5089 lines
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Entry
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- *300550 - PHOSPHATE-REGULATING ENDOPEPTIDASE, X-LINKED; PHEX
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*300550</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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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="#molecularGenetics">Molecular Genetics</a>
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<a href="#nomenclature">Nomenclature</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/300550">Table View</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div 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=ENSG00000102174;t=ENST00000379374" 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=5251" 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=300550" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000102174;t=ENST00000379374" 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_000444,NM_001282754,XM_011545533,XM_011545536,XM_017029579,XM_024452390,XM_047442159" 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_000444" 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=300550" 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=02387&isoform_id=02387_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/PHEX" 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/1381816,1707524,1778836,1815789,1834505,1842090,1843529,1929857,2499917,4164133,85397918,85397920,90403592,119619393,194376938,194385942,194388728,268416832,311643737,544346322,768032502,768032511,1034674492,1370517236,2217392577,2462629722,2462629724,2462629726,2462629728,2462629730" 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/P78562" 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=5251" 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=ENSG00000102174;t=ENST00000379374" 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=PHEX" 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=PHEX" 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+5251" 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/PHEX" 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:5251" 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/5251" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chrX&hgg_gene=ENST00000379374.5&hgg_start=22032325&hgg_end=22251310&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:8918" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/phex" 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=300550[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=300550[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/PHEX/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000102174" 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=PHEX" 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=PHEX" 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=PHEX" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.phexdb.mcgill.ca" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=PHEX&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/PA33258" 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:8918" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0029843.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:107489" 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/PHEX#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:107489" 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/5251/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=5251" 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://wormbase.org/db/gene/gene?name=WBGene00020230;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030103-2" 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="mimCellLines">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" 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="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</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="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:300550" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
|
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</div>
|
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</a>
|
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</span>
|
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</span>
|
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</div>
|
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=PHEX&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
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300550
|
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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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PHOSPHATE-REGULATING ENDOPEPTIDASE, X-LINKED; PHEX
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</span>
|
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
PHOSPHATE-REGULATING ENDOPEPTIDASE HOMOLOG, X-LINKED<br />
|
|
PEX
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
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<br />
|
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=PHEX" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PHEX</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">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/X/115?start=-3&limit=10&highlight=115">Xp22.11</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:22032325-22251310&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">X:22,032,325-22,251,310</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
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|
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</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<br />
|
|
</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/X/115?start=-3&limit=10&highlight=115">
|
|
Xp22.11
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Hypophosphatemic rickets, X-linked dominant
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/307800"> 307800 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked dominant">XLD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</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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<p>The <a href="#26" class="mim-tip-reference" title="HYP Consortium. <strong>A gene (HYP) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets.</strong> Nature Genet. 11: 130-136, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550339</a>] [<a href="https://doi.org/10.1038/ng1095-130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550339">HYP Consortium (1995)</a>, comprising 29 investigators in 5 institutions, isolated a candidate gene for X-linked hypophosphatemic rickets (<a href="/entry/307800">307800</a>) from the Xp22.1 region by positional cloning. The gene exhibited homology to a family of endopeptidase genes, members of which are involved in the degradation or activation of a variety of peptide hormones, including neutral endopeptidase (NEP; <a href="/entry/120520">120520</a>), endothelin-converting enzyme (ECE1; <a href="/entry/600423">600423</a>), and Kell blood group antigen (<a href="/entry/613883">613883</a>). Because of the homology and the function of the gene, the authors referred to it as PEX ('phosphate regulating gene with homologies to endopeptidases, on the X chromosome'). A partial PHEX sequence corresponding to 638 amino acids was presented. The PHEX cDNA was found to be evolutionarily conserved in primate, bovine, mouse, and hamster DNA, and possibly in chicken DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7550339" 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="#24" class="mim-tip-reference" title="Guo, R., Quarles, L. D. <strong>Cloning and sequencing of human PEX from a bone cDNA library: evidence for its developmental stage-specific regulation in osteoblasts.</strong> J. Bone Miner. Res. 12: 1009-1017, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9199999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9199999</a>] [<a href="https://doi.org/10.1359/jbmr.1997.12.7.1009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9199999">Guo and Quarles (1997)</a> isolated a human PHEX cDNA from a bone cDNA library. The deduced 749-amino acid protein has a molecular mass of 86.5 kD and shares 96% identity to the mouse sequence. The PHEX protein is predicted to have a 20-residue N-terminal cytoplasmic tail, a 27-residue transmembrane domain, and a 702-residue extracellular C-terminal region. The protein belongs to the type II integral membrane zinc-dependent endopeptidase family. PHEX transcripts were identified in human osteosarcoma-derived cells and in differentiated mouse osteoblasts, but not in immature mouse preosteoblasts, indicating stage-specific expression. <a href="#24" class="mim-tip-reference" title="Guo, R., Quarles, L. D. <strong>Cloning and sequencing of human PEX from a bone cDNA library: evidence for its developmental stage-specific regulation in osteoblasts.</strong> J. Bone Miner. Res. 12: 1009-1017, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9199999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9199999</a>] [<a href="https://doi.org/10.1359/jbmr.1997.12.7.1009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9199999">Guo and Quarles (1997)</a> suggested that PHEX may play a role in osteoblast-mediated bone mineralization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9199999" 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="#23" class="mim-tip-reference" title="Grieff, M., Mumm, S., Waeltz, P., Mazzarella, R., Whyte, M. P., Thakker, R. V., Schlessinger, D. <strong>Expression and cloning of the human X-linked hypophosphatemia gene cDNA.</strong> Biochem. Biophys. Res. Commun. 231: 635-639, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9070861/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9070861</a>] [<a href="https://doi.org/10.1006/bbrc.1997.6153" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9070861">Grieff et al. (1997)</a> isolated human PHEX clones from an ovary cDNA library. The gene encodes a 749-amino acid polypeptide that is 96% identical to the murine Phex gene product and has significant homology to other members of the membrane-bound zinc metallopeptidase family. Northern blot analysis identified a 6.6-kb PHEX mRNA transcript at high levels in adult ovary and fetal lung and at lower levels in adult lung and fetal liver. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9070861" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Du, L., Desbarats, M., Viel, J., Glorieux, F. H., Cawthorn, C., Ecarot, B. <strong>cDNA cloning of the murine Pex gene implicated in X-linked hypophosphatemia and evidence for expression in bone.</strong> Genomics 36: 22-28, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8812412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8812412</a>] [<a href="https://doi.org/10.1006/geno.1996.0421" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8812412">Du et al. (1996)</a> reported the isolation and characterization of the complete open reading frame of the mouse Phex gene. The deduced 749-amino acid protein showed 95% identity to the available human PHEX sequence and significant homology to members of the membrane-bound metalloendopeptidase family. Northern blot analysis revealed a 6.6-kb mRNA transcript in bone and in cultured osteoblasts from normal mice; the transcript was not detectable in samples from the mutant 'Hyp' mouse but were detectable in Hyp bone by RT-PCR amplification. <a href="#3" class="mim-tip-reference" title="Beck, L., Soumounou, Y., Martel, J., Krishnamurthy, G., Gauthier, C., Goodyer, C. G., Tenenhouse, H. S. <strong>Pex/PEX tissue distribution and evidence for a deletion in the 3-prime region of the Pex gene in X-linked hypophosphatemic mice.</strong> J. Clin. Invest. 99: 1200-1209, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9077527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9077527</a>] [<a href="https://doi.org/10.1172/JCI119276" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9077527">Beck et al. (1997)</a> cloned mouse Phex and human PHEX cDNAs encoding part of the 5-prime untranslated region, the protein coding region, and the entire 3-prime untranslated region. Using RT-PCR and ribonuclease protection assays, they found that Phex/PHEX mRNA is expressed predominantly in human fetal and in adult mouse calvaria and long bone. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9077527+8812412" 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="#25" class="mim-tip-reference" title="Holm, I. A., Huang, X., Kunkel, L. M. <strong>Mutational analysis of the PEX gene in patients with X-linked hypophosphatemic rickets.</strong> Am. J. Hum. Genet. 60: 790-797, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9106524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9106524</a>]" pmid="9106524">Holm et al. (1997)</a> determined that the PHEX gene contains 18 exons. Its genomic organization shares similarity with members of the family of neutral endopeptidases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9106524" 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 3 unrelated patients with X-linked hypophosphatemic rickets (XLHRD; <a href="/entry/307800">307800</a>), the <a href="#26" class="mim-tip-reference" title="HYP Consortium. <strong>A gene (HYP) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets.</strong> Nature Genet. 11: 130-136, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550339</a>] [<a href="https://doi.org/10.1038/ng1095-130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550339">HYP Consortium (1995)</a> identified 3 different mutations in the PHEX gene (<a href="#0001">300550.0001</a>-<a href="#0003">300550.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7550339" 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="#25" class="mim-tip-reference" title="Holm, I. A., Huang, X., Kunkel, L. M. <strong>Mutational analysis of the PEX gene in patients with X-linked hypophosphatemic rickets.</strong> Am. J. Hum. Genet. 60: 790-797, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9106524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9106524</a>]" pmid="9106524">Holm et al. (1997)</a> identified mutations in the PHEX gene in 9 of 22 unrelated patients with X-linked hypophosphatemic rickets: 3 nonsense mutations, a 1-bp deletion leading to a frameshift, a donor-splice site mutation, and missense mutations in 4 patients (see, e.g., <a href="#0004">300550.0004</a>-<a href="#0006">300550.0006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9106524" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Dixon, P. H., Christie, P. T., Wooding, C., Trump, D., Grieff, M., Holm, I., Gertner, J. M., Schmidtke, J., Shah, B., Shaw, N., Smith, C., Tau, C., Schlessinger, D., Whyte, M. P., Thakker, R. V. <strong>Mutational analysis of PHEX gene in X-linked hypophosphatemia.</strong> J. Clin. Endocr. Metab. 83: 3615-3623, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9768674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9768674</a>] [<a href="https://doi.org/10.1210/jcem.83.10.5180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9768674">Dixon et al. (1998)</a> identified a total of 31 mutations in the PHEX gene in 46 unrelated XLH kindreds and 22 unrelated patients with nonfamilial XLH. Thirty of the mutations were scattered throughout the putative extracellular domain. <a href="#13" class="mim-tip-reference" title="Dixon, P. H., Christie, P. T., Wooding, C., Trump, D., Grieff, M., Holm, I., Gertner, J. M., Schmidtke, J., Shah, B., Shaw, N., Smith, C., Tau, C., Schlessinger, D., Whyte, M. P., Thakker, R. V. <strong>Mutational analysis of PHEX gene in X-linked hypophosphatemia.</strong> J. Clin. Endocr. Metab. 83: 3615-3623, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9768674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9768674</a>] [<a href="https://doi.org/10.1210/jcem.83.10.5180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9768674">Dixon et al. (1998)</a> also identified 6 PHEX polymorphisms that had heterozygosity frequencies ranging from less than 1% to 43%. Over 20% of the mutations were observed in nonfamilial XLH patients, who represented de novo occurrences of PHEX mutations. The majority (over 70%) of the mutations were predicted to result in a functional loss of the PHEX protein, rather than haploinsufficiency or a dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9768674" 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="#19" class="mim-tip-reference" title="Filisetti, D., Ostermann, G., von Bredow, M., Strom, T., Filler, G., Ehrich, J., Pannetier, S., Garnier, J.-M., Rowe, P., Francis, F., Julienne, A., Hanauer, A., Econs, M. J., Oudet, C. <strong>Non-random distribution of mutations in the PHEX gene, and under-detected missense mutations at non-conserved residues.</strong> Europ. J. Hum. Genet. 7: 615-619, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10439971/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10439971</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10439971">Filisetti et al. (1999)</a> reported 30 newly detected mutations in the PHEX gene, and pooled findings with all previously published mutations. The spectrum of the mutations displayed 16% deletions, 8% insertions, 34% missense, 27% nonsense, and 15% splice site mutations, with peaks in exons 15 and 17. Since 32.8% of PHEX amino acids are conserved in the family of the endopeptidases, the number of missense mutations detected at nonconserved residues was smaller than expected, whereas the number of nonsense mutations observed at nonconserved residues was very close to the expected number. Compared with conserved amino acids, the changes in nonconserved amino acids may result in benign polymorphisms or possibly mild disease that may go undiagnosed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10439971" 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="#39" class="mim-tip-reference" title="Sabbagh, Y., Jones, A. O., Tenenhouse, H. S. <strong>PHEXdb, a locus-specific database for mutations causing X-linked hypophosphatemia.</strong> Hum. Mutat. 16: 1-6, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10874297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10874297</a>] [<a href="https://doi.org/10.1002/1098-1004(200007)16:1<1::AID-HUMU1>3.0.CO;2-J" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10874297">Sabbagh et al. (2000)</a> stated that 131 HYP-causing mutations in the PHEX gene had been reported. They announced the creation of an online PHEX mutation database for the collection and distribution of information on PHEX mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10874297" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Sabbagh, Y., Boileau, G., DesGroseillers, L., Tenenhouse, H. S. <strong>Disease-causing missense mutations in the PHEX gene interfere with membrane targeting of the recombinant protein.</strong> Hum. Molec. Genet. 10: 1539-1546, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11468271/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11468271</a>] [<a href="https://doi.org/10.1093/hmg/10.15.1539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11468271">Sabbagh et al. (2001)</a> examined the effect of PHEX missense mutations on cellular trafficking of the recombinant protein. Four mutant PHEX cDNAs were generated by PCR mutagenesis (e.g., E581V). Three of the mutants were completely sensitive to endoglycosidase H digestion, indicating that they were not fully glycosylated. Sequestration of the disease-causing mutant proteins in the endoplasmic reticulum and plasma membrane localization of wildtype PHEX proteins was demonstrated by immunofluorescence and cell surface biotinylation. <a href="#36" class="mim-tip-reference" title="Sabbagh, Y., Boileau, G., Campos, M., Carmona, A. K., Tenenhouse, H. S. <strong>Structure and function of disease-causing missense mutations in the PHEX gene.</strong> J. Clin. Endocr. Metab. 88: 2213-2222, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12727977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12727977</a>] [<a href="https://doi.org/10.1210/jc.2002-021809" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12727977">Sabbagh et al. (2003)</a> assessed the impact of 9 PHEX missense mutations on cellular trafficking, endopeptidase activity, and protein conformation. Eight mutations had been identified in XLH patients; the remaining mutation, E581V, had been engineered in NEP (<a href="/entry/120520">120520</a>), to which PHEX shows significant homology, where it was shown to abolish catalytic activity but not interfere with cell surface localization of the recombinant protein (<a href="#12" class="mim-tip-reference" title="Devault, A., Nault, C., Zollinger, M., Fournie-Zaluski, M.-C., Roques, B. P., Crine, P., Boileau, G. <strong>Expression of neutral endopeptidase (enkephalinase) in heterologous COS-1 cells: characterization of the recombinant enzyme and evidence for a glutamic acid residue at the active site.</strong> J. Biol. Chem. 263: 4033-4040, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2894375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2894375</a>]" pmid="2894375">Devault et al., 1988</a>). The authors demonstrated that some mutations in secreted PHEX abrogate catalytic activity, whereas others alter the trafficking and conformation of the protein, thus providing a mechanism whereby missense mutations result in loss of function of the PHEX protein. Endopeptidase activity of secreted and rescued PHEX proteins was assessed using a novel internally quenched fluorogenic peptide substrate. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12727977+11468271+2894375" 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="#21" class="mim-tip-reference" title="Gaucher, C., Walrant-Debray, O., Nguyen, T.-M., Esterle, L., Garabedian, M., Jehan, F. <strong>PHEX analysis in 118 pedigrees reveals new genetic clues in hypophosphatemic rickets.</strong> Hum. Genet. 125: 401-411, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19219621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19219621</a>] [<a href="https://doi.org/10.1007/s00439-009-0631-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19219621">Gaucher et al. (2009)</a> analyzed the PHEX gene in 118 probands with hypophosphatemic rickets and identified mutations in 49 (87%) of 56 familial cases and 44 (73%) of 60 known sporadic cases. Of the 78 different mutations identified, 16 were missense mutations, which all occurred at residues that are highly conserved in mammals. Plotting all reported PHEX missense mutations on a 3D protein model revealed that missense mutations are primarily located in 2 regions in the inner part of the PHEX protein; similar plotting of nonsense mutations showed a random distribution. One patient with late-onset disease was found to have a mutation in an intronic region of PHEX, 2 bp away from the splice site consensus sequence, confirming that late-onset disease is part of the spectrum of X-linked dominant hypophosphatemic rickets. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19219621" 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 mother and her son and 2 daughters with X-linked hypophosphatemic rickets, <a href="#1" class="mim-tip-reference" title="Alhamoudi, K. M., Alghamdi, B., Alswailem, M., Nasir, A., Aljomaiah, A., Al-Hindi, H., Alzahrani, A. S. <strong>A unique mechanism of a novel synonymous PHEX variant causing X-linked hypophosphatemia.</strong> J. Clin. Endocr. Metab. 107: 2883-2891, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35896147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35896147</a>] [<a href="https://doi.org/10.1210/clinem/dgac435" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35896147">Alhamoudi et al. (2022)</a> identified a c.1701A-C transversion (<a href="/entry/148060#0012">148060.0012</a>) at the first nucleotide of exon 17 of the PHEX gene, resulting in a synonymous alteration in the protein (R567R). Using RT-PCR, the authors showed that the variant interfered with splicing of exon 16 with 17, resulting in a shorter PHEX transcript compared to controls. Sanger sequencing of the cDNA showed complete skipping of exon 17 and direct splicing of exons 16 and 18, resulting in a frameshift and premature stop codon. The authors predicted that this led to loss of 2 conserved zinc-binding sites in exons 17 and 19, with loss of normal protein function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35896147" 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 PEX nomenclature conflicts with the use of the same symbol for multiple peroxisomal proteins (peroxins) numbered 1 to 12 or more, e.g., PEX5 (<a href="/entry/600414">600414</a>). The gene symbol PHEX has much to recommend it (<a href="#13" class="mim-tip-reference" title="Dixon, P. H., Christie, P. T., Wooding, C., Trump, D., Grieff, M., Holm, I., Gertner, J. M., Schmidtke, J., Shah, B., Shaw, N., Smith, C., Tau, C., Schlessinger, D., Whyte, M. P., Thakker, R. V. <strong>Mutational analysis of PHEX gene in X-linked hypophosphatemia.</strong> J. Clin. Endocr. Metab. 83: 3615-3623, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9768674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9768674</a>] [<a href="https://doi.org/10.1210/jcem.83.10.5180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9768674">Dixon et al., 1998</a>; <a href="#19" class="mim-tip-reference" title="Filisetti, D., Ostermann, G., von Bredow, M., Strom, T., Filler, G., Ehrich, J., Pannetier, S., Garnier, J.-M., Rowe, P., Francis, F., Julienne, A., Hanauer, A., Econs, M. J., Oudet, C. <strong>Non-random distribution of mutations in the PHEX gene, and under-detected missense mutations at non-conserved residues.</strong> Europ. J. Hum. Genet. 7: 615-619, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10439971/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10439971</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10439971">Filisetti et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10439971+9768674" 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="#18" class="mim-tip-reference" title="Eicher, E. M., Southard, J. L., Scriver, C. R., Glorieux, F. H. <strong>Hypophosphatemia: mouse model for human familial hypophosphatemic (vitamin D-resistant) rickets.</strong> Proc. Nat. Acad. Sci. 73: 4667-4671, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/188049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">188049</a>] [<a href="https://doi.org/10.1073/pnas.73.12.4667" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="188049">Eicher et al. (1976)</a> observed a mouse model for X-linked hypophosphatemia, designated Hyp. Hyp mice have bone changes resembling rickets, dwarfism, and high fractional excretion of phosphate ion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=188049" 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>By various transplantation experiments, <a href="#16" class="mim-tip-reference" title="Ecarot-Charrier, B., Glorieux, F. H., Travers, R., Desbarats, M., Bouchard, F., Hinek, A. <strong>Defective bone formation by transplanted Hyp mouse bone cells into normal mice.</strong> Endocrinology 123: 768-773, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3293983/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3293983</a>] [<a href="https://doi.org/10.1210/endo-123-2-768" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3293983">Ecarot-Charrier et al. (1988)</a> demonstrated an intrinsic defect in osteoblasts in the Hyp mouse. <a href="#4" class="mim-tip-reference" title="Bell, C. L., Tenenhouse, H. S., Scriver, C. R. <strong>Primary cultures of renal epithelial cells from X-linked hypophosphatemic (Hyp) mice express defects in phosphate transport and vitamin D metabolism.</strong> Am. J. Hum. Genet. 43: 293-303, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3414685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3414685</a>]" pmid="3414685">Bell et al. (1988)</a> reported that primary cultures of renal epithelial cells from the Hyp mouse demonstrate a defect in phosphate transport and vitamin D metabolism, suggesting a defect intrinsic to the kidney. However, in cross-transplantation studies of kidneys in normal and Hyp mice, <a href="#34" class="mim-tip-reference" title="Nesbitt, T., Coffman, T. M., Griffiths, R., Drezner, M. K. <strong>Crosstransplantation of kidneys in normal and Hyp mice: evidence that the Hyp mouse phenotype is unrelated to an intrinsic renal defect.</strong> J. Clin. Invest. 89: 1453-1459, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1569185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1569185</a>] [<a href="https://doi.org/10.1172/JCI115735" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1569185">Nesbitt et al. (1992)</a> found that the Hyp phenotype was neither transferred nor corrected by renal transplantation, suggesting that the kidney was not the target organ for the genetic abnormality. <a href="#34" class="mim-tip-reference" title="Nesbitt, T., Coffman, T. M., Griffiths, R., Drezner, M. K. <strong>Crosstransplantation of kidneys in normal and Hyp mice: evidence that the Hyp mouse phenotype is unrelated to an intrinsic renal defect.</strong> J. Clin. Invest. 89: 1453-1459, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1569185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1569185</a>] [<a href="https://doi.org/10.1172/JCI115735" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1569185">Nesbitt et al. (1992)</a> postulated that the disorder in the mouse, and probably in the human, is the result of a humoral factor and is not an intrinsic renal abnormality. <a href="#34" class="mim-tip-reference" title="Nesbitt, T., Coffman, T. M., Griffiths, R., Drezner, M. K. <strong>Crosstransplantation of kidneys in normal and Hyp mice: evidence that the Hyp mouse phenotype is unrelated to an intrinsic renal defect.</strong> J. Clin. Invest. 89: 1453-1459, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1569185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1569185</a>] [<a href="https://doi.org/10.1172/JCI115735" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1569185">Nesbitt et al. (1992)</a> suggested the presence of a unique hormonal effect that results in a blockade of, or failure to express, an essential gene function in a variety of cell types. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3293983+1569185+3414685" 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>Parabiosis (<a href="#33" class="mim-tip-reference" title="Meyer, R. A., Jr., Meyer, M. H., Gray, R. W. <strong>Parabiosis suggests a humoral factor is involved in X-linked hypophosphatemia in mice.</strong> J. Bone Miner. Res. 4: 493-500, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2816498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2816498</a>] [<a href="https://doi.org/10.1002/jbmr.5650040407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2816498">Meyer et al., 1989</a>) and renal transplantation (<a href="#34" class="mim-tip-reference" title="Nesbitt, T., Coffman, T. M., Griffiths, R., Drezner, M. K. <strong>Crosstransplantation of kidneys in normal and Hyp mice: evidence that the Hyp mouse phenotype is unrelated to an intrinsic renal defect.</strong> J. Clin. Invest. 89: 1453-1459, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1569185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1569185</a>] [<a href="https://doi.org/10.1172/JCI115735" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1569185">Nesbitt et al., 1992</a>) experiments demonstrated that the renal defect in brush border membrane sodium-dependent phosphate transport in Hyp mice is not intrinsic to the kidney, but rather depends on a circulating humoral factor, which is not parathyroid hormone (<a href="#33" class="mim-tip-reference" title="Meyer, R. A., Jr., Meyer, M. H., Gray, R. W. <strong>Parabiosis suggests a humoral factor is involved in X-linked hypophosphatemia in mice.</strong> J. Bone Miner. Res. 4: 493-500, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2816498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2816498</a>] [<a href="https://doi.org/10.1002/jbmr.5650040407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2816498">Meyer et al., 1989</a>), for its expression. In Hyp mice, <a href="#42" class="mim-tip-reference" title="Tenenhouse, H. S., Werner, A., Biber, J., Ma, S., Martel, J., Roy, S., Murer, H. <strong>Renal Na(+)-phosphate cotransport in murine X-linked hypophosphatemic rickets: molecular characterization.</strong> J. Clin. Invest. 93: 671-676, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8113402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8113402</a>] [<a href="https://doi.org/10.1172/JCI117019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8113402">Tenenhouse et al. (1994)</a> demonstrated that the specific reduction in renal sodium-phosphate cotransport in brush border membranes could be ascribed to a proportionate decrease in the abundance of kidney NPT2 (<a href="/entry/182309">182309</a>) cotransporter mRNA and protein. However, the NPT2 gene is located on chromosome 5 and, hence, cannot be the site of the mutation primarily responsible for hereditary hypophosphatemia. <a href="#42" class="mim-tip-reference" title="Tenenhouse, H. S., Werner, A., Biber, J., Ma, S., Martel, J., Roy, S., Murer, H. <strong>Renal Na(+)-phosphate cotransport in murine X-linked hypophosphatemic rickets: molecular characterization.</strong> J. Clin. Invest. 93: 671-676, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8113402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8113402</a>] [<a href="https://doi.org/10.1172/JCI117019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8113402">Tenenhouse et al. (1994)</a> suggested that the X-linked gene may encode the postulated circulating humoral factor that regulates the renal sodium-phosphate cotransporter. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8113402+2816498+1569185" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Beck, L., Soumounou, Y., Martel, J., Krishnamurthy, G., Gauthier, C., Goodyer, C. G., Tenenhouse, H. S. <strong>Pex/PEX tissue distribution and evidence for a deletion in the 3-prime region of the Pex gene in X-linked hypophosphatemic mice.</strong> J. Clin. Invest. 99: 1200-1209, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9077527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9077527</a>] [<a href="https://doi.org/10.1172/JCI119276" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9077527">Beck et al. (1997)</a> discovered a large deletion in the 3-prime region of the Phex gene in the Hyp mouse. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9077527" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Baum, M., Loleh, S., Saini, N., Seikaly, M., Dwarakanath, V., Quigley, R. <strong>Correction of proximal tubule phosphate transport defect in Hyp mice in vivo and in vitro with indomethacin.</strong> Proc. Nat. Acad. Sci. 100: 11098-11103, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12953100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12953100</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12953100[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.1834060100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12953100">Baum et al. (2003)</a> demonstrated that Hyp mice have a 2-fold greater urinary prostaglandin E2 (PGE2) excretion than wildtype mice. To determine whether prostaglandins were involved in the pathogenesis of this disorder, Hyp and wildtype C57/B6 mice received intraperitoneal injections with vehicle or indomethacin and were studied approximately 12 hours after the last dose of indomethacin. In the Hyp mice, indomethacin decreased the fractional excretion of phosphate and increased serum phosphate. There was no effect of indomethacin in the wildtype mice. Indomethacin did not affect serum creatine or inulin clearance, demonstrating that the normalization of urinary phosphate excretion was not caused by changes in glomerular filtration rate. Indomethacin treatment increased renal brush border membrane vesicle NaPi2 protein abundance in Hyp mice to levels comparable to that of wildtype mice. <a href="#2" class="mim-tip-reference" title="Baum, M., Loleh, S., Saini, N., Seikaly, M., Dwarakanath, V., Quigley, R. <strong>Correction of proximal tubule phosphate transport defect in Hyp mice in vivo and in vitro with indomethacin.</strong> Proc. Nat. Acad. Sci. 100: 11098-11103, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12953100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12953100</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12953100[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.1834060100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12953100">Baum et al. (2003)</a> concluded that there is dysregulation of renal prostaglandin metabolism in Hyp mice, and that indomethacin treatment normalizes the urinary excretion of phosphate by a direct tubular effect. These studies suggested that indomethacin may be an effective form of therapy in humans with X-linked hypophosphatemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12953100" 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="#28" class="mim-tip-reference" title="Lorenz-Depiereux, B., Guido, V. E., Johnson, K. R., Zheng, Q. Y., Gagnon, L. H., Bauschatz, J. D., Davisson, M. T., Washburn, L. L., Donahue, L. R., Strom, T. M., Eicher, E. M. <strong>New intragenic deletions in the Phex gene clarify X-linked hypophosphatemia-related abnormalities in mice.</strong> Mammalian Genome 15: 151-161, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15029877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15029877</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15029877[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/10.1007/s00335-003-2310-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15029877">Lorenz-Depiereux et al. (2004)</a> studied 2 spontaneous mutations in the mouse Phex gene, Hyp-2J, a 7.3-kb deletion containing exon 15, and Hyp-Duk, a 30-kb deletion containing exons 13 and 14. Both mutations caused similar phenotypes in males, including shortened hind legs and tail, a shortened square trunk, hypophosphatemia, hypocalcemia, and rachitic bone disease. Hyp-Duk males also exhibited background-dependent variable expression of deafness, circling behavior, and cranial dysmorphology. Both Hyp-2J and Hyp-Duk males had thickened temporal bone surrounding the cochlea and a precipitate in the scala tympani, but only the hearing-impaired Hyp-Duk mice had degeneration of the organ of Corti and spiral ganglion. <a href="#28" class="mim-tip-reference" title="Lorenz-Depiereux, B., Guido, V. E., Johnson, K. R., Zheng, Q. Y., Gagnon, L. H., Bauschatz, J. D., Davisson, M. T., Washburn, L. L., Donahue, L. R., Strom, T. M., Eicher, E. M. <strong>New intragenic deletions in the Phex gene clarify X-linked hypophosphatemia-related abnormalities in mice.</strong> Mammalian Genome 15: 151-161, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15029877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15029877</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15029877[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/10.1007/s00335-003-2310-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15029877">Lorenz-Depiereux et al. (2004)</a> noted that XLH phenotypes could now be separated from non-XLH-related phenotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15029877" 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>During development and postnatal growth of the endochondral skeleton, proliferative chondrocytes differentiate into hypertrophic chondrocytes, which subsequently undergo apoptosis and are replaced by bone. <a href="#14" class="mim-tip-reference" title="Donohue, M. M., Demay, M. B. <strong>Rickets in VDR null mice is secondary to decreased apoptosis of hypertrophic chondrocytes.</strong> Endocrinology 143: 3691-3694, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12193585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12193585</a>] [<a href="https://doi.org/10.1210/en.2002-220454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12193585">Donohue and Demay (2002)</a> found that mice with rickets due to ablation of the vitamin D receptor (VDR; <a href="/entry/601769">601769</a>) had expansion of hypertrophic chondrocytes due to impaired apoptosis of these cells. <a href="#38" class="mim-tip-reference" title="Sabbagh, Y., Carpenter, T. O., Demay, M. B. <strong>Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes.</strong> Proc. Nat. Acad. Sci. 102: 9637-9642, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15976027/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15976027</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15976027[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.0502249102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15976027">Sabbagh et al. (2005)</a> showed that institution of a rescue diet that restored mineral ion homeostasis in Vdr-null mice prevented the development of rachitic changes, indicating that mineral ion abnormalities, not ablation of the Vdr gene, were the cause of impaired chondrocyte apoptosis. Similarly, Hyp mice with rickets also showed impaired apoptosis of hypertrophic chondrocytes, and the decreased apoptosis was correlated with hypophosphatemia. Wildtype mice rendered hypercalcemic and hypophosphatemic by dietary means also developed rickets. In vitro studies showed that the apoptosis was mediated by caspase-9 (CASP9; <a href="/entry/602234">602234</a>). <a href="#38" class="mim-tip-reference" title="Sabbagh, Y., Carpenter, T. O., Demay, M. B. <strong>Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes.</strong> Proc. Nat. Acad. Sci. 102: 9637-9642, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15976027/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15976027</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15976027[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.0502249102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15976027">Sabbagh et al. (2005)</a> concluded that hypophosphatemia was the common mediator of rickets in these cases. The findings indicated that normal phosphorus levels are required for growth plate maturation and that circulating phosphate is a key regulator of hypertrophic chondrocyte apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15976027+12193585" 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="#43" class="mim-tip-reference" title="Yuan, B., Takaiwa, M., Clemens, T. L., Feng, J. Q., Kumar, R., Rowe, P. S., Xie, Y., Drezner, M. K. <strong>Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia.</strong> J. Clin. Invest. 118: 722-734, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18172553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18172553</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18172553[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/JCI32702" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18172553">Yuan et al. (2008)</a> generated mice with a global Phex knockout (Phex -/-) and mice with conditional osteocalcin-promoted Phex inactivation only in osteoblasts and osteocytes (OC-Phex -/-). The reduction in serum phosphorus levels and kidney cell membrane phosphate transport as compared to wildtype mice was similar among Hyp, Phex -/-, and OC-Phex -/- mice; all 3 mutant strains had increased bone production and serum FGF23 (<a href="/entry/605370">605370</a>) levels and decreased kidney membrane NPT2, and manifested comparable osteomalacia. <a href="#43" class="mim-tip-reference" title="Yuan, B., Takaiwa, M., Clemens, T. L., Feng, J. Q., Kumar, R., Rowe, P. S., Xie, Y., Drezner, M. K. <strong>Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia.</strong> J. Clin. Invest. 118: 722-734, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18172553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18172553</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18172553[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/JCI32702" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18172553">Yuan et al. (2008)</a> concluded that aberrant Phex function in osteoblasts and/or osteocytes alone is sufficient to underlie the Hyp phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18172553" 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>The Gyro (Gy) Mouse</em></strong></p><p>
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<a href="#29" class="mim-tip-reference" title="Lyon, M. F., Scriver, C. R., Baker, L. R. I., Tenenhouse, H. S., Kronick, J., Mandla, S. <strong>The Gy mutation: another cause of X-linked hypophosphatemia in mouse.</strong> Proc. Nat. Acad. Sci. 83: 4899-4903, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3460077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3460077</a>] [<a href="https://doi.org/10.1073/pnas.83.13.4899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3460077">Lyon et al. (1986)</a> identified a second type of X-linked dominant hypophosphatemia in the mouse in addition to the Hyp. The phenotype, called Gyro (Gy), is characterized by rickets/osteomalacia as in the Hyp mouse, but also shows circling behavior, inner ear abnormalities, sterility in hemizygous males, and a milder phenotype in heterozygous females. The Gy and Hyp mutations have similar expression in the renal tubule, but the Gy mutation has an additional effect on the inner ear. The Gy allele is expressed in the inner ear of some heterozygous mice, which show circling behavior. The authors found that Gy mapped close (crossover value 0.4-0.8%) to Hyp. Lowe syndrome (<a href="/entry/309000">309000</a>) is not a human counterpart of Gy because in that condition the transport defect is not limited to phosphorus; moreover, characteristic morphologic changes in the nephron observed in Lowe syndrome are not seen in the Gy mouse. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3460077" 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="#35" class="mim-tip-reference" title="Nesbitt, T., Lobaugh, B., Drezner, M. K. <strong>Calcitonin stimulation of renal 25-hydroxyvitamin D-1(alpha)-hydroxylase activity in hypophosphatemic mice: evidence that the regulation of calcitriol production is not universally abnormal in X-linked hypophosphatemia.</strong> J. Clin. Invest. 79: 15-19, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3793922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3793922</a>] [<a href="https://doi.org/10.1172/JCI112776" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3793922">Nesbitt et al. (1987)</a> found that PTH-dependent 1-alpha-hydroxylase (CYP27B1; <a href="/entry/609506">609506</a>) activity in the renal proximal convoluted tubule was abnormally regulated in the Hyp mouse, whereas calcitonin-dependent enzyme function in the proximal straight tubule was modulated normally. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3793922" 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 the search for a human equivalent of the Gy mutation, <a href="#5" class="mim-tip-reference" title="Boneh, A., Reade, T. M., Scriver, C. R., Rishikof, E. <strong>Audiometric evidence for two forms of X-linked hypophosphatemia in humans, apparent counterparts of Hyp and Gy mutations in mouse.</strong> Am. J. Med. Genet. 27: 997-1003, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3425609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3425609</a>] [<a href="https://doi.org/10.1002/ajmg.1320270434" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3425609">Boneh et al. (1987)</a> measured hearing in 22 patients with X-linked hypophosphatemia; 5, including 2 mother/son pairs, had sensorineural hearing deficits due to cochlear dysfunction. The authors suggested that the disease in these persons may be the human counterpart of Gy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3425609" 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="Davidai, G. A., Nesbitt, T., Drezner, M. K. <strong>Normal regulation of calcitriol production in Gy mice: evidence for biochemical heterogeneity in the X-linked hypophosphatemic diseases.</strong> J. Clin. Invest. 85: 334-339, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2153705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2153705</a>] [<a href="https://doi.org/10.1172/JCI114442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2153705">Davidai et al. (1990)</a> provided further information on the differences between the Hyp and Gy phenotypes in the mouse. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2153705" 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="Collins, J. F., Ghishan, F. K. <strong>The molecular defect in the renal sodium-phosphate transporter expression pathway of Gyro (Gy) mice is distinct from that of hypophosphatemic (Hyp) mice.</strong> FASEB J. 10: 751-759, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8635692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8635692</a>] [<a href="https://doi.org/10.1096/fasebj.10.7.8635692" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8635692">Collins and Ghishan (1996)</a> found normal expression and location of the renal Na+/P(i) transporter NPT2 in Gy mice, suggesting that the molecular defect in the Gy mice is distinct from that in the Hyp mice, which show a decrease in transporter activity in the renal proximal tubules possibly related to decreased transcription (<a href="#7" class="mim-tip-reference" title="Collins, J. F., Bulus, N., Ghishan, F. K. <strong>Sodium-phosphate transporter adaptation to dietary phosphate deprivation in normal and hypophosphatemic mice.</strong> Am. J. Physiol. 268: G917-G924, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7611412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7611412</a>] [<a href="https://doi.org/10.1152/ajpgi.1995.268.6.G917" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7611412">Collins et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8635692+7611412" 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 Gy mice, <a href="#41" class="mim-tip-reference" title="Strom, T. M., Francis, F., Lorenz, B., Boddrich, A., Econs, M. J., Lehrach, H., Meitinger, T. <strong>Pex gene deletions in Gy and Hyp mice provide mouse models for X-linked hypophosphatemia.</strong> Hum. Molec. Genet. 6: 165-171, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9063736/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9063736</a>] [<a href="https://doi.org/10.1093/hmg/6.2.165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9063736">Strom et al. (1997)</a> found a deletion of the first 3 exons and the promoter region of the PHEX, indicating that Hyp and Gy are allelic disorders. However, <a href="#31" class="mim-tip-reference" title="Meyer, R. A., Jr., Henley, C. M., Meyer, M. H., Morgan, P. L., McDonald, A. G., Mills, C., Price, D. K. <strong>Partial deletion of both the spermine synthase gene and the Pex gene in the X-linked hypophosphatemic, Gyro (Gy) mouse.</strong> Genomics 48: 289-295, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9545633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9545633</a>] [<a href="https://doi.org/10.1006/geno.1997.5169" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9545633">Meyer et al. (1998)</a> found that the Gyro mouse has a partial deletion of both the Phex gene and the upstream spermine synthase gene (<a href="/entry/300105">300105</a>), making it a contiguous gene syndrome in that species. Gy is thus not as useful a model for human XLH as Hyp. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9063736+9545633" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>12 Selected Examples</a>):</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">rs1064793956 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1064793956;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=rs1064793956" 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=rs1064793956" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient with X-linked hypophosphatemia (XLHRD; <a href="/entry/307800">307800</a>), the <a href="#26" class="mim-tip-reference" title="HYP Consortium. <strong>A gene (HYP) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets.</strong> Nature Genet. 11: 130-136, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550339</a>] [<a href="https://doi.org/10.1038/ng1095-130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550339">HYP Consortium (1995)</a> identified a 2-bp deletion (675delTC) in exon 1 of the PHEX gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7550339" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 HYPOPHOSPHATEMIC RICKETS, X-LINKED DOMINANT</strong>
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PHEX, IVS1AS, G-A, -1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2146979490 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2146979490;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=rs2146979490" 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=rs2146979490" 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=RCV000011561" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011561" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011561</a>
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<p>In a patient with X-linked hypophosphatemia (XLHRD; <a href="/entry/307800">307800</a>), the <a href="#26" class="mim-tip-reference" title="HYP Consortium. <strong>A gene (HYP) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets.</strong> Nature Genet. 11: 130-136, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550339</a>] [<a href="https://doi.org/10.1038/ng1095-130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550339">HYP Consortium (1995)</a> identified a splicing mutation in the PHEX gene: a G-to-A transition at the -1 position in the splice acceptor site of exon 2 of the partially cloned gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7550339" 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 HYPOPHOSPHATEMIC RICKETS, X-LINKED DOMINANT</strong>
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PHEX, IVS1AS, G-C, -1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2146979490 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2146979490;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=rs2146979490" 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=rs2146979490" 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=RCV000011562" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011562" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011562</a>
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<p>In a patient with X-linked hypophosphatemia (XLHRD; <a href="/entry/307800">307800</a>), the <a href="#26" class="mim-tip-reference" title="HYP Consortium. <strong>A gene (HYP) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets.</strong> Nature Genet. 11: 130-136, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550339</a>] [<a href="https://doi.org/10.1038/ng1095-130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550339">HYP Consortium (1995)</a> identified a G-to-C transversion at the -1 position in the splice acceptor site of exon 2 of the PHEX gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7550339" 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 HYPOPHOSPHATEMIC RICKETS, X-LINKED DOMINANT</strong>
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PHEX, LEU274TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137853268 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853268;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=rs137853268" 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=rs137853268" 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=RCV000011563 OR RCV005089228" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011563, RCV005089228" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011563...</a>
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<p>In a sporadic case of hypophosphatemia in a female (XLHRD; <a href="/entry/307800">307800</a>), <a href="#25" class="mim-tip-reference" title="Holm, I. A., Huang, X., Kunkel, L. M. <strong>Mutational analysis of the PEX gene in patients with X-linked hypophosphatemic rickets.</strong> Am. J. Hum. Genet. 60: 790-797, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9106524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9106524</a>]" pmid="9106524">Holm et al. (1997)</a> identified an 823T-A transversion in the PHEX gene, resulting in a leu274-to-ter (L274X) substitution. (The nucleotides and amino acids were numbered on the basis of the cDNA sequence published by the <a href="#26" class="mim-tip-reference" title="HYP Consortium. <strong>A gene (HYP) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets.</strong> Nature Genet. 11: 130-136, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550339</a>] [<a href="https://doi.org/10.1038/ng1095-130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550339">HYP Consortium (1995)</a>.) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9106524+7550339" 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 HYPOPHOSPHATEMIC RICKETS, X-LINKED DOMINANT</strong>
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PHEX, CYS82TYR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137853269 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853269;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=rs137853269" 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=rs137853269" 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=RCV000011564 OR RCV001851795" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011564, RCV001851795" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011564...</a>
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<p>In a male with familial X-linked hypophosphatemia (XLHRD; <a href="/entry/307800">307800</a>), <a href="#25" class="mim-tip-reference" title="Holm, I. A., Huang, X., Kunkel, L. M. <strong>Mutational analysis of the PEX gene in patients with X-linked hypophosphatemic rickets.</strong> Am. J. Hum. Genet. 60: 790-797, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9106524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9106524</a>]" pmid="9106524">Holm et al. (1997)</a> identified a 247G-A transition in exon 3 of the PHEX gene, resulting in a cys82-to-tyr (C82Y) substitution. (The nucleotides and amino acids were numbered on the basis of the cDNA sequence published by the <a href="#26" class="mim-tip-reference" title="HYP Consortium. <strong>A gene (HYP) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets.</strong> Nature Genet. 11: 130-136, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550339</a>] [<a href="https://doi.org/10.1038/ng1095-130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550339">HYP Consortium (1995)</a>.) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9106524+7550339" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0006" class="mim-anchor"></a>
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<strong>.0006 HYPOPHOSPHATEMIC RICKETS, X-LINKED DOMINANT</strong>
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PHEX, PHE249SER AND MET250ILE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267606945 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606945;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=rs267606945" 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=rs267606945" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267606946 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606946;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=rs267606946" 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=rs267606946" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000011565 OR RCV001857787 OR RCV001857790" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011565, RCV001857787, RCV001857790" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011565...</a>
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<p>In a female with familial hypophosphatemia (XLHRD; <a href="/entry/307800">307800</a>), <a href="#25" class="mim-tip-reference" title="Holm, I. A., Huang, X., Kunkel, L. M. <strong>Mutational analysis of the PEX gene in patients with X-linked hypophosphatemic rickets.</strong> Am. J. Hum. Genet. 60: 790-797, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9106524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9106524</a>]" pmid="9106524">Holm et al. (1997)</a> identified 2 mutations that were 4-bp apart in exon 7 of the PHEX gene: a 748T-C transition, resulting in a phe249-to-ser (F249S) substitution and a 752G-A transition, resulting in a met250-to-ile (M250I) substitution. The 2 mutations were on the same allele, as demonstrated by sequencing of both alleles. (The nucleotides and amino acids were numbered on the basis of the cDNA sequence published by the <a href="#26" class="mim-tip-reference" title="HYP Consortium. <strong>A gene (HYP) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets.</strong> Nature Genet. 11: 130-136, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550339</a>] [<a href="https://doi.org/10.1038/ng1095-130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550339">HYP Consortium (1995)</a>.) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9106524+7550339" 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">rs137853270 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853270;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=rs137853270" 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=rs137853270" 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=RCV000011566 OR RCV001202583" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011566, RCV001202583" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011566...</a>
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<p>In affected members of a kindred originally reported by <a href="#20" class="mim-tip-reference" title="Frymoyer, J. W., Hodgkin, W. <strong>Adult-onset vitamin D-resistant hypophosphatemic osteomalacia: a possible variant of vitamin D-resistant rickets.</strong> J. Bone Joint Surg. Am. 59: 101-106, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/188828/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">188828</a>]" pmid="188828">Frymoyer and Hodgkin (1977)</a> as having 'adult-onset vitamin D-resistant hypophosphatemic osteomalacia' (AVDRR), <a href="#17" class="mim-tip-reference" title="Econs, M. J., Friedman, N. E., Rowe, P. S. N., Speer, M. C., Francis, F., Strom, T. M., Oudet, C., Smith, J. A., Ninomiya, J. T., Lee, B. E., Bergen, H. <strong>A PHEX gene mutation is responsible for adult-onset vitamin D-resistant hypophosphatemic osteomalacia: evidence that the disorder is not a distinct entity from X-linked hypophosphatemic rickets.</strong> J. Clin. Endocr. Metab. 83: 3459-3462, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9768646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9768646</a>] [<a href="https://doi.org/10.1210/jcem.83.10.5167" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9768646">Econs et al. (1998)</a> identified a T-to-C transition in exon 16 of the PHEX gene, resulting in a leu555-to-pro (L555P) substitution. <a href="#20" class="mim-tip-reference" title="Frymoyer, J. W., Hodgkin, W. <strong>Adult-onset vitamin D-resistant hypophosphatemic osteomalacia: a possible variant of vitamin D-resistant rickets.</strong> J. Bone Joint Surg. Am. 59: 101-106, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/188828/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">188828</a>]" pmid="188828">Frymoyer and Hodgkin (1977)</a> had asserted that the disorder was distinct from X-linked hypophosphatemic rickets (XLHRD; <a href="/entry/307800">307800</a>) because affected children did not display radiographic evidence of rickets and patients typically presented with clinical manifestations of the disease in the fourth or fifth decade of life. However, clinical evaluation of affected family members by <a href="#17" class="mim-tip-reference" title="Econs, M. J., Friedman, N. E., Rowe, P. S. N., Speer, M. C., Francis, F., Strom, T. M., Oudet, C., Smith, J. A., Ninomiya, J. T., Lee, B. E., Bergen, H. <strong>A PHEX gene mutation is responsible for adult-onset vitamin D-resistant hypophosphatemic osteomalacia: evidence that the disorder is not a distinct entity from X-linked hypophosphatemic rickets.</strong> J. Clin. Endocr. Metab. 83: 3459-3462, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9768646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9768646</a>] [<a href="https://doi.org/10.1210/jcem.83.10.5167" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9768646">Econs et al. (1998)</a> indicated that some displayed classic features of X-linked hypophosphatemic rickets. The authors were unable to verify progressive bowing in adults. Because of the clinical spectrum of X-linked hypophosphatemic rickets and the presence of a PHEX mutation in affected members of this kindred, the authors concluded that there is only 1 form of X-linked dominant phosphate wasting. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9768646+188828" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a female patient from the Indian subcontinent with X-linked hypophosphatemic rickets (XLHRD; <a href="/entry/307800">307800</a>) and congenital adrenal hypoplasia originally reported by <a href="#40" class="mim-tip-reference" title="Shah, B. R., Fiordalisi, I., Sheinbaum, K., Finberg, L. <strong>Familial glucocorticoid deficiency in a girl with familial hypophosphatemic rickets.</strong> Am. J. Dis. Child. 142: 900-903, 1988. Note: Erratum: Am. J. Dis. Child. 142: 1330 only, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3394683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3394683</a>] [<a href="https://doi.org/10.1001/archpedi.1988.02150080106036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3394683">Shah et al. (1988)</a>, <a href="#13" class="mim-tip-reference" title="Dixon, P. H., Christie, P. T., Wooding, C., Trump, D., Grieff, M., Holm, I., Gertner, J. M., Schmidtke, J., Shah, B., Shaw, N., Smith, C., Tau, C., Schlessinger, D., Whyte, M. P., Thakker, R. V. <strong>Mutational analysis of PHEX gene in X-linked hypophosphatemia.</strong> J. Clin. Endocr. Metab. 83: 3615-3623, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9768674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9768674</a>] [<a href="https://doi.org/10.1210/jcem.83.10.5180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9768674">Dixon et al. (1998)</a> identified an A-to-G transition at codon -429 of the 5-prime untranslated region in the PHEX gene. The A-to-G transition was found to cosegregate with the disease and was absent in 247 alleles examined. <a href="#13" class="mim-tip-reference" title="Dixon, P. H., Christie, P. T., Wooding, C., Trump, D., Grieff, M., Holm, I., Gertner, J. M., Schmidtke, J., Shah, B., Shaw, N., Smith, C., Tau, C., Schlessinger, D., Whyte, M. P., Thakker, R. V. <strong>Mutational analysis of PHEX gene in X-linked hypophosphatemia.</strong> J. Clin. Endocr. Metab. 83: 3615-3623, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9768674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9768674</a>] [<a href="https://doi.org/10.1210/jcem.83.10.5180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9768674">Dixon et al. (1998)</a> suggested that the mutation may lead to an alteration in the binding sites for ribosomal and other translation factors, such as tissue-specific regulatory proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9768674+3394683" 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="#40" class="mim-tip-reference" title="Shah, B. R., Fiordalisi, I., Sheinbaum, K., Finberg, L. <strong>Familial glucocorticoid deficiency in a girl with familial hypophosphatemic rickets.</strong> Am. J. Dis. Child. 142: 900-903, 1988. Note: Erratum: Am. J. Dis. Child. 142: 1330 only, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3394683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3394683</a>] [<a href="https://doi.org/10.1001/archpedi.1988.02150080106036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3394683">Shah et al. (1988)</a> had termed the disorders in this Indian girl as 'familial glucocorticoid deficiency' and familial hypophosphatemic rickets, and had suggested the possibility of a chromosomal abnormality in activating both the X-linked hypophosphatemia locus and a closely situated locus for glucocorticoid deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3394683" 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> rs919011936 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs919011936;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/rs919011936?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=rs919011936" 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=rs919011936" 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=RCV000011568 OR RCV001367140" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011568, RCV001367140" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011568...</a>
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<p>Using lymphoblastoid RNA and RT-PCR, <a href="#6" class="mim-tip-reference" title="Christie, P. T., Harding, B., Nesbit, M. A., Whyte, M. P., Thakker, R. V. <strong>X-linked hypophosphatemia attributable to pseudoexons of the PHEX gene.</strong> J. Clin. Endocr. Metab. 86: 3840-3844, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11502821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11502821</a>] [<a href="https://doi.org/10.1210/jcem.86.8.7730" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11502821">Christie et al. (2001)</a> investigated 11 unrelated X-linked hypophosphatemic rickets (XLHRD; <a href="/entry/307800">307800</a>) patients in whom coding region mutations had been excluded for intronic mutations that could lead to mRNA splicing abnormalities. One X-linked hypophosphatemia patient was found to have 3 abnormally large transcripts resulting from 51-, 100-, and 170-bp insertions, all of which would lead to missense peptides and premature termination codons. The origin of these transcripts was a G-to-T transversion at position +1268 of intron 7, which resulted in the occurrence of a high quality novel donor splice site (ggaagg to gtaagg). Splicing between this novel donor splice site and 3 preexisting, but normally silent, acceptor splice sites within intron 7 resulted in the occurrence of the 3 pseudoexons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11502821" 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> rs137853271 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853271;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/rs137853271?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=rs137853271" 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=rs137853271" 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=RCV000011569 OR RCV000414471" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011569, RCV000414471" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011569...</a>
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<p><a href="#22" class="mim-tip-reference" title="Goji, K., Ozaki, K., Sadewa, A. H., Nishio, H., Matsuo, M. <strong>Somatic and germline mosaicism for a mutation of the PHEX gene can lead to genetic transmission of X-linked hypophosphatemic rickets that mimics an autosomal dominant trait.</strong> J. Clin. Endocr. Metab. 91: 365-370, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16303832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16303832</a>] [<a href="https://doi.org/10.1210/jc.2005-1776" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16303832">Goji et al. (2006)</a> described a family in which the father and only 1 of his 2 daughters were affected by hypophosphatemic rickets (XLHRD; <a href="/entry/307800">307800</a>). The pedigree interpretation of the family suggested that genetic transmission of the disorder occurred as an autosomal dominant trait. However, the affected daughter was heterozygous for an arg567-to-ter (R567X) mutation in the PHEX gene, rather than in the FGF23 gene (<a href="/entry/605370">605370</a>), suggesting that the genetic transmission occurred as an X-linked dominant trait. Unexpectedly, the father was heterozygous for this mutation. Single-nucleotide primer extension and denaturing HPLC analysis of the father using DNA from single hair roots revealed that he was a somatic mosaic for the mutation. Haplotype analysis confirmed that the father transmitted the genotypes for 18 markers on the X chromosome equally to his 2 daughters. The fact that he transmitted the mutation to only 1 his 2 daughters indicated that he was a germline mosaic for the mutation. <a href="#22" class="mim-tip-reference" title="Goji, K., Ozaki, K., Sadewa, A. H., Nishio, H., Matsuo, M. <strong>Somatic and germline mosaicism for a mutation of the PHEX gene can lead to genetic transmission of X-linked hypophosphatemic rickets that mimics an autosomal dominant trait.</strong> J. Clin. Endocr. Metab. 91: 365-370, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16303832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16303832</a>] [<a href="https://doi.org/10.1210/jc.2005-1776" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16303832">Goji et al. (2006)</a> concluded that somatic and germline mosaicism for an X-linked dominant mutation in PHEX may mimic autosomal dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16303832" 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>.0011 HYPOPHOSPHATEMIC RICKETS, X-LINKED DOMINANT</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">rs1556020485 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1556020485;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=rs1556020485" 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=rs1556020485" 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=RCV000505454" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000505454" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000505454</a>
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<p><a href="#30" class="mim-tip-reference" title="Makras, P., Hamdy, N. A. T., Kant, S. G., Papapoulos, S. E. <strong>Normal growth and muscle dysfunction in X-linked hypophosphatemic rickets associated with a novel mutation in the PHEX gene.</strong> J. Clin. Endocr. Metab. 93: 1386-1389, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252791</a>] [<a href="https://doi.org/10.1210/jc.2007-1296" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18252791">Makras et al. (2008)</a> described a mother and 2 sons with X-linked hypophosphatemic rickets (XLHRD; <a href="/entry/307800">307800</a>) with unusual clinical features, including normal growth. A novel splice site mutation in intron 4 of the PHEX gene, IVS4+6G-T, that resulted in skipping of exon 4 was present in all 3 individuals. The mother and her sons were followed in the same institution for nearly 30 years. The mother had hypophosphatemia and normal height without ever receiving any treatment. Her 2 sons achieved final heights of 183.7 cm (Z score, -0.01) and 182.7 cm (Z score, -0.18), respectively, despite late initiation of treatment with phosphate and low serum phosphate levels. In addition, they had reversible proximal myopathy, which took approximately 7 years to resolve in the more severely affected son and 8 months to resolve in the other. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18252791" 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>.0012 HYPOPHOSPHATEMIC RICKETS, X-LINKED DOMINANT</strong>
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PHEX, c.1701A-C
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003236696" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003236696" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003236696</a>
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<p>In a Saudi mother and her son and 2 daughters with X-linked hypophosphatemic rickets (XLDHD; <a href="/entry/307800">307800</a>), <a href="#1" class="mim-tip-reference" title="Alhamoudi, K. M., Alghamdi, B., Alswailem, M., Nasir, A., Aljomaiah, A., Al-Hindi, H., Alzahrani, A. S. <strong>A unique mechanism of a novel synonymous PHEX variant causing X-linked hypophosphatemia.</strong> J. Clin. Endocr. Metab. 107: 2883-2891, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35896147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35896147</a>] [<a href="https://doi.org/10.1210/clinem/dgac435" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35896147">Alhamoudi et al. (2022)</a> identified a c.1701A-C transversion (c.1701A-C, NM_000444.6) at the first nucleotide of exon 17 of the PHEX gene, resulting in a synonymous alteration in the protein (arg567-to-arg; R567R). Using RT-PCR, the authors showed that the variant interfered with splicing of exons 16 and 17, resulting in a shorter PHEX transcript compared to controls. Sanger sequencing of the cDNA showed complete skipping of exon 17 and direct splicing of exons 16 and 18, resulting in a frameshift and premature stop codon at glu568, with loss of the final 183 amino acids of the protein. The authors predicted that this led to loss of 2 conserved zinc-binding sites in exons 17 and 19, with loss of normal protein function. The variant was not present in public databases, including gnomAD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35896147" 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="#Collins1994" class="mim-tip-reference" title="Collins, J. F., Ghishan, F. K. <strong>Molecular cloning, functional expression, tissue distribution and in situ hybridization of the renal sodium phosphate (Na+/P(i)) transporter in the control and hypophosphatemic mouse.</strong> FASEB J. 8: 862-868, 1994.">Collins and Ghishan (1994)</a>; <a href="#Dennis1977" class="mim-tip-reference" title="Dennis, V. W., Bello-Reuss, E., Robinson, R. R. <strong>Response of phosphate transport to parathyroid hormone in segments of rabbit nephron.</strong> Am. J. Physiol. 233: F29-F38, 1977.">Dennis et al. (1977)</a>; <a href="#Lobaugh1983" class="mim-tip-reference" title="Lobaugh, B., Drezner, M. K. <strong>Abnormal regulation of renal 25-hydroxyvitamin D-1-alpha-hydroxylase activity in the X-linked hypophosphatemic mouse.</strong> J. Clin. Invest. 71: 400-403, 1983.">Lobaugh and Drezner
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(1983)</a>; <a href="#Meyer1979" class="mim-tip-reference" title="Meyer, R. A., Jr., Jowsey, J., Meyer, M. H. <strong>Osteomalacia and altered magnesium metabolism in the X-linked hypophosphatemic mouse.</strong> Calcif. Tissue Int. 27: 19-26, 1979.">Meyer et al. (1979)</a>
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Alhamoudi, K. M., Alghamdi, B., Alswailem, M., Nasir, A., Aljomaiah, A., Al-Hindi, H., Alzahrani, A. S.
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<strong>A unique mechanism of a novel synonymous PHEX variant causing X-linked hypophosphatemia.</strong>
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J. Clin. Endocr. Metab. 107: 2883-2891, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35896147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35896147</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35896147" 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/clinem/dgac435" target="_blank">Full Text</a>]
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Baum, M., Loleh, S., Saini, N., Seikaly, M., Dwarakanath, V., Quigley, R.
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<strong>Correction of proximal tubule phosphate transport defect in Hyp mice in vivo and in vitro with indomethacin.</strong>
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Proc. Nat. Acad. Sci. 100: 11098-11103, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12953100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12953100</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12953100[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12953100" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.1834060100" target="_blank">Full Text</a>]
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Beck, L., Soumounou, Y., Martel, J., Krishnamurthy, G., Gauthier, C., Goodyer, C. G., Tenenhouse, H. S.
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<strong>Pex/PEX tissue distribution and evidence for a deletion in the 3-prime region of the Pex gene in X-linked hypophosphatemic mice.</strong>
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J. Clin. Invest. 99: 1200-1209, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9077527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9077527</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9077527" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI119276" target="_blank">Full Text</a>]
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Bell, C. L., Tenenhouse, H. S., Scriver, C. R.
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<strong>Primary cultures of renal epithelial cells from X-linked hypophosphatemic (Hyp) mice express defects in phosphate transport and vitamin D metabolism.</strong>
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Am. J. Hum. Genet. 43: 293-303, 1988.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3414685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3414685</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3414685" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Boneh, A., Reade, T. M., Scriver, C. R., Rishikof, E.
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<strong>Audiometric evidence for two forms of X-linked hypophosphatemia in humans, apparent counterparts of Hyp and Gy mutations in mouse.</strong>
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Am. J. Med. Genet. 27: 997-1003, 1987.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3425609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3425609</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3425609" 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/10.1002/ajmg.1320270434" target="_blank">Full Text</a>]
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Christie, P. T., Harding, B., Nesbit, M. A., Whyte, M. P., Thakker, R. V.
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<strong>X-linked hypophosphatemia attributable to pseudoexons of the PHEX gene.</strong>
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J. Clin. Endocr. Metab. 86: 3840-3844, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11502821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11502821</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11502821" 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/jcem.86.8.7730" target="_blank">Full Text</a>]
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Collins, J. F., Bulus, N., Ghishan, F. K.
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<strong>Sodium-phosphate transporter adaptation to dietary phosphate deprivation in normal and hypophosphatemic mice.</strong>
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Am. J. Physiol. 268: G917-G924, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7611412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7611412</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7611412" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1152/ajpgi.1995.268.6.G917" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1096/fasebj.8.11.8070635" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1096/fasebj.10.7.8635692" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI114442" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1152/ajprenal.1977.233.1.F29" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.83.10.5180" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/en.2002-220454" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1996.0421" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.83.10.5167" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2005-1776" target="_blank">Full Text</a>]
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Tenenhouse, H. S., Werner, A., Biber, J., Ma, S., Martel, J., Roy, S., Murer, H.
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<strong>Renal Na(+)-phosphate cotransport in murine X-linked hypophosphatemic rickets: molecular characterization.</strong>
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J. Clin. Invest. 93: 671-676, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8113402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8113402</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8113402" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI117019" target="_blank">Full Text</a>]
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<a id="Yuan2008" class="mim-anchor"></a>
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Yuan, B., Takaiwa, M., Clemens, T. L., Feng, J. Q., Kumar, R., Rowe, P. S., Xie, Y., Drezner, M. K.
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<strong>Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia.</strong>
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J. Clin. Invest. 118: 722-734, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18172553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18172553</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18172553[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18172553" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI32702" target="_blank">Full Text</a>]
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Sonja A. Rasmussen - updated : 06/23/2023
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Marla J. F. O'Neill - updated : 10/6/2010<br>John A. Phillips, III - updated : 1/14/2009<br>Marla J. F. O'Neill - updated : 3/20/2008<br>John A. Phillips, III - updated : 3/21/2007<br>Cassandra L. Kniffin - updated : 9/7/2005<br>Cassandra L. Kniffin - updated : 8/15/2005
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Cassandra L. Kniffin : 7/28/2005
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carol : 04/30/2024
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carol : 10/17/2023<br>carol : 06/23/2023<br>alopez : 10/14/2016<br>terry : 04/04/2013<br>alopez : 4/18/2011<br>terry : 1/13/2011<br>wwang : 10/8/2010<br>terry : 10/6/2010<br>alopez : 1/14/2009<br>wwang : 3/25/2008<br>terry : 3/20/2008<br>terry : 8/6/2007<br>carol : 3/21/2007<br>wwang : 9/23/2005<br>wwang : 9/19/2005<br>ckniffin : 9/7/2005<br>carol : 9/1/2005<br>ckniffin : 8/15/2005
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<strong>*</strong> 300550
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PHOSPHATE-REGULATING ENDOPEPTIDASE, X-LINKED; PHEX
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PHOSPHATE-REGULATING ENDOPEPTIDASE HOMOLOG, X-LINKED<br />
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PEX
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: PHEX</em></strong>
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Cytogenetic location: Xp22.11
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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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Xp22.11
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Hypophosphatemic rickets, X-linked dominant
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307800
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X-linked dominant
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3
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<strong>TEXT</strong>
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<strong>Cloning and Expression</strong>
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<p>The HYP Consortium (1995), comprising 29 investigators in 5 institutions, isolated a candidate gene for X-linked hypophosphatemic rickets (307800) from the Xp22.1 region by positional cloning. The gene exhibited homology to a family of endopeptidase genes, members of which are involved in the degradation or activation of a variety of peptide hormones, including neutral endopeptidase (NEP; 120520), endothelin-converting enzyme (ECE1; 600423), and Kell blood group antigen (613883). Because of the homology and the function of the gene, the authors referred to it as PEX ('phosphate regulating gene with homologies to endopeptidases, on the X chromosome'). A partial PHEX sequence corresponding to 638 amino acids was presented. The PHEX cDNA was found to be evolutionarily conserved in primate, bovine, mouse, and hamster DNA, and possibly in chicken DNA. </p><p>Guo and Quarles (1997) isolated a human PHEX cDNA from a bone cDNA library. The deduced 749-amino acid protein has a molecular mass of 86.5 kD and shares 96% identity to the mouse sequence. The PHEX protein is predicted to have a 20-residue N-terminal cytoplasmic tail, a 27-residue transmembrane domain, and a 702-residue extracellular C-terminal region. The protein belongs to the type II integral membrane zinc-dependent endopeptidase family. PHEX transcripts were identified in human osteosarcoma-derived cells and in differentiated mouse osteoblasts, but not in immature mouse preosteoblasts, indicating stage-specific expression. Guo and Quarles (1997) suggested that PHEX may play a role in osteoblast-mediated bone mineralization. </p><p>Grieff et al. (1997) isolated human PHEX clones from an ovary cDNA library. The gene encodes a 749-amino acid polypeptide that is 96% identical to the murine Phex gene product and has significant homology to other members of the membrane-bound zinc metallopeptidase family. Northern blot analysis identified a 6.6-kb PHEX mRNA transcript at high levels in adult ovary and fetal lung and at lower levels in adult lung and fetal liver. </p><p>Du et al. (1996) reported the isolation and characterization of the complete open reading frame of the mouse Phex gene. The deduced 749-amino acid protein showed 95% identity to the available human PHEX sequence and significant homology to members of the membrane-bound metalloendopeptidase family. Northern blot analysis revealed a 6.6-kb mRNA transcript in bone and in cultured osteoblasts from normal mice; the transcript was not detectable in samples from the mutant 'Hyp' mouse but were detectable in Hyp bone by RT-PCR amplification. Beck et al. (1997) cloned mouse Phex and human PHEX cDNAs encoding part of the 5-prime untranslated region, the protein coding region, and the entire 3-prime untranslated region. Using RT-PCR and ribonuclease protection assays, they found that Phex/PHEX mRNA is expressed predominantly in human fetal and in adult mouse calvaria and long bone. </p>
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<strong>Gene Structure</strong>
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<p>Holm et al. (1997) determined that the PHEX gene contains 18 exons. Its genomic organization shares similarity with members of the family of neutral endopeptidases. </p>
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<strong>Molecular Genetics</strong>
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<p>In 3 unrelated patients with X-linked hypophosphatemic rickets (XLHRD; 307800), the HYP Consortium (1995) identified 3 different mutations in the PHEX gene (300550.0001-300550.0003). </p><p>Holm et al. (1997) identified mutations in the PHEX gene in 9 of 22 unrelated patients with X-linked hypophosphatemic rickets: 3 nonsense mutations, a 1-bp deletion leading to a frameshift, a donor-splice site mutation, and missense mutations in 4 patients (see, e.g., 300550.0004-300550.0006). </p><p>Dixon et al. (1998) identified a total of 31 mutations in the PHEX gene in 46 unrelated XLH kindreds and 22 unrelated patients with nonfamilial XLH. Thirty of the mutations were scattered throughout the putative extracellular domain. Dixon et al. (1998) also identified 6 PHEX polymorphisms that had heterozygosity frequencies ranging from less than 1% to 43%. Over 20% of the mutations were observed in nonfamilial XLH patients, who represented de novo occurrences of PHEX mutations. The majority (over 70%) of the mutations were predicted to result in a functional loss of the PHEX protein, rather than haploinsufficiency or a dominant-negative effect. </p><p>Filisetti et al. (1999) reported 30 newly detected mutations in the PHEX gene, and pooled findings with all previously published mutations. The spectrum of the mutations displayed 16% deletions, 8% insertions, 34% missense, 27% nonsense, and 15% splice site mutations, with peaks in exons 15 and 17. Since 32.8% of PHEX amino acids are conserved in the family of the endopeptidases, the number of missense mutations detected at nonconserved residues was smaller than expected, whereas the number of nonsense mutations observed at nonconserved residues was very close to the expected number. Compared with conserved amino acids, the changes in nonconserved amino acids may result in benign polymorphisms or possibly mild disease that may go undiagnosed. </p><p>Sabbagh et al. (2000) stated that 131 HYP-causing mutations in the PHEX gene had been reported. They announced the creation of an online PHEX mutation database for the collection and distribution of information on PHEX mutations. </p><p>Sabbagh et al. (2001) examined the effect of PHEX missense mutations on cellular trafficking of the recombinant protein. Four mutant PHEX cDNAs were generated by PCR mutagenesis (e.g., E581V). Three of the mutants were completely sensitive to endoglycosidase H digestion, indicating that they were not fully glycosylated. Sequestration of the disease-causing mutant proteins in the endoplasmic reticulum and plasma membrane localization of wildtype PHEX proteins was demonstrated by immunofluorescence and cell surface biotinylation. Sabbagh et al. (2003) assessed the impact of 9 PHEX missense mutations on cellular trafficking, endopeptidase activity, and protein conformation. Eight mutations had been identified in XLH patients; the remaining mutation, E581V, had been engineered in NEP (120520), to which PHEX shows significant homology, where it was shown to abolish catalytic activity but not interfere with cell surface localization of the recombinant protein (Devault et al., 1988). The authors demonstrated that some mutations in secreted PHEX abrogate catalytic activity, whereas others alter the trafficking and conformation of the protein, thus providing a mechanism whereby missense mutations result in loss of function of the PHEX protein. Endopeptidase activity of secreted and rescued PHEX proteins was assessed using a novel internally quenched fluorogenic peptide substrate. </p><p>Gaucher et al. (2009) analyzed the PHEX gene in 118 probands with hypophosphatemic rickets and identified mutations in 49 (87%) of 56 familial cases and 44 (73%) of 60 known sporadic cases. Of the 78 different mutations identified, 16 were missense mutations, which all occurred at residues that are highly conserved in mammals. Plotting all reported PHEX missense mutations on a 3D protein model revealed that missense mutations are primarily located in 2 regions in the inner part of the PHEX protein; similar plotting of nonsense mutations showed a random distribution. One patient with late-onset disease was found to have a mutation in an intronic region of PHEX, 2 bp away from the splice site consensus sequence, confirming that late-onset disease is part of the spectrum of X-linked dominant hypophosphatemic rickets. </p><p>In a mother and her son and 2 daughters with X-linked hypophosphatemic rickets, Alhamoudi et al. (2022) identified a c.1701A-C transversion (148060.0012) at the first nucleotide of exon 17 of the PHEX gene, resulting in a synonymous alteration in the protein (R567R). Using RT-PCR, the authors showed that the variant interfered with splicing of exon 16 with 17, resulting in a shorter PHEX transcript compared to controls. Sanger sequencing of the cDNA showed complete skipping of exon 17 and direct splicing of exons 16 and 18, resulting in a frameshift and premature stop codon. The authors predicted that this led to loss of 2 conserved zinc-binding sites in exons 17 and 19, with loss of normal protein function. </p>
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<p>The PEX nomenclature conflicts with the use of the same symbol for multiple peroxisomal proteins (peroxins) numbered 1 to 12 or more, e.g., PEX5 (600414). The gene symbol PHEX has much to recommend it (Dixon et al., 1998; Filisetti et al., 1999). </p>
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<p><strong><em>The 'Hyp' Mouse</em></strong></p><p>
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Eicher et al. (1976) observed a mouse model for X-linked hypophosphatemia, designated Hyp. Hyp mice have bone changes resembling rickets, dwarfism, and high fractional excretion of phosphate ion. </p><p>By various transplantation experiments, Ecarot-Charrier et al. (1988) demonstrated an intrinsic defect in osteoblasts in the Hyp mouse. Bell et al. (1988) reported that primary cultures of renal epithelial cells from the Hyp mouse demonstrate a defect in phosphate transport and vitamin D metabolism, suggesting a defect intrinsic to the kidney. However, in cross-transplantation studies of kidneys in normal and Hyp mice, Nesbitt et al. (1992) found that the Hyp phenotype was neither transferred nor corrected by renal transplantation, suggesting that the kidney was not the target organ for the genetic abnormality. Nesbitt et al. (1992) postulated that the disorder in the mouse, and probably in the human, is the result of a humoral factor and is not an intrinsic renal abnormality. Nesbitt et al. (1992) suggested the presence of a unique hormonal effect that results in a blockade of, or failure to express, an essential gene function in a variety of cell types. </p><p>Parabiosis (Meyer et al., 1989) and renal transplantation (Nesbitt et al., 1992) experiments demonstrated that the renal defect in brush border membrane sodium-dependent phosphate transport in Hyp mice is not intrinsic to the kidney, but rather depends on a circulating humoral factor, which is not parathyroid hormone (Meyer et al., 1989), for its expression. In Hyp mice, Tenenhouse et al. (1994) demonstrated that the specific reduction in renal sodium-phosphate cotransport in brush border membranes could be ascribed to a proportionate decrease in the abundance of kidney NPT2 (182309) cotransporter mRNA and protein. However, the NPT2 gene is located on chromosome 5 and, hence, cannot be the site of the mutation primarily responsible for hereditary hypophosphatemia. Tenenhouse et al. (1994) suggested that the X-linked gene may encode the postulated circulating humoral factor that regulates the renal sodium-phosphate cotransporter. </p><p>Beck et al. (1997) discovered a large deletion in the 3-prime region of the Phex gene in the Hyp mouse. </p><p>Baum et al. (2003) demonstrated that Hyp mice have a 2-fold greater urinary prostaglandin E2 (PGE2) excretion than wildtype mice. To determine whether prostaglandins were involved in the pathogenesis of this disorder, Hyp and wildtype C57/B6 mice received intraperitoneal injections with vehicle or indomethacin and were studied approximately 12 hours after the last dose of indomethacin. In the Hyp mice, indomethacin decreased the fractional excretion of phosphate and increased serum phosphate. There was no effect of indomethacin in the wildtype mice. Indomethacin did not affect serum creatine or inulin clearance, demonstrating that the normalization of urinary phosphate excretion was not caused by changes in glomerular filtration rate. Indomethacin treatment increased renal brush border membrane vesicle NaPi2 protein abundance in Hyp mice to levels comparable to that of wildtype mice. Baum et al. (2003) concluded that there is dysregulation of renal prostaglandin metabolism in Hyp mice, and that indomethacin treatment normalizes the urinary excretion of phosphate by a direct tubular effect. These studies suggested that indomethacin may be an effective form of therapy in humans with X-linked hypophosphatemia. </p><p>Lorenz-Depiereux et al. (2004) studied 2 spontaneous mutations in the mouse Phex gene, Hyp-2J, a 7.3-kb deletion containing exon 15, and Hyp-Duk, a 30-kb deletion containing exons 13 and 14. Both mutations caused similar phenotypes in males, including shortened hind legs and tail, a shortened square trunk, hypophosphatemia, hypocalcemia, and rachitic bone disease. Hyp-Duk males also exhibited background-dependent variable expression of deafness, circling behavior, and cranial dysmorphology. Both Hyp-2J and Hyp-Duk males had thickened temporal bone surrounding the cochlea and a precipitate in the scala tympani, but only the hearing-impaired Hyp-Duk mice had degeneration of the organ of Corti and spiral ganglion. Lorenz-Depiereux et al. (2004) noted that XLH phenotypes could now be separated from non-XLH-related phenotypes. </p><p>During development and postnatal growth of the endochondral skeleton, proliferative chondrocytes differentiate into hypertrophic chondrocytes, which subsequently undergo apoptosis and are replaced by bone. Donohue and Demay (2002) found that mice with rickets due to ablation of the vitamin D receptor (VDR; 601769) had expansion of hypertrophic chondrocytes due to impaired apoptosis of these cells. Sabbagh et al. (2005) showed that institution of a rescue diet that restored mineral ion homeostasis in Vdr-null mice prevented the development of rachitic changes, indicating that mineral ion abnormalities, not ablation of the Vdr gene, were the cause of impaired chondrocyte apoptosis. Similarly, Hyp mice with rickets also showed impaired apoptosis of hypertrophic chondrocytes, and the decreased apoptosis was correlated with hypophosphatemia. Wildtype mice rendered hypercalcemic and hypophosphatemic by dietary means also developed rickets. In vitro studies showed that the apoptosis was mediated by caspase-9 (CASP9; 602234). Sabbagh et al. (2005) concluded that hypophosphatemia was the common mediator of rickets in these cases. The findings indicated that normal phosphorus levels are required for growth plate maturation and that circulating phosphate is a key regulator of hypertrophic chondrocyte apoptosis. </p><p>Yuan et al. (2008) generated mice with a global Phex knockout (Phex -/-) and mice with conditional osteocalcin-promoted Phex inactivation only in osteoblasts and osteocytes (OC-Phex -/-). The reduction in serum phosphorus levels and kidney cell membrane phosphate transport as compared to wildtype mice was similar among Hyp, Phex -/-, and OC-Phex -/- mice; all 3 mutant strains had increased bone production and serum FGF23 (605370) levels and decreased kidney membrane NPT2, and manifested comparable osteomalacia. Yuan et al. (2008) concluded that aberrant Phex function in osteoblasts and/or osteocytes alone is sufficient to underlie the Hyp phenotype. </p><p><strong><em>The Gyro (Gy) Mouse</em></strong></p><p>
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Lyon et al. (1986) identified a second type of X-linked dominant hypophosphatemia in the mouse in addition to the Hyp. The phenotype, called Gyro (Gy), is characterized by rickets/osteomalacia as in the Hyp mouse, but also shows circling behavior, inner ear abnormalities, sterility in hemizygous males, and a milder phenotype in heterozygous females. The Gy and Hyp mutations have similar expression in the renal tubule, but the Gy mutation has an additional effect on the inner ear. The Gy allele is expressed in the inner ear of some heterozygous mice, which show circling behavior. The authors found that Gy mapped close (crossover value 0.4-0.8%) to Hyp. Lowe syndrome (309000) is not a human counterpart of Gy because in that condition the transport defect is not limited to phosphorus; moreover, characteristic morphologic changes in the nephron observed in Lowe syndrome are not seen in the Gy mouse. </p><p>Nesbitt et al. (1987) found that PTH-dependent 1-alpha-hydroxylase (CYP27B1; 609506) activity in the renal proximal convoluted tubule was abnormally regulated in the Hyp mouse, whereas calcitonin-dependent enzyme function in the proximal straight tubule was modulated normally. </p><p>In the search for a human equivalent of the Gy mutation, Boneh et al. (1987) measured hearing in 22 patients with X-linked hypophosphatemia; 5, including 2 mother/son pairs, had sensorineural hearing deficits due to cochlear dysfunction. The authors suggested that the disease in these persons may be the human counterpart of Gy. </p><p>Davidai et al. (1990) provided further information on the differences between the Hyp and Gy phenotypes in the mouse. </p><p>Collins and Ghishan (1996) found normal expression and location of the renal Na+/P(i) transporter NPT2 in Gy mice, suggesting that the molecular defect in the Gy mice is distinct from that in the Hyp mice, which show a decrease in transporter activity in the renal proximal tubules possibly related to decreased transcription (Collins et al., 1995). </p><p>In Gy mice, Strom et al. (1997) found a deletion of the first 3 exons and the promoter region of the PHEX, indicating that Hyp and Gy are allelic disorders. However, Meyer et al. (1998) found that the Gyro mouse has a partial deletion of both the Phex gene and the upstream spermine synthase gene (300105), making it a contiguous gene syndrome in that species. Gy is thus not as useful a model for human XLH as Hyp. </p>
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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>12 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, X-LINKED 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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PHEX, 2-BP DEL, 675TC
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<br />
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SNP: rs1064793956,
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ClinVar: RCV000486799, RCV000505406
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with X-linked hypophosphatemia (XLHRD; 307800), the HYP Consortium (1995) identified a 2-bp deletion (675delTC) in exon 1 of the PHEX gene. </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, X-LINKED 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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PHEX, IVS1AS, G-A, -1
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<br />
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SNP: rs2146979490,
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ClinVar: RCV000011561
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with X-linked hypophosphatemia (XLHRD; 307800), the HYP Consortium (1995) identified a splicing mutation in the PHEX gene: a G-to-A transition at the -1 position in the splice acceptor site of exon 2 of the partially cloned gene. </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 HYPOPHOSPHATEMIC RICKETS, X-LINKED 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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PHEX, IVS1AS, G-C, -1
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<br />
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SNP: rs2146979490,
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ClinVar: RCV000011562
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with X-linked hypophosphatemia (XLHRD; 307800), the HYP Consortium (1995) identified a G-to-C transversion at the -1 position in the splice acceptor site of exon 2 of the PHEX gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 HYPOPHOSPHATEMIC RICKETS, X-LINKED 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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PHEX, LEU274TER
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<br />
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SNP: rs137853268,
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ClinVar: RCV000011563, RCV005089228
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a sporadic case of hypophosphatemia in a female (XLHRD; 307800), Holm et al. (1997) identified an 823T-A transversion in the PHEX gene, resulting in a leu274-to-ter (L274X) substitution. (The nucleotides and amino acids were numbered on the basis of the cDNA sequence published by the HYP Consortium (1995).) </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 HYPOPHOSPHATEMIC RICKETS, X-LINKED 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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PHEX, CYS82TYR
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<br />
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SNP: rs137853269,
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ClinVar: RCV000011564, RCV001851795
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a male with familial X-linked hypophosphatemia (XLHRD; 307800), Holm et al. (1997) identified a 247G-A transition in exon 3 of the PHEX gene, resulting in a cys82-to-tyr (C82Y) substitution. (The nucleotides and amino acids were numbered on the basis of the cDNA sequence published by the HYP Consortium (1995).) </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0006 HYPOPHOSPHATEMIC RICKETS, X-LINKED 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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PHEX, PHE249SER AND MET250ILE
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<br />
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SNP: rs267606945, rs267606946,
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ClinVar: RCV000011565, RCV001857787, RCV001857790
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a female with familial hypophosphatemia (XLHRD; 307800), Holm et al. (1997) identified 2 mutations that were 4-bp apart in exon 7 of the PHEX gene: a 748T-C transition, resulting in a phe249-to-ser (F249S) substitution and a 752G-A transition, resulting in a met250-to-ile (M250I) substitution. The 2 mutations were on the same allele, as demonstrated by sequencing of both alleles. (The nucleotides and amino acids were numbered on the basis of the cDNA sequence published by the HYP Consortium (1995).) </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0007 HYPOPHOSPHATEMIC RICKETS, X-LINKED 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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PHEX, LEU555PRO
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<br />
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SNP: rs137853270,
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ClinVar: RCV000011566, RCV001202583
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In affected members of a kindred originally reported by Frymoyer and Hodgkin (1977) as having 'adult-onset vitamin D-resistant hypophosphatemic osteomalacia' (AVDRR), Econs et al. (1998) identified a T-to-C transition in exon 16 of the PHEX gene, resulting in a leu555-to-pro (L555P) substitution. Frymoyer and Hodgkin (1977) had asserted that the disorder was distinct from X-linked hypophosphatemic rickets (XLHRD; 307800) because affected children did not display radiographic evidence of rickets and patients typically presented with clinical manifestations of the disease in the fourth or fifth decade of life. However, clinical evaluation of affected family members by Econs et al. (1998) indicated that some displayed classic features of X-linked hypophosphatemic rickets. The authors were unable to verify progressive bowing in adults. Because of the clinical spectrum of X-linked hypophosphatemic rickets and the presence of a PHEX mutation in affected members of this kindred, the authors concluded that there is only 1 form of X-linked dominant phosphate wasting. </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>.0008 HYPOPHOSPHATEMIC RICKETS, X-LINKED 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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PHEX, A-G, NT-429
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<br />
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ClinVar: RCV000011567
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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 female patient from the Indian subcontinent with X-linked hypophosphatemic rickets (XLHRD; 307800) and congenital adrenal hypoplasia originally reported by Shah et al. (1988), Dixon et al. (1998) identified an A-to-G transition at codon -429 of the 5-prime untranslated region in the PHEX gene. The A-to-G transition was found to cosegregate with the disease and was absent in 247 alleles examined. Dixon et al. (1998) suggested that the mutation may lead to an alteration in the binding sites for ribosomal and other translation factors, such as tissue-specific regulatory proteins. </p><p>Shah et al. (1988) had termed the disorders in this Indian girl as 'familial glucocorticoid deficiency' and familial hypophosphatemic rickets, and had suggested the possibility of a chromosomal abnormality in activating both the X-linked hypophosphatemia locus and a closely situated locus for glucocorticoid deficiency. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0009 HYPOPHOSPHATEMIC RICKETS, X-LINKED 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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PHEX, IVS7, +1268, G-T
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<br />
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SNP: rs919011936,
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gnomAD: rs919011936,
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ClinVar: RCV000011568, RCV001367140
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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>Using lymphoblastoid RNA and RT-PCR, Christie et al. (2001) investigated 11 unrelated X-linked hypophosphatemic rickets (XLHRD; 307800) patients in whom coding region mutations had been excluded for intronic mutations that could lead to mRNA splicing abnormalities. One X-linked hypophosphatemia patient was found to have 3 abnormally large transcripts resulting from 51-, 100-, and 170-bp insertions, all of which would lead to missense peptides and premature termination codons. The origin of these transcripts was a G-to-T transversion at position +1268 of intron 7, which resulted in the occurrence of a high quality novel donor splice site (ggaagg to gtaagg). Splicing between this novel donor splice site and 3 preexisting, but normally silent, acceptor splice sites within intron 7 resulted in the occurrence of the 3 pseudoexons. </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>.0010 HYPOPHOSPHATEMIC RICKETS, X-LINKED 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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PHEX, ARG567TER
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<br />
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SNP: rs137853271,
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gnomAD: rs137853271,
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ClinVar: RCV000011569, RCV000414471
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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>Goji et al. (2006) described a family in which the father and only 1 of his 2 daughters were affected by hypophosphatemic rickets (XLHRD; 307800). The pedigree interpretation of the family suggested that genetic transmission of the disorder occurred as an autosomal dominant trait. However, the affected daughter was heterozygous for an arg567-to-ter (R567X) mutation in the PHEX gene, rather than in the FGF23 gene (605370), suggesting that the genetic transmission occurred as an X-linked dominant trait. Unexpectedly, the father was heterozygous for this mutation. Single-nucleotide primer extension and denaturing HPLC analysis of the father using DNA from single hair roots revealed that he was a somatic mosaic for the mutation. Haplotype analysis confirmed that the father transmitted the genotypes for 18 markers on the X chromosome equally to his 2 daughters. The fact that he transmitted the mutation to only 1 his 2 daughters indicated that he was a germline mosaic for the mutation. Goji et al. (2006) concluded that somatic and germline mosaicism for an X-linked dominant mutation in PHEX may mimic autosomal dominant inheritance. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0011 HYPOPHOSPHATEMIC RICKETS, X-LINKED 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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PHEX, IVS4, T-C, +6
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<br />
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SNP: rs1556020485,
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ClinVar: RCV000505454
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</span>
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<span class="mim-text-font">
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<p>Makras et al. (2008) described a mother and 2 sons with X-linked hypophosphatemic rickets (XLHRD; 307800) with unusual clinical features, including normal growth. A novel splice site mutation in intron 4 of the PHEX gene, IVS4+6G-T, that resulted in skipping of exon 4 was present in all 3 individuals. The mother and her sons were followed in the same institution for nearly 30 years. The mother had hypophosphatemia and normal height without ever receiving any treatment. Her 2 sons achieved final heights of 183.7 cm (Z score, -0.01) and 182.7 cm (Z score, -0.18), respectively, despite late initiation of treatment with phosphate and low serum phosphate levels. In addition, they had reversible proximal myopathy, which took approximately 7 years to resolve in the more severely affected son and 8 months to resolve in the other. </p>
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</span>
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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>.0012 HYPOPHOSPHATEMIC RICKETS, X-LINKED 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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PHEX, c.1701A-C
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<br />
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ClinVar: RCV003236696
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</span>
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<span class="mim-text-font">
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<p>In a Saudi mother and her son and 2 daughters with X-linked hypophosphatemic rickets (XLDHD; 307800), Alhamoudi et al. (2022) identified a c.1701A-C transversion (c.1701A-C, NM_000444.6) at the first nucleotide of exon 17 of the PHEX gene, resulting in a synonymous alteration in the protein (arg567-to-arg; R567R). Using RT-PCR, the authors showed that the variant interfered with splicing of exons 16 and 17, resulting in a shorter PHEX transcript compared to controls. Sanger sequencing of the cDNA showed complete skipping of exon 17 and direct splicing of exons 16 and 18, resulting in a frameshift and premature stop codon at glu568, with loss of the final 183 amino acids of the protein. The authors predicted that this led to loss of 2 conserved zinc-binding sites in exons 17 and 19, with loss of normal protein function. The variant was not present in public databases, including gnomAD. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Collins and Ghishan (1994); Dennis et al. (1977); Lobaugh and Drezner
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(1983); Meyer et al. (1979)
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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>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<strong>A unique mechanism of a novel synonymous PHEX variant causing X-linked hypophosphatemia.</strong>
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J. Clin. Endocr. Metab. 107: 2883-2891, 2022.
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<strong>Pex/PEX tissue distribution and evidence for a deletion in the 3-prime region of the Pex gene in X-linked hypophosphatemic mice.</strong>
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<strong>Primary cultures of renal epithelial cells from X-linked hypophosphatemic (Hyp) mice express defects in phosphate transport and vitamin D metabolism.</strong>
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Am. J. Hum. Genet. 43: 293-303, 1988.
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Boneh, A., Reade, T. M., Scriver, C. R., Rishikof, E.
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<strong>Audiometric evidence for two forms of X-linked hypophosphatemia in humans, apparent counterparts of Hyp and Gy mutations in mouse.</strong>
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Am. J. Med. Genet. 27: 997-1003, 1987.
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Christie, P. T., Harding, B., Nesbit, M. A., Whyte, M. P., Thakker, R. V.
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<strong>X-linked hypophosphatemia attributable to pseudoexons of the PHEX gene.</strong>
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[Full Text: https://doi.org/10.1210/jcem.86.8.7730]
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Collins, J. F., Bulus, N., Ghishan, F. K.
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<strong>Sodium-phosphate transporter adaptation to dietary phosphate deprivation in normal and hypophosphatemic mice.</strong>
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Am. J. Physiol. 268: G917-G924, 1995.
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[PubMed: 7611412]
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Collins, J. F., Ghishan, F. K.
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<strong>Molecular cloning, functional expression, tissue distribution and in situ hybridization of the renal sodium phosphate (Na+/P(i)) transporter in the control and hypophosphatemic mouse.</strong>
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FASEB J. 8: 862-868, 1994.
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Collins, J. F., Ghishan, F. K.
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<strong>The molecular defect in the renal sodium-phosphate transporter expression pathway of Gyro (Gy) mice is distinct from that of hypophosphatemic (Hyp) mice.</strong>
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FASEB J. 10: 751-759, 1996.
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[PubMed: 8635692]
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[Full Text: https://doi.org/10.1096/fasebj.10.7.8635692]
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Davidai, G. A., Nesbitt, T., Drezner, M. K.
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<strong>Normal regulation of calcitriol production in Gy mice: evidence for biochemical heterogeneity in the X-linked hypophosphatemic diseases.</strong>
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J. Clin. Invest. 85: 334-339, 1990.
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[PubMed: 2153705]
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Dennis, V. W., Bello-Reuss, E., Robinson, R. R.
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<strong>Response of phosphate transport to parathyroid hormone in segments of rabbit nephron.</strong>
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Am. J. Physiol. 233: F29-F38, 1977.
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[Full Text: https://doi.org/10.1152/ajprenal.1977.233.1.F29]
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Devault, A., Nault, C., Zollinger, M., Fournie-Zaluski, M.-C., Roques, B. P., Crine, P., Boileau, G.
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<strong>Expression of neutral endopeptidase (enkephalinase) in heterologous COS-1 cells: characterization of the recombinant enzyme and evidence for a glutamic acid residue at the active site.</strong>
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J. Biol. Chem. 263: 4033-4040, 1988.
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<p class="mim-text-font">
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Dixon, P. H., Christie, P. T., Wooding, C., Trump, D., Grieff, M., Holm, I., Gertner, J. M., Schmidtke, J., Shah, B., Shaw, N., Smith, C., Tau, C., Schlessinger, D., Whyte, M. P., Thakker, R. V.
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<strong>Mutational analysis of PHEX gene in X-linked hypophosphatemia.</strong>
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[PubMed: 9768674]
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<p class="mim-text-font">
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Donohue, M. M., Demay, M. B.
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<strong>Rickets in VDR null mice is secondary to decreased apoptosis of hypertrophic chondrocytes.</strong>
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[PubMed: 12193585]
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<p class="mim-text-font">
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Du, L., Desbarats, M., Viel, J., Glorieux, F. H., Cawthorn, C., Ecarot, B.
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<strong>cDNA cloning of the murine Pex gene implicated in X-linked hypophosphatemia and evidence for expression in bone.</strong>
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Genomics 36: 22-28, 1996.
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<p class="mim-text-font">
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Ecarot-Charrier, B., Glorieux, F. H., Travers, R., Desbarats, M., Bouchard, F., Hinek, A.
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<strong>Defective bone formation by transplanted Hyp mouse bone cells into normal mice.</strong>
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Endocrinology 123: 768-773, 1988.
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Econs, M. J., Friedman, N. E., Rowe, P. S. N., Speer, M. C., Francis, F., Strom, T. M., Oudet, C., Smith, J. A., Ninomiya, J. T., Lee, B. E., Bergen, H.
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<strong>A PHEX gene mutation is responsible for adult-onset vitamin D-resistant hypophosphatemic osteomalacia: evidence that the disorder is not a distinct entity from X-linked hypophosphatemic rickets.</strong>
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J. Clin. Endocr. Metab. 83: 3459-3462, 1998.
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[PubMed: 9768646]
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[Full Text: https://doi.org/10.1210/jcem.83.10.5167]
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</p>
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<p class="mim-text-font">
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Eicher, E. M., Southard, J. L., Scriver, C. R., Glorieux, F. H.
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<strong>Hypophosphatemia: mouse model for human familial hypophosphatemic (vitamin D-resistant) rickets.</strong>
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Proc. Nat. Acad. Sci. 73: 4667-4671, 1976.
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[PubMed: 188049]
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[Full Text: https://doi.org/10.1073/pnas.73.12.4667]
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</p>
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<p class="mim-text-font">
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Filisetti, D., Ostermann, G., von Bredow, M., Strom, T., Filler, G., Ehrich, J., Pannetier, S., Garnier, J.-M., Rowe, P., Francis, F., Julienne, A., Hanauer, A., Econs, M. J., Oudet, C.
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<strong>Non-random distribution of mutations in the PHEX gene, and under-detected missense mutations at non-conserved residues.</strong>
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Europ. J. Hum. Genet. 7: 615-619, 1999.
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[PubMed: 10439971]
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<p class="mim-text-font">
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Frymoyer, J. W., Hodgkin, W.
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<strong>Adult-onset vitamin D-resistant hypophosphatemic osteomalacia: a possible variant of vitamin D-resistant rickets.</strong>
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J. Bone Joint Surg. Am. 59: 101-106, 1977.
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[PubMed: 188828]
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</p>
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<li>
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<p class="mim-text-font">
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Gaucher, C., Walrant-Debray, O., Nguyen, T.-M., Esterle, L., Garabedian, M., Jehan, F.
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<strong>PHEX analysis in 118 pedigrees reveals new genetic clues in hypophosphatemic rickets.</strong>
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Hum. Genet. 125: 401-411, 2009.
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[PubMed: 19219621]
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<li>
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<p class="mim-text-font">
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Goji, K., Ozaki, K., Sadewa, A. H., Nishio, H., Matsuo, M.
|
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<strong>Somatic and germline mosaicism for a mutation of the PHEX gene can lead to genetic transmission of X-linked hypophosphatemic rickets that mimics an autosomal dominant trait.</strong>
|
|
J. Clin. Endocr. Metab. 91: 365-370, 2006.
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[PubMed: 16303832]
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[Full Text: https://doi.org/10.1210/jc.2005-1776]
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</p>
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<p class="mim-text-font">
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Grieff, M., Mumm, S., Waeltz, P., Mazzarella, R., Whyte, M. P., Thakker, R. V., Schlessinger, D.
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<strong>Expression and cloning of the human X-linked hypophosphatemia gene cDNA.</strong>
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Biochem. Biophys. Res. Commun. 231: 635-639, 1997.
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[PubMed: 9070861]
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[Full Text: https://doi.org/10.1006/bbrc.1997.6153]
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</p>
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<li>
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<p class="mim-text-font">
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Guo, R., Quarles, L. D.
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<strong>Cloning and sequencing of human PEX from a bone cDNA library: evidence for its developmental stage-specific regulation in osteoblasts.</strong>
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J. Bone Miner. Res. 12: 1009-1017, 1997.
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[PubMed: 9199999]
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[Full Text: https://doi.org/10.1359/jbmr.1997.12.7.1009]
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</p>
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<li>
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<p class="mim-text-font">
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Holm, I. A., Huang, X., Kunkel, L. M.
|
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<strong>Mutational analysis of the PEX gene in patients with X-linked hypophosphatemic rickets.</strong>
|
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Am. J. Hum. Genet. 60: 790-797, 1997.
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[PubMed: 9106524]
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</p>
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</li>
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