygous ser71-to-gly (S71G) substitution in the FGF23 gene (605380.0003). Whereas wildtype FGF23 is secreted as an intact protein as well as processed N-terminal and C-terminal fragments, transfection experiments revealed that the mutated protein was only secreted as the C-terminal fragment; the intact protein was retained in the Golgi complex. Benet-Pages et al. (2005) suggested that FGF23 function is decreased by absent or extremely reduced secretion of intact FGF23 and that FGF23 mutations in hypophosphatemic rickets and familial tumoral calcinosis have opposite effects on phosphate homeostasis. </p><p>In a patient with hyperphosphatemic tumoral calcinosis, Chefetz et al. (2005) identified a homozygous missense mutation (M6T; 605380.0004) in the FGF23 gene. </p><p>In 2 affected members of a consanguineous Arabian family with hyperphosphatemic tumoral calcinosis, Araya et al. (2005) identified a homozygous missense mutation (S129F; 605380.0005) in the FGF23 gene. Two other members of the family were affected, but were unavailable for testing. </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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</h4>
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<span class="mim-text-font">
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<p>Shimada et al. (2004) generated Fgf23 -/- mice which exhibited severe growth retardation with an abnormal bone phenotype and markedly short life span, as well as severe hyperphosphatemia, enhanced renal phosphate reabsorption. They also showed high serum 1,25-dihydroxyvitamin D due to increased expression of renal 25-hydroxyvitamin D-1-alpha-hydroxylase. Heterozygotes showed no abnormality in any of the parameters examined, including serum FGF23. Because these phenotypes could not be explained by known regulators of mineral homeostasis, Shimada et al. (2004) concluded that FGF23 is essential for normal phosphate and vitamin D metabolism. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>5 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 HYPOPHOSPHATEMIC RICKETS, AUTOSOMAL DOMINANT</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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FGF23, ARG176GLN
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<br />
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SNP: rs104894347,
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ClinVar: RCV000005328, RCV000254829
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of 2 unrelated families with autosomal dominant hypophosphatemic rickets (193100), the ADHR Consortium (2000) identified a heterozygous 527G-A transition in the FGF23 gene, resulting in an arg176-to-gln (R176Q) substitution. The families had been reported by Bianchine et al. (1971) and Econs and McEnery (1997). </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 HYPOPHOSPHATEMIC RICKETS, AUTOSOMAL DOMINANT</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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FGF23, ARG179TRP
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<br />
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SNP: rs28937882,
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gnomAD: rs28937882,
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ClinVar: RCV000005329, RCV000424624
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with autosomal dominant hypophosphatemic rickets (193100) reported by Rowe et al. (1992), the ADHR Consortium (2000) identified a 535C-T transition in the FGF23 gene, resulting in an arg179-to-trp (R179W) substitution. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 TUMORAL CALCINOSIS, FAMILIAL, HYPERPHOSPHATEMIC, 2</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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FGF23, SER71GLY
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<br />
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SNP: rs104894342,
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gnomAD: rs104894342,
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ClinVar: RCV000005330, RCV000412723, RCV000662354, RCV000984806, RCV005007825
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an individual with tumoral calcinosis with hyperphosphatemia (HFTC2; 617993), Benet-Pages et al. (2005) identified a homozygous 211A-G transition in the FGF23 gene, resulting in a ser71-to-gly (S71G) substitution at an evolutionarily conserved residue. Expression of the mutated protein in HEK293 cells showed that only the C-terminal fragment was secreted, whereas the intact protein was retained in the Golgi complex. Circulating FGF23 in the patient showed a marked increase in the C-terminal fragment. Benet-Pages et al. (2005) suggested that FGF23 function is decreased by absent or extremely reduced secretion of intact FGF23. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0004 TUMORAL CALCINOSIS, FAMILIAL, HYPERPHOSPHATEMIC, 2</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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FGF23, MET96THR
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<br />
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SNP: rs104894343,
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ClinVar: RCV000005331, RCV001528527
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a severe case of tumoral calcinosis (HFTC2; 617993) displaying calcifications of cutaneous and numerous extracutaneous tissues, Chefetz et al. (2005) identified a homozygous T-to-C transition at position 287 of the FGF23 gene that resulted in a met96-to-thr (M96T) amino acid substitution. The M96T mutation affected a highly conserved methionine residue. No direct familial relationship between the parents of the index patient could be established, although they both originated from the same Greek village located near the Turkish border. The patient was first seen at 5 years of age for surgical removal of calcified foci from the oral mucosa. Subsequently, he developed large subcutaneous tumors around his wrists, knees, and ankles. Small calcified deposits were visible at the external border of the lower eyelids. He showed persistent hyperphosphatemia at the age of 13 years. There was sonographic evidence of calcinosis of the renal medullae, and disseminated foci of vascular calcifications including aortic valve and arch. Eruption of permanent teeth was delayed, with 8 primary teeth still in place at the age of 12 years and 4 months. The patient suffered a left-sided facial nerve palsy at 13 years of age that was thought possibly to be caused by bony compression. Hearing was not impaired. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 TUMORAL CALCINOSIS, FAMILIAL, HYPERPHOSPHATEMIC, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
FGF23, SER129PHE
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<br />
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|
SNP: rs104894344,
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|
|
ClinVar: RCV000005332
|
|
|
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|
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In the proband of a consanguineous Arabian family with hyperphosphatemic tumoral calcinosis (HFTC2; 617993), Araya et al. (2005) detected homozygosity for a C-to-T transition at codon 129 of FGF23 that resulted in substitution of phenylalanine for serine (S129F). The same mutation was found in the proband's brother; 2 other members of the family who were unavailable for analysis were also affected. Serum FGF23 in the proband was extremely high when measured by C-terminal assay. In contrast, it was low normal by full-length assay. When the mutant FGF23 was expressed in vitro, full-length and N-terminal fragments were barely detectable by Western blotting, whereas a C-terminal fragment with the same molecular weight as that from wildtype FGF23 could be detected. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
ADHR Consortium.
|
|
<strong>Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23.</strong>
|
|
Nature Genet. 26: 345-348, 2000.
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|
|
[PubMed: 11062477]
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[Full Text: https://doi.org/10.1038/81664]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Araya, K., Fukumoto, S., Backenroth, R., Takeuchi, Y., Nakayama, K., Ito, N., Yoshii, N., Yamazaki, Y., Yamashita, T., Silver, J., Igarashi, T., Fujita, T.
|
|
<strong>A novel mutation in fibroblast growth factor 23 gene as a cause of tumoral calcinosis.</strong>
|
|
J. Clin. Endocr. Metab. 90: 5523-5527, 2005.
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|
[PubMed: 16030159]
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[Full Text: https://doi.org/10.1210/jc.2005-0301]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Benet-Pages, A., Orlik, P., Strom, T. M., Lorenz-Depiereux, B.
|
|
<strong>An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia.</strong>
|
|
Hum. Molec. Genet. 14: 385-390, 2005.
|
|
|
|
|
|
[PubMed: 15590700]
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|
[Full Text: https://doi.org/10.1093/hmg/ddi034]
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</p>
|
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</li>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bianchine, J. W., Stambler, A. A., Harrison, H. E.
|
|
<strong>Familial hypophosphatemic rickets showing autosomal dominant inheritance.</strong>
|
|
Birth Defects Orig. Art. Ser. VII(6): 287-294, 1971.
|
|
|
|
|
|
[PubMed: 5173181]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Bowe, A. E., Finnegan, R., Jan de Beur, S. M., Cho, J., Levine, M. A., Kumar, R., Schiavi, S. C.
|
|
<strong>FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate.</strong>
|
|
Biochem. Biophys. Res. Commun. 284: 977-981, 2001.
|
|
|
|
|
|
[PubMed: 11409890]
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|
|
[Full Text: https://doi.org/10.1006/bbrc.2001.5084]
|
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</p>
|
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</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Chefetz, I., Heller, R., Galli-Tsinopoulou, A., Richard, G., Wollnik, B., Indelman, M., Koerber, F., Topaz, O., Bergman, R., Sprecher, E., Schoenau, E.
|
|
<strong>A novel homozygous missense mutation in FGF23 causes familial tumoral calcinosis associated with disseminated visceral calcification.</strong>
|
|
Hum. Genet. 118: 261-266, 2005.
|
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|
|
[PubMed: 16151858]
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|
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[Full Text: https://doi.org/10.1007/s00439-005-0026-8]
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</p>
|
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</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
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: 29342138]
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|
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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>
|
|
<p class="mim-text-font">
|
|
Econs, M. J., McEnery, P. T.
|
|
<strong>Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder.</strong>
|
|
J. Clin. Endocr. Metab. 82: 674-681, 1997.
|
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|
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|
|
[PubMed: 9024275]
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|
|
[Full Text: https://doi.org/10.1210/jcem.82.2.3765]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Jonsson, K. B., Zahradnik, R., Larsson, T., White, K. E., Sugimoto, T., Imanishi, Y., Yamamoto, T., Hampson, G., Koshiyama, H., Ljunggren, O., Oba, K., Yang, I. M., Miyauchi, A., Econs, M. J., Lavigne, J., Juppner, H.
|
|
<strong>Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia.</strong>
|
|
New Eng. J. Med. 348: 1656-1663, 2003.
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|
|
[PubMed: 12711740]
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|
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|
|
[Full Text: https://doi.org/10.1056/NEJMoa020881]
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</p>
|
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</li>
|
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<li>
|
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<p class="mim-text-font">
|
|
Kato, K., Jeanneau, C., Tarp, M. A., Benet-Pages, A., Lorenz-Depiereux, B., Bennett, E. P., Mandel, U., Strom, T. M., Clausen, H.
|
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<strong>Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation.</strong>
|
|
J. Biol. Chem. 281: 18370-18377, 2006.
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|
|
[PubMed: 16638743]
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|
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[Full Text: https://doi.org/10.1074/jbc.M602469200]
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</p>
|
|
</li>
|
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|
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<li>
|
|
<p class="mim-text-font">
|
|
Rowe, P. S. N., Read, A. P., Mountford, R., Benham, F., Kruse, T. A., Camerino, G., Davies, K. E., O'Riordan, J. L. H.
|
|
<strong>Three DNA markers for hypophosphataemic rickets.</strong>
|
|
Hum. Genet. 89: 539-542, 1992.
|
|
|
|
|
|
[PubMed: 1353055]
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|
|
|
|
[Full Text: https://doi.org/10.1007/BF00219180]
|
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</p>
|
|
</li>
|
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|
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<li>
|
|
<p class="mim-text-font">
|
|
Shimada, T., Kakitani, M., Yamazaki, Y., Hasegawa, H., Takeuchi, Y., Fujita, T., Fukumoto, S., Tomizuka, K., Yamashita, T.
|
|
<strong>Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism.</strong>
|
|
J. Clin. Invest. 113: 561-568, 2004.
|
|
|
|
|
|
[PubMed: 14966565]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1172/JCI19081]
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Shimada, T., Mizutani, S., Muto, T., Yoneya, T., Hino, R., Takeda, S., Takeuchi, Y., Fujita, T., Fukumoto, S., Yamashita, T.
|
|
<strong>Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia.</strong>
|
|
Proc. Nat. Acad. Sci. 98: 6500-6505, 2001.
|
|
|
|
|
|
[PubMed: 11344269]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.101545198]
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Shimada, T., Muto, T., Urakawa, I., Yoneya, T., Yamazaki, Y., Okawa, K., Takeuchi, Y., Fujita, T., Fukumoto, S., Yamashita, T.
|
|
<strong>Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo.</strong>
|
|
Endocrinology 143: 3179-3182, 2002.
|
|
|
|
|
|
[PubMed: 12130585]
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|
|
|
|
|
[Full Text: https://doi.org/10.1210/endo.143.8.8795]
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</p>
|
|
</li>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Strewler, G. J.
|
|
<strong>FGF23, hypophosphatemia, and rickets: has phosphorylation been found? (Commentary)</strong>
|
|
Proc. Nat. Acad. Sci. 98: 5945-5946, 2001.
|
|
|
|
|
|
[PubMed: 11371627]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.111154898]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
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: 17086194]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature05315]
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
White, K. E., Jonsson, K. B., Carn, G., Hampson, G., Spector, T. D., Mannstadt, M., Lorenz-Depiereux, B., Miyauchi, A., Yang, I. M., Ljunggren, O., Meitinger, T., Strom, T. M., Juppner, H., Econs, M. J.
|
|
<strong>The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting.</strong>
|
|
J. Clin. Endocr. Metab. 86: 497-500, 2001.
|
|
|
|
|
|
[PubMed: 11157998]
|
|
|
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|
|
[Full Text: https://doi.org/10.1210/jcem.86.2.7408]
|
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|
</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Yamashita, T., Yoshioka, M., Itoh, N.
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<strong>Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain.</strong>
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Biochem. Biophys. Res. Commun. 277: 494-498, 2000.
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[PubMed: 11032749]
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[Full Text: https://doi.org/10.1006/bbrc.2000.3696]
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Yamazaki, Y., Okazaki, R., Shibata, M., Hasegawa, Y., Satoh, K., Tajima, T., Takeuchi, Y., Fujita, T., Nakahara, K., Yamashita, T., Fukumoto, S.
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<strong>Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia.</strong>
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J. Clin. Endocr. Metab. 87: 4957-4960, 2002.
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[PubMed: 12414858]
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[Full Text: https://doi.org/10.1210/jc.2002-021105]
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Ada Hamosh - updated : 08/21/2018<br>Cassandra L. Kniffin - updated : 11/11/2010<br>John A. Phillips, III - updated : 5/15/2007<br>Ada Hamosh - updated : 1/23/2007<br>Victor A. McKusick - updated : 2/14/2006<br>Cassandra L. Kniffin - updated : 8/15/2005<br>George E. Tiller - updated : 5/19/2005<br>Marla J. F. O'Neill - updated : 3/4/2004<br>Victor A. McKusick - updated : 5/28/2003<br>John A. Phillips, III - updated : 4/8/2003<br>Patricia A. Hartz - updated : 7/2/2002<br>John A. Phillips, III - updated : 7/27/2001<br>Victor A. McKusick - updated : 6/27/2001
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Victor A. McKusick : 10/31/2000
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