6411 lines
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Entry
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- *171760 - ALKALINE PHOSPHATASE, LIVER; ALPL
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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">*171760</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/171760">Table View</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<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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<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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<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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<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=ENSG00000162551;t=ENST00000374840" 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=249" 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=171760" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<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=ENSG00000162551;t=ENST00000374840" 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_000478,NM_001127501,NM_001177520,NM_001369803,NM_001369804,NM_001369805,XM_017000903" 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_000478" 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=171760" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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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=01377&isoform_id=01377_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/ALPL" 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/178462,3401945,4572574,6580028,62089214,68067533,116734717,118835602,119615380,119615381,119615382,119615383,127796485,127799243,127799935,127801853,187954299,189069211,221039408,221040844,221042090,294660770,294660772,354620144,1034557351,1621574609,1621574611,1621574613,2462507410" 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/P05186" 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 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=249" 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=ENSG00000162551;t=ENST00000374840" 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=ALPL" 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=ALPL" 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+249" 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/ALPL" 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:249" 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/249" 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=chr1&hgg_gene=ENST00000696766.1&hgg_start=21508984&hgg_end=21578410&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:438" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/alpl" 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=171760[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=171760[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000162551" 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=ALPL" 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=ALPL" 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=ALPL" 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.sesep.uvsq.fr/Database.html" 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=ALPL&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/PA24729" 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:438" 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/FBgn0033423.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:87983" 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/ALPL#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:87983" 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/249/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA002162/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=249" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040420-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="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:171760" 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://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:249" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=ALPL&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
|
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 20756002, 30174008, 55236002, 708672004<br />
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
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171760
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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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ALKALINE PHOSPHATASE, LIVER; ALPL
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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">
|
|
ALKALINE PHOSPHATASE, LIVER/BONE/KIDNEY TYPE<br />
|
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ALKALINE PHOSPHATASE, TISSUE-NONSPECIFIC; TNSALP; TNAP
|
|
</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>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=ALPL" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ALPL</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>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/1/251?start=-3&limit=10&highlight=251">1p36.12</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:21508984-21578410&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'})">1:21,508,984-21,578,410</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
|
|
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|
|
</span>
|
|
</p>
|
|
</div>
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
<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
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=146300,241510,241500,146300" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/251?start=-3&limit=10&highlight=251">
|
|
1p36.12
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Hypophosphatasia, adult
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/146300"> 146300 </a>
|
|
|
|
</span>
|
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</td>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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PheneGene Graphics <span class="caret"></span>
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<li><a href="/graph/linear/171760" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/171760" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>Alkaline phosphatases are membrane-bound glycoproteins that hydrolyze various monophosphate esters at a high pH optimum (<a href="#32" class="mim-tip-reference" title="Weiss, M. J., Henthorn, P. S., Lafferty, M. A., Slaughter, C., Raducha, M., Harris, H. <strong>Isolation and characterization of a cDNA encoding a human liver/bone/kidney-type alkaline phosphatase.</strong> Proc. Nat. Acad. Sci. 83: 7182-7186, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3532105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3532105</a>] [<a href="https://doi.org/10.1073/pnas.83.19.7182" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3532105">Weiss et al., 1986</a>). Liver/bone/kidney alkaline phosphatase, also known as tissue-nonspecific alkaline phosphatase, acts physiologically as a lipid-anchored phosphoethanolamine (PEA) and pyridoxal-5-prime-phosphate (PLP) ectophosphatase (<a href="#2" class="mim-tip-reference" title="Fedde, K. N., Whyte, M. P. <strong>Alkaline phosphatase (tissue-nonspecific isoenzyme) is a phosphoethanolamine and pyridoxal-5-prime-phosphate ectophosphatase: normal and hypophosphatasia fibroblast study.</strong> Am. J. Hum. Genet. 47: 767-775, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2220817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2220817</a>]" pmid="2220817">Fedde and Whyte, 1990</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2220817+3532105" 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>See ALPQTL1 (<a href="/entry/171720">171720</a>) for information on quantitative trait loci influencing the plasma level of alkaline phosphatase.</p>
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<p>Using quantitative inhibition and thermostability studies, <a href="#3" class="mim-tip-reference" title="Goldstein, D. J., Rogers, C. E., Harris, H. <strong>Expression of alkaline phosphatase loci in mammalian tissues.</strong> Proc. Nat. Acad. Sci. 77: 2857-2860, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6930672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6930672</a>] [<a href="https://doi.org/10.1073/pnas.77.5.2857" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6930672">Goldstein et al. (1980)</a> presented evidence for the existence of at least 3 distinct forms of human alkaline phosphatase (<a href="https://enzyme.expasy.org/EC/3.1.3.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 3.1.3.1</a>): intestinal (ALPI; <a href="/entry/171740">171740</a>), placental (ALPP; <a href="/entry/171800">171800</a>), and liver/bone/kidney (ALPL). <a href="#6" class="mim-tip-reference" title="Harris, H., Hopkinson, D. A., Robson, E. B. <strong>The incidence of rare alleles determining electrophoretic variants: data on 43 enzyme loci in man.</strong> Ann. Hum. Genet. 37: 237-253, 1974.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4812947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4812947</a>] [<a href="https://doi.org/10.1111/j.1469-1809.1974.tb01832.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4812947">Harris et al. (1974)</a> found no genetic variants by electrophoretic means. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6930672+4812947" 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="#32" class="mim-tip-reference" title="Weiss, M. J., Henthorn, P. S., Lafferty, M. A., Slaughter, C., Raducha, M., Harris, H. <strong>Isolation and characterization of a cDNA encoding a human liver/bone/kidney-type alkaline phosphatase.</strong> Proc. Nat. Acad. Sci. 83: 7182-7186, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3532105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3532105</a>] [<a href="https://doi.org/10.1073/pnas.83.19.7182" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3532105">Weiss et al. (1986)</a> cloned a cDNA for liver/bone/kidney alkaline phosphatase from a human osteosarcoma cell line. The deduced 524-amino acid ALPL protein has a presumed signal peptide of 17 amino acids and a predicted molecular mass of 57.2 kD. The ALPL protein shares 52% sequence identity with placental alkaline phosphatase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3532105" 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="#2" class="mim-tip-reference" title="Fedde, K. N., Whyte, M. P. <strong>Alkaline phosphatase (tissue-nonspecific isoenzyme) is a phosphoethanolamine and pyridoxal-5-prime-phosphate ectophosphatase: normal and hypophosphatasia fibroblast study.</strong> Am. J. Hum. Genet. 47: 767-775, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2220817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2220817</a>]" pmid="2220817">Fedde and Whyte (1990)</a> demonstrated that the alkaline phosphatase of skin fibroblasts is ALPL, the tissue-nonspecific type, and that it is active toward millimolar concentrations of the putative natural substrates phosphoethanolamine and pyridoxal-5-prime-phosphate. Both activities were deficient in hypophosphatasia (see <a href="/entry/241500">241500</a>) fibroblasts. They presented evidence that normal fibroblast ALP is linked to the outside of the plasma membrane; thus, the enzyme acts physiologically as a lipid-anchored PEA and PLP ectophosphatase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2220817" 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="#33" class="mim-tip-reference" title="Weiss, M. J., Ray, K., Henthorn, P. S., Lamb, B., Kadesch, T., Harris, H. <strong>Structure of the human liver/bone/kidney alkaline phosphatase gene.</strong> J. Biol. Chem. 263: 12002-12010, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3165380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3165380</a>]" pmid="3165380">Weiss et al. (1988)</a> and <a href="#17" class="mim-tip-reference" title="Matsuura, S., Kishi, F., Kajii, T. <strong>Characterization of a 5-prime-flanking region of the human liver/bone/kidney alkaline phosphatase gene: two kinds of mRNA from a single gene.</strong> Biochem. Biophys. Res. Commun. 168: 993-1000, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2346496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2346496</a>] [<a href="https://doi.org/10.1016/0006-291x(90)91127-e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2346496">Matsuura et al. (1990)</a> found that the ALPL gene exists in single copy in the haploid genome and contains 12 exons distributed over more than 50 kb. As compared with the gene isolated using a bone-type ALPL cDNA (<a href="#33" class="mim-tip-reference" title="Weiss, M. J., Ray, K., Henthorn, P. S., Lamb, B., Kadesch, T., Harris, H. <strong>Structure of the human liver/bone/kidney alkaline phosphatase gene.</strong> J. Biol. Chem. 263: 12002-12010, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3165380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3165380</a>]" pmid="3165380">Weiss et al., 1988</a>), liver-type ALPL mRNA was found to have another leader exon about 3.4 kb upstream from exon 2 and alternative splicing in the first exon was indicated (<a href="#17" class="mim-tip-reference" title="Matsuura, S., Kishi, F., Kajii, T. <strong>Characterization of a 5-prime-flanking region of the human liver/bone/kidney alkaline phosphatase gene: two kinds of mRNA from a single gene.</strong> Biochem. Biophys. Res. Commun. 168: 993-1000, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2346496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2346496</a>] [<a href="https://doi.org/10.1016/0006-291x(90)91127-e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2346496">Matsuura et al., 1990</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3165380+2346496" 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>Using human-rodent somatic cell hybrids, Swallow et al. (<a href="#28" class="mim-tip-reference" title="Swallow, D. M., Povey, S., Goodfellow, P. N. G., Andrews, P., Harris, H. <strong>The liver/bone/kidney isozyme of alkaline phosphatase (ALPL) is coded by a gene on chromosome 1. (Abstract)</strong> Cytogenet. Cell Genet. 40: 756 only, 1985."None>1985</a>, <a href="#29" class="mim-tip-reference" title="Swallow, D. M., Povey, S., Parkar, M., Andrews, P. W., Harris, H., Pym, B., Goodfellow, P. <strong>Mapping of the gene coding for the human liver/bone/kidney isozyme of alkaline phosphatase to chromosome 1.</strong> Ann. Hum. Genet. 50: 229-235, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3446011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3446011</a>] [<a href="https://doi.org/10.1111/j.1469-1809.1986.tb01043.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3446011">1986</a>) mapped the gene for liver/bone/kidney alkaline phosphatase to chromosome 1. Mouse Akp2, which is homologous, is on chromosome 4 between Pgm2 and Pgd. Thus, ALPL might be located on 1p between PGM1 (<a href="/entry/171900">171900</a>) and PGD (<a href="/entry/172200">172200</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3446011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a DNA polymorphism of the ALPL gene, <a href="#1" class="mim-tip-reference" title="Ardinger, R. H., Jr., Buetow, K. H., Weiss, M. J., Nemer, M., DeHaven, C. R., Murray, J. C. <strong>Multipoint linkage relationships of 6 loci on 1p (ALPL, GLUT, PGD, PGM1, PND, RH). (Abstract)</strong> Am. J. Hum. Genet. 41: A154 only, 1987."None>Ardinger et al. (1987)</a> found linkage to Rh (theta = 0.08; lod = 5.50). Multipoint analysis indicated the following order: Rh--3--ALPL--12--GLUT--23--PGM1, with the interlocus intervals as percent recombination in males (the female rate about 2.8 times the male rate).</p><p><a href="#34" class="mim-tip-reference" title="Weiss, M., Smith, M., Griffin, C., Nussbaum, R., Murray, J., Emanuel, B., Harris, H. <strong>Assignment of the gene encoding the liver/bone/kidney form of alkaline phosphatase ALPL to the region 1p34-p36.1. (Abstract)</strong> Cytogenet. Cell Genet. 46: 714 only, 1987."None>Weiss et al. (1987)</a> assigned the ALPL locus to 1p36.1-p34 by demonstrating linkage to Rh (maximum lod score = 5.50, theta = 0.10). In the full report, <a href="#26" class="mim-tip-reference" title="Smith, M., Weiss, M. J., Griffin, C. A., Murray, J. C., Buetow, K. H., Emanuel, B. S., Henthorn, P. S., Harris, H. <strong>Regional assignment of the gene for human liver/bone/kidney alkaline phosphatase to chromosome 1p36.1-p34.</strong> Genomics 2: 139-143, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3410475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3410475</a>] [<a href="https://doi.org/10.1016/0888-7543(88)90095-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3410475">Smith et al. (1988)</a> established the location in 1p36.1-p34 by a combination of Southern blot analysis of hybrid cell DNA, in situ hybridization, and genetic linkage analysis. Linkage to Rh was indicated by a maximum lod score of 15.66 at a recombination fraction of 0.10 and to alpha-L-fucosidase (FUCA1; <a href="/entry/612280">612280</a>) by a maximum lod score of 8.24 at a recombination fraction of 0.02. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3410475" 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><strong><em>Hypophosphatasia</em></strong></p><p>
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In a male infant with infantile hypophosphatasia (HPPI; <a href="/entry/241500">241500</a>) who was born of second-cousin parents and died at 3 months of age, <a href="#31" class="mim-tip-reference" title="Weiss, M. J., Cole, D. E. C., Ray, K., Whyte, M. P., Lafferty, M. A., Mulivor, R. A., Harris, H. <strong>A missense mutation in the human liver/bone/kidney alkaline phosphatase gene causing a lethal form of hypophosphatasia.</strong> Proc. Nat. Acad. Sci. 85: 7666-7669, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3174660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3174660</a>] [<a href="https://doi.org/10.1073/pnas.85.20.7666" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3174660">Weiss et al. (1988)</a> identified homozygosity for a mutation in the ALPL gene (A162T; <a href="#0001">171760.0001</a>). Functional studies demonstrated that the mutation abolished the expression of active enzyme. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3174660" 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 studies of fibroblasts from 4 unrelated patients with severe (perinatal or infantile) hypophosphatasia (see <a href="/entry/241500">241500</a>), <a href="#7" class="mim-tip-reference" title="Henthorn, P. S., Raducha, M., Fedde, K. N., Lafferty, M. A., Whyte, M. P. <strong>Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia.</strong> Proc. Nat. Acad. Sci. 89: 9924-9928, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1409720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1409720</a>] [<a href="https://doi.org/10.1073/pnas.89.20.9924" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1409720">Henthorn et al. (1992)</a> identified compound heterozygosity for 8 different mutations in the ALPL gene (<a href="#0002">171760.0002</a>-<a href="#0009">171760.0009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1409720" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Henthorn, P. S., Whyte, M. P. <strong>Missense mutations of the tissue-nonspecific alkaline phosphatase gene in hypophosphatasia.</strong> Clin. Chem. 38: 2501-2505, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1360878/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1360878</a>]" pmid="1360878">Henthorn and Whyte (1992)</a> reviewed 9 missense mutations in the ALPL gene found in hypophosphatasia. They showed that the 9 amino acid residues affected in these mutations are identical in all mammals examined, indicating evolutionary conservation. Indeed, 3 of the mutations resulted in amino acid substitutions in regions of the polypeptide that are conserved throughout evolution, being identical in mammals, yeast, and bacteria. Four of the mutations were observed in a single patient and the others in only a few. The asp378-to-val mutation (<a href="#0009">171760.0009</a>) had the highest frequency, being found in 9 of 42 patients and none of 63 controls. Thus, the experience is similar to that in so many other disorders in which many different allelic mutations can produce the same or a similar phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1360878" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Mornet, E., Taillandier, A., Peyramaure, S., Kaper, F., Muller, F., Brenner, R., Bussiere, P., Freisinger, P., Godard, J., Le Merrer, M., Oury, J. F., Plauchu, H., Puddu, R., Rival, J. M., Superti-Furga, A., Touraine, R. L., Serre, J. L., Simon-Bouy, B. <strong>Identification of fifteen novel mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in European patients with severe hypophosphatasia.</strong> Europ. J. Hum. Genet. 6: 308-314, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9781036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9781036</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200190" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9781036">Mornet et al. (1998)</a> characterized tissue-nonspecific alkaline phosphatase gene mutations in 13 European families affected by perinatal, infantile, or childhood hypophosphatasia (HPPC; <a href="/entry/241510">241510</a>). Eighteen distinct mutations were found, only 3 of which had previously been reported, in North American and Japanese populations. Most of the 15 newly identified mutations were missense mutations, but 2 mutations affected donor splice sites and 1 was a nonsense mutation. A missense mutation in the last codon of the putative signal peptide probably affected the final maturation of the protein. Despite extensive sequencing of the gene and its promoter region, only 1 mutation was identified in 2 cases, 1 of which was compatible with a possible dominant effect of certain mutations and the putative role of polymorphisms of the ALPL gene. In 12 of the 13 tested families, genetic diagnosis was possible by characterization of the mutations or by use of polymorphisms as genetic markers. In 2 families where clinical, laboratory, and radiographic data were unclear, the diagnosis of hypophosphatasia could be made, and prenatal diagnosis was performed in 1 case. Thus, severe hypophosphatasia is due to a very large spectrum of mutations in European populations with no prevalent mutation; genetic diagnosis must be performed by extensive analysis of the gene. Combined with previous reports, a total of 43 ALPL mutations had been identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9781036" 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="#38" class="mim-tip-reference" title="Zurutuza, L., Muller, F., Gibrat, J. F., Taillandier, A., Simon-Bouy, B., Serre, J. L., Mornet, E. <strong>Correlations of genotype and phenotype in hypophosphatasia.</strong> Hum. Molec. Genet. 8: 1039-1046, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10332035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10332035</a>] [<a href="https://doi.org/10.1093/hmg/8.6.1039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10332035">Zurutuza et al. (1999)</a> used clinical data, site-directed mutagenesis, and computer-assisted modeling to propose a classification of 32 ALPL gene mutations found in 23 European patients (17 with lethal hypophosphatasia and 6 with nonlethal hypophosphatasia). Transfection studies of the missense mutations found in nonlethal hypophosphatasia showed that 6 of them allowed significant residual in vitro enzymatic activity, suggesting that these mutations corresponded to moderate alleles. Each of the 6 patients with nonlethal hypophosphatasia carried at least 1 of these alleles. The 3-dimensional model study showed that moderate mutations were not found in the active site, and that most of the severe missense mutations were localized in crucial domains such as the active site, the vicinity of the active site, and homodimer interface. Some mutations appeared to be organized in clusters on the surface of the molecule that may represent candidates for regions interacting with the C-terminal end involved in glycosylphosphatidylinositol (GPI) attachment or with other dimers to form tetramers. The results of these studies showed a good correlation between clinical forms of the disease, mutagenesis experiments, and the 3-dimensional structure study, and allowed the authors to distinguish moderate alleles from severe alleles. They also confirmed that the extremely high phenotypic heterogeneity observed in patients with hypophosphatasia was due mainly to variable residual enzymatic activities allowed by missense mutations in the gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10332035" 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="Mornet, E. <strong>Personal Communication.</strong> Paris, France 6/3/1999."None>Mornet (1999)</a> studied 2 large families with adult hypophosphatasia (HPPA; <a href="/entry/146300">146300</a>). In 1 family, hypophosphatasia was dominantly inherited and was due to a missense mutation in the ALPL gene. In the other family, hypophosphatasia was recessively transmitted and was due to compound heterozygosity of a missense mutation and a splicing mutation in the ALPL gene. Thus, adult hypophosphatasia can be transmitted as either a dominant or recessive trait.</p><p><a href="#22" class="mim-tip-reference" title="Mornet, E. <strong>Hypophosphatasia: the mutations in the tissue-nonspecific alkaline phosphatase gene.</strong> Hum. Mutat. 15: 309-315, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10737975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10737975</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(200004)15:4<309::AID-HUMU2>3.0.CO;2-C" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10737975">Mornet (2000)</a> stated that most of the 65 distinct mutations that had been described to that time were missense mutations. Correlations of genotype and phenotype had been established on the basis of clinical data exhibited by the patients, transfection studies, computer-assisted modeling, and examination of biochemical properties of alkaline phosphatase in cultured fibroblasts of patients. <a href="#22" class="mim-tip-reference" title="Mornet, E. <strong>Hypophosphatasia: the mutations in the tissue-nonspecific alkaline phosphatase gene.</strong> Hum. Mutat. 15: 309-315, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10737975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10737975</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(200004)15:4<309::AID-HUMU2>3.0.CO;2-C" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10737975">Mornet (2000)</a> also discussed the dominantly inherited form of adult hypophosphatasia. It appeared that dominant and recessive hypophosphatasia could in some instances be due to the same mutations. The findings also suggested that parents of patients affected with severe recessive forms of the disease may show, in addition to the well-known hypophosphatasemia, undiagnosed mild symptoms corresponding to adult hypophosphatasia or odontohypophosphatasia (HPPO; see <a href="/entry/146300">146300</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10737975" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Lia-Baldini, A. S., Muller, F., Taillandier, A., Gibrat, J. F., Mouchard, M., Robin, B., Simon-Bouy, B., Serre, J. L., Aylsworth, A. S., Bieth, E., Delanote, S., Freisinger, P., Hu, J. C.-C., Krohn, H.-P., Nunes, M. E., Mornet, E. <strong>A molecular approach to dominance in hypophosphatasia.</strong> Hum. Genet. 109: 99-108, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479741</a>] [<a href="https://doi.org/10.1007/s004390100546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479741">Lia-Baldini et al. (2001)</a> stated that in approximately 14% of patients tested in their laboratories, only 1 ALPL gene mutation was found, despite exhaustive sequencing of the gene, suggesting that missing mutations are harbored in intron or regulatory sequences or that the disease is dominantly transmitted. The distinction between these 2 situations is of obvious importance to genetic counseling. <a href="#14" class="mim-tip-reference" title="Lia-Baldini, A. S., Muller, F., Taillandier, A., Gibrat, J. F., Mouchard, M., Robin, B., Simon-Bouy, B., Serre, J. L., Aylsworth, A. S., Bieth, E., Delanote, S., Freisinger, P., Hu, J. C.-C., Krohn, H.-P., Nunes, M. E., Mornet, E. <strong>A molecular approach to dominance in hypophosphatasia.</strong> Hum. Genet. 109: 99-108, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479741</a>] [<a href="https://doi.org/10.1007/s004390100546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479741">Lia-Baldini et al. (2001)</a> studied 8 point mutations found in patients with no other detectable mutation. Three of these mutations, G46V, S164L, and I473F, had not previously been described; the others were A99T (<a href="#0015">171760.0015</a>), R167W, R206W, G232V (<a href="#0021">171760.0021</a>), and N461I. By means of site-directed mutagenesis, transfections in COS-1 cells, and 3-dimensional modeling, <a href="#14" class="mim-tip-reference" title="Lia-Baldini, A. S., Muller, F., Taillandier, A., Gibrat, J. F., Mouchard, M., Robin, B., Simon-Bouy, B., Serre, J. L., Aylsworth, A. S., Bieth, E., Delanote, S., Freisinger, P., Hu, J. C.-C., Krohn, H.-P., Nunes, M. E., Mornet, E. <strong>A molecular approach to dominance in hypophosphatasia.</strong> Hum. Genet. 109: 99-108, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479741</a>] [<a href="https://doi.org/10.1007/s004390100546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479741">Lia-Baldini et al. (2001)</a> evaluated the possible dominant effect of these 8 mutations. Four exhibited dominant-negative effect by inhibiting the enzymatic activity of the heterodimer, whereas the other 4 did not show such inhibition. Strong inhibition resulted in severe hypophosphatasia, whereas partial inhibition resulted in milder forms of the disease. Analysis of the 3D model of the enzyme showed that mutations exhibiting a dominant-negative effect were clustered in 2 regions, namely, the active site and an area probably interacting with a region having a particular biologic function such as dimerization, tetramerization, or membrane anchoring. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11479741" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with lethal perinatal hypophosphatasia with a unique clinical presentation of convulsions that responded to pyridoxine, <a href="#15" class="mim-tip-reference" title="Litmanovitz, I., Reish, O., Dolfin, T., Arnon, S., Regev, R., Grinshpan, G., Yamazaki, M., Ozono, K. <strong>Glu274lys/gly309arg mutation of the tissue-nonspecific alkaline phosphatase gene in neonatal hypophosphatasia associated with convulsions.</strong> J. Inherit. Metab. Dis. 25: 35-40, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11999978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11999978</a>] [<a href="https://doi.org/10.1023/a:1015121414782" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11999978">Litmanovitz et al. (2002)</a> identified 2 mutations in the ALPL gene. One mutation was considered to be moderate (<a href="#38" class="mim-tip-reference" title="Zurutuza, L., Muller, F., Gibrat, J. F., Taillandier, A., Simon-Bouy, B., Serre, J. L., Mornet, E. <strong>Correlations of genotype and phenotype in hypophosphatasia.</strong> Hum. Molec. Genet. 8: 1039-1046, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10332035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10332035</a>] [<a href="https://doi.org/10.1093/hmg/8.6.1039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10332035">Zurutuza et al., 1999</a>); the other was novel. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10332035+11999978" 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>According to <a href="#10" class="mim-tip-reference" title="Herasse, M., Spentchian, M., Taillandier, A., Mornet, E. <strong>Evidence of a founder effect for the tissue-nonspecific alkaline phosphatase (TNSALP) gene E174K mutation in hypophosphatasia patients.</strong> Europ. J. Hum. Genet. 10: 666-668, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12357339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12357339</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200857" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12357339">Herasse et al. (2002)</a>, the glu174-to-lys (E174K; <a href="#0008">171760.0008</a>) mutation in the ALPL gene is common in Caucasians, widely distributed geographically, and present in 31% of patients with mild hypophosphatasia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12357339" 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="Herasse, M., Spentchian, M., Taillandier, A., Keppler-Noreuil, K., Fliorito, A. N. M., Bergoffen, J., Wallerstein, R., Muti, C., Simon-Bouy, B., Mornet, E. <strong>Molecular study of three cases of odontohypophosphatasia resulting from heterozygosity for mutations in the tissue non-specific alkaline phosphatase gene.</strong> J. Med. Genet. 40: 605-609, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12920074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12920074</a>] [<a href="https://doi.org/10.1136/jmg.40.8.605" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12920074">Herasse et al. (2003)</a> reported 3 patients with odontohypophosphatasia (see <a href="/entry/146300">146300</a>) resulting from heterozygosity for a mutation in the ALPL gene; 2 of the mutations had previously been reported (see A99T; <a href="#0015">171760.0015</a>), whereas the third, pro91 to leu, was novel (P91L; <a href="#0018">171760.0018</a>). The proband with the P91L mutation was 9 years old and the other 2 were 2 years old. The 39-year-old mother of the proband with the P91L mutation had lost her permanent teeth and had hypophosphatasia. The 38-year-old mother of the proband with the A99T mutation had an unusual number of dental caries, numerous treatments of dental root canals, and low serum ALP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12920074" 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="Whyte, M. P., Zhang, F., Wenkert, D., McAlister, W. H., Mack, K. E., Benigno, M. C., Coburn, S. P., Wagy, S., Griffin, D. M., Ericson, K. L., Mumm, S. <strong>Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients.</strong> Bone 75: 229-239, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25731960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25731960</a>] [<a href="https://doi.org/10.1016/j.bone.2015.02.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25731960">Whyte et al. (2015)</a> evaluated clinical and molecular features in 173 patients with hypophosphatasia, including 64 patients with odontohypophosphatasia, 38 with mild childhood HPP, 58 with severe childhood HPP, and 13 with infantile HPP. Sequencing of the ALPL gene was performed in 105 patients, of whom 63 had a single heterozygous mutation consistent with autosomal dominant HPP and 42 had compound heterozygous mutations consistent with autosomal recessive HPP. No homozygotes were identified. An autosomal recessive inheritance pattern predominated in infantile- and severe childhood-onset HPP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25731960" 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="Mornet, E., Taillandier, A., Domingues, C., Dufour, A., Benaloun, E., Lavaud, N., Wallon, F., Rousseau, N., Charle, C., Guberto, M., Muti, C., Simon-Bouy, B. <strong>Hypophosphatasia: a genetic-based nosology and new insights in genotype-phenotype correlation.</strong> Europ. J. Hum. Genet. 29: 289-299, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32973344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32973344</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32973344[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41431-020-00732-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32973344">Mornet et al. (2021)</a> evaluated mutations in the ALPL gene in a cohort of 424 European patients with HPP. The patient phenotypes were categorized into perinatal HPP, infantile HPP, childhood HPP, odontoHPP, and adult HPP, and the mutations in ALPL were categorized as normal (N), severe with no dominant effect (s), severe with a dominant-negative effect (Sd), moderate (m), and not classifiable (NC) based on prior functional testing. In the cohort, 166 patients had heterozygous mutations and 258 patients had compound heterozygous or homozygous mutations, comprising 682 mutant alleles and 249 distinct mutations. Some mutations were found to be anchored to specific geographic regions (e.g., R184Q was more common in France), indicating likely founder effects as opposed to individual mutational events. Patients with perinatal HPP had s/s, s/Sd, and Sd/Sd genotypes; patients with infantile HPP had s/s, Sd/m, s/m, and m/m genotypes; patients with childhood HPP had Sd/m, s/m and Sd/N genotypes; patients with adult HPP had Sd/N, Sd/m, s/m, m/N, and s/N genotypes; and patients with odontoHPP had mostly Sd/N genotypes. A subset of mutations identified in patients with autosomal recessive disease were also seen in patients with autosomal dominant disease, which had implications for genetic counseling in families. Notably, a newly recognized cohort of patients with adult HPP had a heterozygous mutation in ALPL without a dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32973344" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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---Vitamin B6 Levels</p><p>For discussion of a possible association between variation in the ALPL gene and plasma levels of vitamin B6, see <a href="/entry/612957">612957</a>.</p>
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<p>Using homologous recombination in embryonic stem cells to generate null mutant mice, <a href="#30" class="mim-tip-reference" title="Waymire, K. G., Mahuren, J. D., Jaje, J. M., Guilarte, T. R., Coburn, S. P., MacGregor, G. R. <strong>Mice lacking tissue non-specific alkaline phosphatase die from seizures due to defective metabolism of vitamin B-6.</strong> Nature Genet. 11: 45-51, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550313</a>] [<a href="https://doi.org/10.1038/ng0995-45" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550313">Waymire et al. (1995)</a> found that mice lacking ALPL (which they referred to as tissue-nonspecific alkaline phosphatase) have normal skeletal development. However, at approximately 2 weeks after birth, homozygous mutant mice developed seizures that were subsequently fatal. Defective metabolism of PLP, characterized by elevated serum PLP levels, resulted in reduced levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the brain. The mutant seizure phenotype could be rescued by the administration of pyridoxal and a semisolid diet. <a href="#30" class="mim-tip-reference" title="Waymire, K. G., Mahuren, J. D., Jaje, J. M., Guilarte, T. R., Coburn, S. P., MacGregor, G. R. <strong>Mice lacking tissue non-specific alkaline phosphatase die from seizures due to defective metabolism of vitamin B-6.</strong> Nature Genet. 11: 45-51, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550313</a>] [<a href="https://doi.org/10.1038/ng0995-45" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550313">Waymire et al. (1995)</a> observed at about 3 weeks of age both a color difference and malformation of the incisor teeth in the TNAP mutant mice who were administered pyridoxal. Significantly, TNAP is expressed in the tissues within which incisor development takes place. At the growth level, the teeth of the mutants were unusually white and brittle, suggestive of hypocalcification. Between 25 and 60 days of age, mutant animals that responded to pyridoxal injections and were fed a high-fat solid diet started to display signs of paralysis. This progressed to complete inability of the animals to move and death presumably from respiratory and/or cardiac failure. During the time that pyridoxal was being administered, the incisors became progressively more deformed and often broke. (The feeding of a semisolid diet was intended to maximize their food intake.) None of the mutants fed this diet developed symptoms of paralysis; however, if pyridoxal supplementation was withdrawn, all died from seizures within 72 hours. As in humans, mouse TNAP functions as an ectoenzyme to convert PLP to pyridoxal. <a href="#30" class="mim-tip-reference" title="Waymire, K. G., Mahuren, J. D., Jaje, J. M., Guilarte, T. R., Coburn, S. P., MacGregor, G. R. <strong>Mice lacking tissue non-specific alkaline phosphatase die from seizures due to defective metabolism of vitamin B-6.</strong> Nature Genet. 11: 45-51, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550313</a>] [<a href="https://doi.org/10.1038/ng0995-45" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550313">Waymire et al. (1995)</a> suggested that the fact that pyridoxal is undetectable in the plasma of only rare cases of the severe perinatal form of human hypophosphatasia is probably a reflection of the type of mutation and the degree of residual alkaline phosphatase activity. Some of the TNAP mutants administered pyridoxine responded to the treatment, but the effect on longevity was minimal and mutants succumbed to seizure-related death within 2 weeks. <a href="#35" class="mim-tip-reference" title="Whyte, M. P., Mahuren, J. D., Fedde, K. N., Cole, F. S., McCabe, E. R., Coburn, S. P. <strong>Perinatal hypophosphatasia: tissue levels of vitamin B-6 are unremarkable despite markedly increased circulating concentrations of pyridoxal-5-prime-phosphate: evidence for an ectoenzyme role for tissue-nonspecific alkaline phosphatase.</strong> J. Clin. Invest. 81: 1234-1239, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3350970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3350970</a>] [<a href="https://doi.org/10.1172/JCI113440" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3350970">Whyte et al. (1988)</a> observed essentially the same progression in an infant with severe neonatal hypophosphatemia who presented with seizures, had undetectable levels of plasma pyridoxal, and was administered pyridoxine. In mammals, following uptake, the majority of pyridoxine is phosphorylated to form pyridoxine phosphate before being oxidized to yield pyridoxal 5-prime phosphate. The PLP is subsequently converted to pyridoxal by alkaline phosphatase. Very little, if any, pyridoxine is converted directly to pyridoxal. Individuals with hypophosphatasia would not be expected to interconvert pyridoxine to pyridoxal with any degree of efficiency and, based on the findings in the knockout mice by <a href="#30" class="mim-tip-reference" title="Waymire, K. G., Mahuren, J. D., Jaje, J. M., Guilarte, T. R., Coburn, S. P., MacGregor, G. R. <strong>Mice lacking tissue non-specific alkaline phosphatase die from seizures due to defective metabolism of vitamin B-6.</strong> Nature Genet. 11: 45-51, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550313</a>] [<a href="https://doi.org/10.1038/ng0995-45" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550313">Waymire et al. (1995)</a>, administration of pyridoxal would theoretically be more appropriate. It is noteworthy that <a href="#30" class="mim-tip-reference" title="Waymire, K. G., Mahuren, J. D., Jaje, J. M., Guilarte, T. R., Coburn, S. P., MacGregor, G. R. <strong>Mice lacking tissue non-specific alkaline phosphatase die from seizures due to defective metabolism of vitamin B-6.</strong> Nature Genet. 11: 45-51, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550313</a>] [<a href="https://doi.org/10.1038/ng0995-45" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550313">Waymire et al. (1995)</a> found that pyridoxal administration was relatively ineffective in mice with certain genetic backgrounds. This suggested the existence of genetic modifiers specific to some backgrounds that lead to variable expressivity within the mutants on that background. <a href="#16" class="mim-tip-reference" title="Macfarlane, J. D., Kroon, H. M., van der Harten, J. J. <strong>Phenotypically dissimilar hypophosphatasia in two sibships.</strong> Am. J. Med. Genet. 42: 117-121, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1308350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1308350</a>] [<a href="https://doi.org/10.1002/ajmg.1320420124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1308350">Macfarlane et al. (1992)</a> found a similar phenomenon in human sibs with hypoplasia. Humans and rodents fed a diet with a high-fat content have elevated levels of circulating alkaline phosphatase whose source is the intestinal isozyme, IAP (ALPI; <a href="/entry/171740">171740</a>). Extrapolation from the mouse model suggested to <a href="#30" class="mim-tip-reference" title="Waymire, K. G., Mahuren, J. D., Jaje, J. M., Guilarte, T. R., Coburn, S. P., MacGregor, G. R. <strong>Mice lacking tissue non-specific alkaline phosphatase die from seizures due to defective metabolism of vitamin B-6.</strong> Nature Genet. 11: 45-51, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550313</a>] [<a href="https://doi.org/10.1038/ng0995-45" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550313">Waymire et al. (1995)</a> that, in those rare cases of hypophosphatasia associated with seizures, it would be better to substitute pyridoxal for pyridoxine, and to administer a high-fat diet to maximize IAP expression which might compensate at least partially for loss of function of the TNAP isozyme. However, because of the high dose of pyridoxal and the paralysis observed in the 'knockout' mice, such treatment would need to be carefully monitored. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7550313+1308350+3350970" 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>23 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"><span class="text-primary">●</span> rs121918000 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918000;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/rs121918000?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=rs121918000" 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=rs121918000" 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 male infant with hypophosphatasia (<a href="/entry/241500">241500</a>) who was born of second-cousin parents and died at 3 months of age, <a href="#31" class="mim-tip-reference" title="Weiss, M. J., Cole, D. E. C., Ray, K., Whyte, M. P., Lafferty, M. A., Mulivor, R. A., Harris, H. <strong>A missense mutation in the human liver/bone/kidney alkaline phosphatase gene causing a lethal form of hypophosphatasia.</strong> Proc. Nat. Acad. Sci. 85: 7666-7669, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3174660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3174660</a>] [<a href="https://doi.org/10.1073/pnas.85.20.7666" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3174660">Weiss et al. (1988)</a> identified homozygosity for a 711G-A transition in exon 6 of the ALPL gene, resulting in an ala162-to-thr (A162T) substitution. Introduction of this mutation into an otherwise normal cDNA by site-directed mutagenesis abolished the expression of active enzyme. The parents and other clinically unaffected relatives were found to be heterozygous for A162T, and the mutation cosegregated with levels of liver/bone/kidney alkaline phosphatase activity that were below the normal range. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3174660" 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">rs121918001 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918001;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=rs121918001" 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=rs121918001" 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=RCV000014649 OR RCV001851857 OR RCV003466857 OR RCV004700234 OR RCV004739304" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014649, RCV001851857, RCV003466857, RCV004700234, RCV004739304" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014649...</a>
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<p>In fibroblasts from a 5-month-old boy with hypophosphatasia (<a href="/entry/241500">241500</a>) who died at 6 months of age, <a href="#7" class="mim-tip-reference" title="Henthorn, P. S., Raducha, M., Fedde, K. N., Lafferty, M. A., Whyte, M. P. <strong>Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia.</strong> Proc. Nat. Acad. Sci. 89: 9924-9928, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1409720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1409720</a>] [<a href="https://doi.org/10.1073/pnas.89.20.9924" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1409720">Henthorn et al. (1992)</a> identified compound heterozygosity for 2 mutations in the ALPL gene: a 387C-T transition in exon 4, resulting in an arg54-to-cys (R54C) substitution, and a 1057A-C transversion in exon 9, resulting in an asp277-to-ala (D277A) substitution (<a href="#0003">171760.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1409720" 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 HYPOPHOSPHATASIA, INFANTILE</strong>
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HYPOPHOSPHATASIA, CHILDHOOD, INCLUDED<br />
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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> rs121918002 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918002;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/rs121918002?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=rs121918002" 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=rs121918002" 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=RCV000014650 OR RCV000014651 OR RCV000014652 OR RCV000224505 OR RCV000589324 OR RCV002276545 OR RCV002496362 OR RCV004549362" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014650, RCV000014651, RCV000014652, RCV000224505, RCV000589324, RCV002276545, RCV002496362, RCV004549362" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014650...</a>
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<p>For discussion of the asp277-to-ala (D277A) mutation in the ALPL gene that was found in compound heterozygous state in a patient with infantile hypophosphatasia (<a href="/entry/241500">241500</a>) by <a href="#7" class="mim-tip-reference" title="Henthorn, P. S., Raducha, M., Fedde, K. N., Lafferty, M. A., Whyte, M. P. <strong>Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia.</strong> Proc. Nat. Acad. Sci. 89: 9924-9928, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1409720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1409720</a>] [<a href="https://doi.org/10.1073/pnas.89.20.9924" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1409720">Henthorn et al. (1992)</a>, see <a href="#0002">171760.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1409720" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 sibs with the mild childhood form of hypophosphatasia and in a 65-year-old woman with adult hypophosphatasia (<a href="/entry/146300">146300</a>), <a href="#7" class="mim-tip-reference" title="Henthorn, P. S., Raducha, M., Fedde, K. N., Lafferty, M. A., Whyte, M. P. <strong>Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia.</strong> Proc. Nat. Acad. Sci. 89: 9924-9928, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1409720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1409720</a>] [<a href="https://doi.org/10.1073/pnas.89.20.9924" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1409720">Henthorn et al. (1992)</a> identified compound heterozygosity for 2 mutations in the ALPL gene: a D277A mutation, and 747G-A transition, resulting in a glu174-to-lys (E174K) substitution (<a href="#0008">171760.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1409720" 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 HYPOPHOSPHATASIA, INFANTILE</strong>
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ALPL, ARG54PRO
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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> rs121918003 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918003;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/rs121918003?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=rs121918003" 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=rs121918003" 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=RCV000014653 OR RCV001362179 OR RCV003460473 OR RCV003486545" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014653, RCV001362179, RCV003460473, RCV003486545" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014653...</a>
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<p>In fibroblasts from a girl with hypophosphatasia (<a href="/entry/241500">241500</a>) who died 3 hours after birth, <a href="#7" class="mim-tip-reference" title="Henthorn, P. S., Raducha, M., Fedde, K. N., Lafferty, M. A., Whyte, M. P. <strong>Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia.</strong> Proc. Nat. Acad. Sci. 89: 9924-9928, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1409720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1409720</a>] [<a href="https://doi.org/10.1073/pnas.89.20.9924" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1409720">Henthorn et al. (1992)</a> identified compound heterozygosity for 2 mutations in the ALPL gene: a 388G-C transversion in exon 4, resulting in an arg54-to-pro (R54P) substitution, and a 796A-C transversion in exon 6, resulting in a gln190-to-pro (Q190P) substitution (<a href="#0005">171760.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1409720" 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="0005" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0005 HYPOPHOSPHATASIA, INFANTILE</strong>
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ALPL, GLN190PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918004 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918004;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=rs121918004" 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=rs121918004" 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=RCV000014654 OR RCV000224906 OR RCV003230364" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014654, RCV000224906, RCV003230364" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014654...</a>
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<p>For discussion of the gln190-to-pro (Q190P) mutation in the ALPL gene that was found in compound heterozygous state in a patient with infantile hypophosphatasia (<a href="/entry/241500">241500</a>) by <a href="#7" class="mim-tip-reference" title="Henthorn, P. S., Raducha, M., Fedde, K. N., Lafferty, M. A., Whyte, M. P. <strong>Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia.</strong> Proc. Nat. Acad. Sci. 89: 9924-9928, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1409720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1409720</a>] [<a href="https://doi.org/10.1073/pnas.89.20.9924" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1409720">Henthorn et al. (1992)</a>, see <a href="#0004">171760.0004</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1409720" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 HYPOPHOSPHATASIA, INFANTILE</strong>
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ALPL, ALA16VAL
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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> rs121918005 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918005;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/rs121918005?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=rs121918005" 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=rs121918005" 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=RCV000014655 OR RCV001042961 OR RCV001273156 OR RCV001333468 OR RCV003473099 OR RCV005016263" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014655, RCV001042961, RCV001273156, RCV001333468, RCV003473099, RCV005016263" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014655...</a>
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<p>In a cell line designated MW10 from a patient with hypophosphatasia (<a href="/entry/241500">241500</a>), <a href="#7" class="mim-tip-reference" title="Henthorn, P. S., Raducha, M., Fedde, K. N., Lafferty, M. A., Whyte, M. P. <strong>Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia.</strong> Proc. Nat. Acad. Sci. 89: 9924-9928, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1409720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1409720</a>] [<a href="https://doi.org/10.1073/pnas.89.20.9924" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1409720">Henthorn et al. (1992)</a> found compound heterozygosity for an ala16-to-val (A16V) mutation and a tyr419-to-his mutation (Y419H; <a href="#0007">171760.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1409720" 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="0007" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0007 HYPOPHOSPHATASIA, INFANTILE</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">rs121918006 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918006;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=rs121918006" 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=rs121918006" 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=RCV000014656" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014656" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014656</a>
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<p>For discussion of the tyr419-to-his (Y419H) mutation in the ALPL gene that was found in compound heterozygous state in a patient with infantile hypophosphatasia (<a href="/entry/241500">241500</a>) by <a href="#7" class="mim-tip-reference" title="Henthorn, P. S., Raducha, M., Fedde, K. N., Lafferty, M. A., Whyte, M. P. <strong>Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia.</strong> Proc. Nat. Acad. Sci. 89: 9924-9928, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1409720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1409720</a>] [<a href="https://doi.org/10.1073/pnas.89.20.9924" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1409720">Henthorn et al. (1992)</a>, see <a href="#0006">171760.0006</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1409720" 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>.0008 HYPOPHOSPHATASIA, INFANTILE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918007 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918007;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/rs121918007?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=rs121918007" 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=rs121918007" 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=RCV000014658 OR RCV000014659 OR RCV000014660 OR RCV000207183 OR RCV000224962 OR RCV000763300 OR RCV001250150 OR RCV002276546 OR RCV002513051 OR RCV004584327 OR RCV004739305" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014658, RCV000014659, RCV000014660, RCV000207183, RCV000224962, RCV000763300, RCV001250150, RCV002276546, RCV002513051, RCV004584327, RCV004739305" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014658...</a>
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<p>In fibroblasts from a girl who presented at 2 months of age with severe hypophosphatasia (<a href="/entry/241500">241500</a>) and died at age 8 months, <a href="#7" class="mim-tip-reference" title="Henthorn, P. S., Raducha, M., Fedde, K. N., Lafferty, M. A., Whyte, M. P. <strong>Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia.</strong> Proc. Nat. Acad. Sci. 89: 9924-9928, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1409720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1409720</a>] [<a href="https://doi.org/10.1073/pnas.89.20.9924" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1409720">Henthorn et al. (1992)</a> identified compound heterozygosity for 2 mutations in the ALPL gene: a 747G-A transition in exon 6, resulting in a glu174-to-lys (E174K) substitution, and a 1309A-T transversion in exon 10, resulting in an asp361-to-val (D361V) substitution (<a href="#0009">171760.0009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1409720" 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>For discussion of the asp378-to-val (D378V) mutation found in compound heterozygous state in the ALPL gene in patients with childhood (<a href="/entry/241510">241510</a>) or adult (<a href="/entry/146300">146300</a>) hypophosphatasia by <a href="#7" class="mim-tip-reference" title="Henthorn, P. S., Raducha, M., Fedde, K. N., Lafferty, M. A., Whyte, M. P. <strong>Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia.</strong> Proc. Nat. Acad. Sci. 89: 9924-9928, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1409720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1409720</a>] [<a href="https://doi.org/10.1073/pnas.89.20.9924" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1409720">Henthorn et al. (1992)</a>, see <a href="#0003">171760.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1409720" 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="Herasse, M., Spentchian, M., Taillandier, A., Mornet, E. <strong>Evidence of a founder effect for the tissue-nonspecific alkaline phosphatase (TNSALP) gene E174K mutation in hypophosphatasia patients.</strong> Europ. J. Hum. Genet. 10: 666-668, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12357339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12357339</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200857" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12357339">Herasse et al. (2002)</a> investigated whether the E174K mutation had a unique origin or multiple origins arising from de novo mutations by genotyping 3 intragenic polymorphisms in patients with E174K and unaffected related individuals. Because all of the E174K mutations were found on a common ancestral haplotype, the authors suggested that a founder mutation occurred on a single chromosome in northwestern Europe and spread by human migration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12357339" 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>.0009 HYPOPHOSPHATASIA, INFANTILE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918008 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918008;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/rs121918008?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=rs121918008" 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=rs121918008" 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=RCV000014661 OR RCV000014662 OR RCV000207084 OR RCV000224520 OR RCV000763302 OR RCV001847606 OR RCV004549364 OR RCV004984641" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014661, RCV000014662, RCV000207084, RCV000224520, RCV000763302, RCV001847606, RCV004549364, RCV004984641" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014661...</a>
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<p><a href="#36" class="mim-tip-reference" title="Whyte, M. P., Mumm, S., Deal, C. <strong>Adult hypophosphatasia treated with teriparatide.</strong> J. Clin. Endocr. Metab. 92: 1203-1208, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17213282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17213282</a>] [<a href="https://doi.org/10.1210/jc.2006-1902" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17213282">Whyte et al. (2007)</a> stated that the ASP361VAL designation has been changed to ASP378VAL. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17213282" 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>For discussion of the asp378-to-val (D378V) mutation in the ALPL gene that was found in compound heterozygous state in a patient with infantile hypophosphatasia (<a href="/entry/241500">241500</a>) by <a href="#7" class="mim-tip-reference" title="Henthorn, P. S., Raducha, M., Fedde, K. N., Lafferty, M. A., Whyte, M. P. <strong>Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia.</strong> Proc. Nat. Acad. Sci. 89: 9924-9928, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1409720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1409720</a>] [<a href="https://doi.org/10.1073/pnas.89.20.9924" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1409720">Henthorn et al. (1992)</a>, see <a href="#0008">171760.0008</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1409720" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Moore, C. A., Curry, C. J. R., Henthorn, P. S., Smith, J. A., Smith, J. C., O'Lague, P., Coburn, S. P., Weaver, D. D., Whyte, M. P. <strong>Mild autosomal dominant hypophosphatasia: in utero presentation in two families.</strong> Am. J. Med. Genet. 86: 410-415, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508980</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19991029)86:5<410::aid-ajmg3>3.0.co;2-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508980">Moore et al. (1999)</a> described a family with mild hypophosphatasia, apparently transmitted as an autosomal dominant trait, in which ultrasonography detected an affected fetus with severe long bone bowing. In contrast to the progressive deterioration typical of both the perinatal and infantile forms of hypophosphatasia, these skeletal defects improved spontaneously during infancy and early childhood. Biochemical evidence of hypophosphatasia was present in this family, and <a href="#18" class="mim-tip-reference" title="Moore, C. A., Curry, C. J. R., Henthorn, P. S., Smith, J. A., Smith, J. C., O'Lague, P., Coburn, S. P., Weaver, D. D., Whyte, M. P. <strong>Mild autosomal dominant hypophosphatasia: in utero presentation in two families.</strong> Am. J. Med. Genet. 86: 410-415, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508980</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19991029)86:5<410::aid-ajmg3>3.0.co;2-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508980">Moore et al. (1999)</a> identified the D378V mutation in the ALPL gene of all affected members. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Whyte, M. P., Mumm, S., Deal, C. <strong>Adult hypophosphatasia treated with teriparatide.</strong> J. Clin. Endocr. Metab. 92: 1203-1208, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17213282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17213282</a>] [<a href="https://doi.org/10.1210/jc.2006-1902" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17213282">Whyte et al. (2007)</a> identified heterozygosity for the D378V mutation in a middle-aged woman with adult hypophosphatasia (<a href="/entry/146300">146300</a>) who was successfully treated with teriparatide. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17213282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014663 OR RCV000207270 OR RCV000224376 OR RCV000763301 OR RCV000786923 OR RCV002276547 OR RCV004549365" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014663, RCV000207270, RCV000224376, RCV000763301, RCV000786923, RCV002276547, RCV004549365" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014663...</a>
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<p>In individuals with the Mennonite perinatal, lethal form of hypophosphatasia (<a href="/entry/241500">241500</a>), <a href="#5" class="mim-tip-reference" title="Greenberg, C. R., Taylor, C. L. D., Haworth, J. C., Seargeant, L. E., Philipps, S., Triggs-Raine, B., Chodirker, B. N. <strong>A homoallelic gly317-to-asp mutation in ALPL causes the perinatal (lethal) form of hypophosphatasia in Canadian Mennonites.</strong> Genomics 17: 215-217, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8406453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8406453</a>] [<a href="https://doi.org/10.1006/geno.1993.1305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8406453">Greenberg et al. (1993)</a> demonstrated a homoallelic G-to-A transition in exon 10 of the ALPL gene at position 1177, changing a polar glycine to an acidic aspartate (gly317-to-asp, or G317D). A patient with a juvenile form of hypophosphatasia, with a Mennonite mother and a non-Mennonite father, was found to be heteroallelic for a maternally inherited G317D allele and a paternally inherited glu174-to-lys (E174K; <a href="#0008">171760.0008</a>) allele. The authors reported finding the same 2 mutations present as a genetic compound in other late-onset hypophosphatasia patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8406453" 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> rs121918010 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918010;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/rs121918010?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=rs121918010" 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=rs121918010" 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=RCV000014664 OR RCV000207096 OR RCV000380876 OR RCV000724148 OR RCV002504786 OR RCV004549366" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014664, RCV000207096, RCV000380876, RCV000724148, RCV002504786, RCV004549366" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014664...</a>
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<p>In fibroblasts of a neonate with hypophosphatasia (<a href="/entry/241500">241500</a>), <a href="#24" class="mim-tip-reference" title="Ozono, K., Yamagata, M., Michigami, T., Nakajima, S., Sakai, N., Cai, G., Satomura, K., Yasui, N., Okada, S., Nakayama, M. <strong>Identification of novel missense mutations (phe310leu and gly439arg) in a neonatal case of hypophosphatasia.</strong> J. Clin. Endocr. Metab. 81: 4458-4461, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8954059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8954059</a>] [<a href="https://doi.org/10.1210/jcem.81.12.8954059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8954059">Ozono et al. (1996)</a> identified compound heterozygosity for 2 mutations in the ALPL gene: a 1155T-C transition, resulting in a phe3101-to-leu (F3101L) substitution, and a 1542G-A transition, resulting in a gly439-to-arg (G439R) substitution (<a href="#0019">171760.0019</a>). The F3101L mutant exhibited an ALPL activity level 65% of normal, while the G439R mutant had no activity. Each parent was heterozygous for 1 of the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8954059" 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> rs387906525 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906525;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/rs387906525?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=rs387906525" 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=rs387906525" 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=RCV000014665 OR RCV000207209 OR RCV000346130 OR RCV003460475" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014665, RCV000207209, RCV000346130, RCV003460475" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014665...</a>
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<p>In a Japanese patient with infantile hypophosphatasia (<a href="/entry/241500">241500</a>), <a href="#23" class="mim-tip-reference" title="Orimo, H., Hayashi, Z., Watanabe, A., Hirayama, T., Hirayama, T., Shimada, T. <strong>Novel missense and frameshift mutations in the tissue-nonspecific alkaline phosphatase gene in a Japanese patient with hypophosphatasia.</strong> Hum. Molec. Genet. 3: 1683-1684, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7833929/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7833929</a>] [<a href="https://doi.org/10.1093/hmg/3.9.1683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7833929">Orimo et al. (1994)</a> identified compound heterozygosity for 2 mutations in the ALPL gene. One mutation, inherited from the mother, was a 1-bp deletion in exon 12 (1735delT). The deletion caused a frameshift downstream from codon 503 (leu), and the normal termination codon at 508 was eliminated. Since a new in-frame termination codon appeared at codon 588 in the mutant DNA, the resultant protein was predicted to have 80 additional amino acids. The other mutation, inherited from the father, was a 1068G-A transition in exon 9, resulting in a glu281-to-lys (E281K; <a href="#0020">171760.0020</a>) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7833929" 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="#4" class="mim-tip-reference" title="Goseki-Sone, M., Orimo, H., Iimura, T., Miyazaki, H., Oda, K., Shibata, H., Yanagishita, M., Takagi, Y., Watanabe, H., Shimada, T., Oida, S. <strong>Expression of the mutant (1735T-DEL) tissue-nonspecific alkaline phosphatase gene from hypophosphatasia patients.</strong> J. Bone Miner. Res. 13: 1827-1834, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9844100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9844100</a>] [<a href="https://doi.org/10.1359/jbmr.1998.13.12.1827" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9844100">Goseki-Sone et al. (1998)</a> studied expression of the mutant 1735delT ALPL cDNA in COS-1 cells. They found that the protein translated from the mutant gene had undetectable ALPL activity, and its molecular size was larger than the wildtype protein. Detection of the mutant protein in cells transfected with the 1735delT mutation with an immunofluorescent method exhibited only a faint signal on the cell surface, but an intense intracellular fluorescence after permeabilization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9844100" 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> rs121918011 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918011;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/rs121918011?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=rs121918011" 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=rs121918011" 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=RCV000014666 OR RCV000169168 OR RCV000364426 OR RCV000767525 OR RCV000770988 OR RCV002276548 OR RCV002490366 OR RCV004798728" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014666, RCV000169168, RCV000364426, RCV000767525, RCV000770988, RCV002276548, RCV002490366, RCV004798728" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014666...</a>
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<p><a href="#38" class="mim-tip-reference" title="Zurutuza, L., Muller, F., Gibrat, J. F., Taillandier, A., Simon-Bouy, B., Serre, J. L., Mornet, E. <strong>Correlations of genotype and phenotype in hypophosphatasia.</strong> Hum. Molec. Genet. 8: 1039-1046, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10332035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10332035</a>] [<a href="https://doi.org/10.1093/hmg/8.6.1039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10332035">Zurutuza et al. (1999)</a> divided hypophosphatasia into lethal and nonlethal types. They studied 32 ALPL mutations found in 23 European patients, 17 with lethal hypophosphatasia (see <a href="/entry/241500">241500</a>) and 6 with nonlethal hypophosphatasia (<a href="/entry/241510">241510</a>). They identified 6 mutations which on transfection studies were shown to allow significant residual in vitro enzymatic activity. The oldest patient in their study, aged 11 years, was a compound heterozygote for arg119 to his (R119H) and gly145 to val (G145V; <a href="#0014">171760.0014</a>). The former was apparently a 'moderate' allele, whereas the latter was a 'severe' allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10332035" 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">rs121918012 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918012;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=rs121918012" 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=rs121918012" 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=RCV000014667 OR RCV000670940 OR RCV001239346" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014667, RCV000670940, RCV001239346" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014667...</a>
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<p>For discussion of the gly145-to-val (G145V) mutation in the ALPL gene that was found in compound heterozygous state in a patient with childhood-onset hypophosphatasia (<a href="/entry/241510">241510</a>) by <a href="#38" class="mim-tip-reference" title="Zurutuza, L., Muller, F., Gibrat, J. F., Taillandier, A., Simon-Bouy, B., Serre, J. L., Mornet, E. <strong>Correlations of genotype and phenotype in hypophosphatasia.</strong> Hum. Molec. Genet. 8: 1039-1046, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10332035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10332035</a>] [<a href="https://doi.org/10.1093/hmg/8.6.1039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10332035">Zurutuza et al. (1999)</a>, see <a href="#0013">171760.0013</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10332035" 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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HYPOPHOSPHATASIA, ADULT, INCLUDED<br />
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918013 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918013;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=rs121918013" 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=rs121918013" 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=RCV000014668 OR RCV000014669 OR RCV000014670 OR RCV000169426 OR RCV000224118 OR RCV000590781 OR RCV004549367" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014668, RCV000014669, RCV000014670, RCV000169426, RCV000224118, RCV000590781, RCV004549367" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014668...</a>
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<p>In 13 affected members of a 4-generation Texas family segregating autosomal dominant hypophosphatasia in both children (<a href="/entry/241510">241510</a>) and adults (<a href="/entry/146300">146300</a>), <a href="#11" class="mim-tip-reference" title="Hu, J. C.-C., Plaetke, R., Mornet, E., Zhang, C., Sun, X., Thomas, H. F., Simmer, J. P. <strong>Characterization of a family with dominant hypophosphatasia.</strong> Europ. J. Oral Sci. 108: 189-194, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10872988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10872988</a>] [<a href="https://doi.org/10.1034/j.1600-0722.2000.108003189.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10872988">Hu et al. (2000)</a> identified heterozygosity for an ala99-to-thr (A99T) substitution in the ALPL gene. The mutation was also found in 1 clinically unaffected individual who had an elevated urinary phosphoethanolamine (PEA) level. <a href="#14" class="mim-tip-reference" title="Lia-Baldini, A. S., Muller, F., Taillandier, A., Gibrat, J. F., Mouchard, M., Robin, B., Simon-Bouy, B., Serre, J. L., Aylsworth, A. S., Bieth, E., Delanote, S., Freisinger, P., Hu, J. C.-C., Krohn, H.-P., Nunes, M. E., Mornet, E. <strong>A molecular approach to dominance in hypophosphatasia.</strong> Hum. Genet. 109: 99-108, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479741</a>] [<a href="https://doi.org/10.1007/s004390100546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479741">Lia-Baldini et al. (2001)</a> performed functional studies of the A99T mutation and observed a moderate dominant negative effect. Complete sequencing of the gene in the brother and sister twin probands from the Texas family, including the untranslated exon 1 and intron/exon borders, revealed no mutation other than the heterozygous 346G-A transition in exon 5 of the ALPL gene that results in the A99T substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10872988+11479741" 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="Herasse, M., Spentchian, M., Taillandier, A., Keppler-Noreuil, K., Fliorito, A. N. M., Bergoffen, J., Wallerstein, R., Muti, C., Simon-Bouy, B., Mornet, E. <strong>Molecular study of three cases of odontohypophosphatasia resulting from heterozygosity for mutations in the tissue non-specific alkaline phosphatase gene.</strong> J. Med. Genet. 40: 605-609, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12920074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12920074</a>] [<a href="https://doi.org/10.1136/jmg.40.8.605" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12920074">Herasse et al. (2003)</a> identified the A99T mutation in heterozygous state in a 2-year-old male and his mother; the former had only dental manifestations and low serum alkaline phosphatase and the latter did not have odontohypophosphatasia (<a href="/entry/146300">146300</a>) but had an unusual number of dental caries and had had numerous treatments of dental root canals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12920074" 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>.0016 HYPOPHOSPHATASIA, PERINATAL LETHAL</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs749544042 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs749544042;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/rs749544042?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=rs749544042" 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=rs749544042" 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=RCV000014671 OR RCV000710058 OR RCV001227927 OR RCV001553715 OR RCV003466858 OR RCV004549368 OR RCV005016264" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014671, RCV000710058, RCV001227927, RCV001553715, RCV003466858, RCV004549368, RCV005016264" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014671...</a>
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<p><a href="#25" class="mim-tip-reference" title="Sergi, C., Mornet, E., Troeger, J., Voigtlaender, T. <strong>Perinatal hypophosphatasia: radiology, pathology and molecular biology studies in a family harboring a splicing mutation (648+1A) and a novel missense mutation (N400S) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene.</strong> Am. J. Med. Genet. 103: 235-240, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11745997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11745997</a>]" pmid="11745997">Sergi et al. (2001)</a> made a postmortem diagnosis of perinatal lethal hypophosphatasia (see <a href="/entry/241500">241500</a>) on the basis of radiologic and pathologic changes of a generalized bone mineralization defect including asymmetry of the cervical vertebral arches. The parents were nonconsanguineous. The fetus was found to be a compound heterozygote: the first nucleotide of intron 6 of the ALPL gene was changed from G to A; the other chromosome carried an asn400-to-ser missense mutation in exon 11 (N400S; <a href="#0017">171760.0017</a>). The former was of maternal origin and the latter of paternal origin. DNA-based prenatal testing in a subsequent pregnancy following a chorionic villus sampling performed at 10 weeks of gestation showed no mutation and a healthy baby was born at term. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11745997" 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>.0017 HYPOPHOSPHATASIA, PERINATAL LETHAL</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918014 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918014;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/rs121918014?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=rs121918014" 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=rs121918014" 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=RCV000014672 OR RCV000169778 OR RCV000710510 OR RCV001194283 OR RCV001253058 OR RCV004719646 OR RCV004739306 OR RCV005016265" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014672, RCV000169778, RCV000710510, RCV001194283, RCV001253058, RCV004719646, RCV004739306, RCV005016265" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014672...</a>
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<p>For discussion of the asn400-to-ser (N400S) mutation in the ALPL gene that was found in compound heterozygous state in a fetus with perinatal lethal hypophosphatasia (see <a href="/entry/241500">241500</a>) by <a href="#25" class="mim-tip-reference" title="Sergi, C., Mornet, E., Troeger, J., Voigtlaender, T. <strong>Perinatal hypophosphatasia: radiology, pathology and molecular biology studies in a family harboring a splicing mutation (648+1A) and a novel missense mutation (N400S) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene.</strong> Am. J. Med. Genet. 103: 235-240, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11745997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11745997</a>]" pmid="11745997">Sergi et al. (2001)</a>, see <a href="#0016">171760.0016</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11745997" 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>.0018 ODONTOHYPOPHOSPHATASIA</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">rs121918015 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918015;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=rs121918015" 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=rs121918015" 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=RCV000014673" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014673" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014673</a>
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<p>In a 9-year-old boy with Down syndrome (<a href="/entry/190685">190685</a>) and odontohypophosphatasia (<a href="/entry/146300">146300</a>) and his 39-year-old mother, <a href="#9" class="mim-tip-reference" title="Herasse, M., Spentchian, M., Taillandier, A., Keppler-Noreuil, K., Fliorito, A. N. M., Bergoffen, J., Wallerstein, R., Muti, C., Simon-Bouy, B., Mornet, E. <strong>Molecular study of three cases of odontohypophosphatasia resulting from heterozygosity for mutations in the tissue non-specific alkaline phosphatase gene.</strong> J. Med. Genet. 40: 605-609, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12920074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12920074</a>] [<a href="https://doi.org/10.1136/jmg.40.8.605" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12920074">Herasse et al. (2003)</a> identified heterozygosity for a 323C-T transition in the ALPL gene, resulting in a pro91-to-leu (P91L) change. The boy had lost 7 deciduous teeth, mostly incisors, beginning at the age of 2 years and had low serum alkaline phosphatase, and his mother had lost her permanent teeth and had a low alkaline phosphatase level, indicating that the findings could not be attributed to Down syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12920074" 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>.0019 HYPOPHOSPHATASIA, INFANTILE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918016 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918016;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/rs121918016?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=rs121918016" 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=rs121918016" 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=RCV000014674 OR RCV001387538 OR RCV003448247 OR RCV004786260" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014674, RCV001387538, RCV003448247, RCV004786260" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014674...</a>
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<p>For discussion of the gly439-to-arg (G439R) mutation in the ALPL gene that was found in compound heterozygous state in a patient with infantile hypophosphatasia (<a href="/entry/241500">241500</a>) by <a href="#24" class="mim-tip-reference" title="Ozono, K., Yamagata, M., Michigami, T., Nakajima, S., Sakai, N., Cai, G., Satomura, K., Yasui, N., Okada, S., Nakayama, M. <strong>Identification of novel missense mutations (phe310leu and gly439arg) in a neonatal case of hypophosphatasia.</strong> J. Clin. Endocr. Metab. 81: 4458-4461, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8954059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8954059</a>] [<a href="https://doi.org/10.1210/jcem.81.12.8954059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8954059">Ozono et al. (1996)</a>, see <a href="#0011">171760.0011</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8954059" 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> rs121918017 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918017;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/rs121918017?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=rs121918017" 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=rs121918017" 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=RCV000014657 OR RCV001549327 OR RCV001582483 OR RCV002504785 OR RCV003460474 OR RCV004549363" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014657, RCV001549327, RCV001582483, RCV002504785, RCV003460474, RCV004549363" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014657...</a>
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<p>For discussion of the glu281-to-lys (E281K) mutation in the ALPL gene that was found in compound heterozygous state in a patient with infantile hypophosphatasia (<a href="/entry/241500">241500</a>) by <a href="#23" class="mim-tip-reference" title="Orimo, H., Hayashi, Z., Watanabe, A., Hirayama, T., Hirayama, T., Shimada, T. <strong>Novel missense and frameshift mutations in the tissue-nonspecific alkaline phosphatase gene in a Japanese patient with hypophosphatasia.</strong> Hum. Molec. Genet. 3: 1683-1684, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7833929/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7833929</a>] [<a href="https://doi.org/10.1093/hmg/3.9.1683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7833929">Orimo et al. (1994)</a>, see <a href="#0012">171760.0012</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7833929" 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>.0021 HYPOPHOSPHATASIA, CHILDHOOD</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918018 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918018;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/rs121918018?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=rs121918018" 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=rs121918018" 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=RCV000014675 OR RCV000014676 OR RCV000668001 OR RCV000723607 OR RCV001826462 OR RCV003335039 OR RCV003466859" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014675, RCV000014676, RCV000668001, RCV000723607, RCV001826462, RCV003335039, RCV003466859" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014675...</a>
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<p>In a 15-month-old girl with a phenotype suggestive of childhood hypophosphatasia (<a href="/entry/241510">241510</a>), <a href="#14" class="mim-tip-reference" title="Lia-Baldini, A. S., Muller, F., Taillandier, A., Gibrat, J. F., Mouchard, M., Robin, B., Simon-Bouy, B., Serre, J. L., Aylsworth, A. S., Bieth, E., Delanote, S., Freisinger, P., Hu, J. C.-C., Krohn, H.-P., Nunes, M. E., Mornet, E. <strong>A molecular approach to dominance in hypophosphatasia.</strong> Hum. Genet. 109: 99-108, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479741</a>] [<a href="https://doi.org/10.1007/s004390100546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479741">Lia-Baldini et al. (2001)</a> identified heterozygosity for a 746G-T transversion in exon 7 of the ALPL gene, resulting in a gly232-to-val (G232V) substitution. The mutation was inherited from her father, who had recurrent dental caries in his 3rd decade despite being raised with fluoridated water; the authors suggested that this represented odontohypophosphatasia (<a href="/entry/146300">146300</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11479741" 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="Lia-Baldini, A. S., Brun-Heath, I., Carrion, C., Simon-Bouy, B., Serre, J. L., Nunes, M. E., Mornet, E. <strong>A new mechanism of dominance in hypophosphatasia: the mutated protein can disturb the cell localization of the wild-type protein.</strong> Hum. Genet. 123: 429-432, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18340466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18340466</a>] [<a href="https://doi.org/10.1007/s00439-008-0480-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18340466">Lia-Baldini et al. (2008)</a> performed functional analysis of the G232V mutation in the ALPL gene and demonstrated that the mutant protein sequestrates some of the wildtype protein in the cells and prevents it from reaching the membrane. These results suggested a new mechanism for dominance in hypophosphatasia, involving mutated homodimers and heterodimers that are sequestrated in the cells with only wildtype homodimers (approximately 25% of the total dimers) able to play a physiologic role in the cell. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18340466" 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>.0022 HYPOPHOSPHATASIA, INFANTILE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918019 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918019;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/rs121918019?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=rs121918019" 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=rs121918019" 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=RCV000014677 OR RCV000014678 OR RCV000763299 OR RCV000808101 OR RCV001275108 OR RCV002276549 OR RCV002288490 OR RCV004549369" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014677, RCV000014678, RCV000763299, RCV000808101, RCV001275108, RCV002276549, RCV002288490, RCV004549369" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014677...</a>
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<p><a href="#27" class="mim-tip-reference" title="Stevenson, D. A., Carey, J. C., Coburn, S. P., Ericson, K. L., Byrne, J. L. B., Mumm, S., Whyte, M. P. <strong>Autosomal recessive hypophosphatasia manifesting in utero with long bone deformity but showing spontaneous postnatal improvement.</strong> J. Clin. Endocr. Metab. 93: 3443-3448, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18559907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18559907</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18559907[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/10.1210/jc.2008-0318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18559907">Stevenson et al. (2008)</a> described a boy with prenatal presentation of hypophosphatasia (<a href="/entry/241500">241500</a>) manifesting as long bone deformity detected in utero by sonography at 18 weeks' gestation who had spontaneous pre- and postnatal improvement. He was compound heterozygous for missense mutations in the ALPL gene, one in exon 6 (526G-A, ala176 to thr, A176T) and the other in exon 8 (814C-T, arg272 to cys, R272C). His affected older brother, who carried the same mutations, had childhood hypophosphatasia (<a href="/entry/241510">241510</a>). His sonography at 20 weeks was reported as normal, and he was first evaluated at 19 months of age for premature tooth loss. At 18 weeks' gestation, the proband presented with sharp angulation of the midshaft of the right humerus, radius, and ulna. All major long bones were subjectively of slightly narrow diameter and poorly ossified. At birth there was bowing of the right arm with dimpling of the skin near the apex of the bowing, but the physical examination was otherwise unremarkable. Evidence of healing and healed fractures in the right humerus, radius, and ulna was seen on radiographs at birth and 6 months of age. At age 17 months he was evaluated for premature tooth loss, and at that time bowing of the right upper arm was present. The female twin of the proband carried neither mutation and was clinically unaffected. Each parent was heterozygous for one of the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18559907" 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> rs121918020 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918020;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/rs121918020?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=rs121918020" 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=rs121918020" 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=RCV000014679 OR RCV000169779 OR RCV000817506 OR RCV001804731 OR RCV003473100 OR RCV004549370 OR RCV005007851" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014679, RCV000169779, RCV000817506, RCV001804731, RCV003473100, RCV004549370, RCV005007851" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014679...</a>
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<p>For discussion of the arg272-to-cys (R272C) mutation in the ALPL gene that was found in compound heterozygous state in brothers, one with infantile hypophosphatasia (<a href="/entry/241500">241500</a>) and the other with childhood hypophosphatasia (<a href="/entry/241510">241510</a>) by <a href="#27" class="mim-tip-reference" title="Stevenson, D. A., Carey, J. C., Coburn, S. P., Ericson, K. L., Byrne, J. L. B., Mumm, S., Whyte, M. P. <strong>Autosomal recessive hypophosphatasia manifesting in utero with long bone deformity but showing spontaneous postnatal improvement.</strong> J. Clin. Endocr. Metab. 93: 3443-3448, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18559907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18559907</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18559907[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/10.1210/jc.2008-0318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18559907">Stevenson et al. (2008)</a>, see <a href="#0022">171760.0022</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18559907" 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="#Hua1986" class="mim-tip-reference" title="Hua, J.-C., Berger, J., Pan, Y.-C. E., Hulmes, J. D., Udenfriend, S. <strong>Partial sequencing of human adult, human fetal, and bovine intestinal alkaline phosphatases: comparison with the human placental and liver isozymes.</strong> Proc. Nat. Acad. Sci. 83: 2368-2372, 1986.">Hua et al. (1986)</a>
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[<a href="https://doi.org/10.1073/pnas.77.5.2857" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1359/jbmr.1998.13.12.1827" target="_blank">Full Text</a>]
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<strong>A homoallelic gly317-to-asp mutation in ALPL causes the perinatal (lethal) form of hypophosphatasia in Canadian Mennonites.</strong>
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Genomics 17: 215-217, 1993.
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[<a href="https://doi.org/10.1006/geno.1993.1305" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1469-1809.1974.tb01832.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.89.20.9924" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.40.8.605" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5200857" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1034/j.1600-0722.2000.108003189.x" target="_blank">Full Text</a>]
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Hua, J.-C., Berger, J., Pan, Y.-C. E., Hulmes, J. D., Udenfriend, S.
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<strong>Partial sequencing of human adult, human fetal, and bovine intestinal alkaline phosphatases: comparison with the human placental and liver isozymes.</strong>
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[<a href="https://doi.org/10.1073/pnas.83.8.2368" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-008-0480-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s004390100546" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1023/a:1015121414782" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320420124" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(200004)15:4<309::AID-HUMU2>3.0.CO;2-C" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.81.12.8954059" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3165380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3165380</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3165380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="34" class="mim-anchor"></a>
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<a id="Weiss1987" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
|
Weiss, M., Smith, M., Griffin, C., Nussbaum, R., Murray, J., Emanuel, B., Harris, H.
|
|
<strong>Assignment of the gene encoding the liver/bone/kidney form of alkaline phosphatase ALPL to the region 1p34-p36.1. (Abstract)</strong>
|
|
Cytogenet. Cell Genet. 46: 714 only, 1987.
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</p>
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</div>
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</li>
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<li>
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<a id="35" class="mim-anchor"></a>
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<a id="Whyte1988" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Whyte, M. P., Mahuren, J. D., Fedde, K. N., Cole, F. S., McCabe, E. R., Coburn, S. P.
|
|
<strong>Perinatal hypophosphatasia: tissue levels of vitamin B-6 are unremarkable despite markedly increased circulating concentrations of pyridoxal-5-prime-phosphate: evidence for an ectoenzyme role for tissue-nonspecific alkaline phosphatase.</strong>
|
|
J. Clin. Invest. 81: 1234-1239, 1988.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3350970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3350970</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3350970" 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/JCI113440" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="36" class="mim-anchor"></a>
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<a id="Whyte2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Whyte, M. P., Mumm, S., Deal, C.
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|
<strong>Adult hypophosphatasia treated with teriparatide.</strong>
|
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J. Clin. Endocr. Metab. 92: 1203-1208, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17213282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17213282</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17213282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jc.2006-1902" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="37" class="mim-anchor"></a>
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<a id="Whyte2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Whyte, M. P., Zhang, F., Wenkert, D., McAlister, W. H., Mack, K. E., Benigno, M. C., Coburn, S. P., Wagy, S., Griffin, D. M., Ericson, K. L., Mumm, S.
|
|
<strong>Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients.</strong>
|
|
Bone 75: 229-239, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25731960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25731960</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25731960" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.bone.2015.02.022" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="38" class="mim-anchor"></a>
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<a id="Zurutuza1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zurutuza, L., Muller, F., Gibrat, J. F., Taillandier, A., Simon-Bouy, B., Serre, J. L., Mornet, E.
|
|
<strong>Correlations of genotype and phenotype in hypophosphatasia.</strong>
|
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Hum. Molec. Genet. 8: 1039-1046, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10332035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10332035</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10332035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/8.6.1039" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 10/30/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 8/3/2009<br>John A. Phillips, III - updated : 6/9/2009<br>Marla J. F. O'Neill - updated : 10/17/2008<br>Carol A. Bocchini - updated : 9/17/2008<br>John A. Phillips, III - updated : 3/24/2008<br>Natalie E. Krasikov - updated : 6/1/2004<br>Victor A. McKusick - updated : 10/1/2003<br>Ada Hamosh - updated : 9/22/2003<br>Victor A. McKusick - updated : 10/5/2001<br>Victor A. McKusick - updated : 9/10/2001<br>Victor A. McKusick - updated : 4/19/2000<br>Sonja A. Rasmussen - updated : 12/15/1999<br>Victor A. McKusick - updated : 6/8/1999<br>Victor A. McKusick - updated : 6/1/1999<br>Victor A. McKusick - updated : 2/15/1999<br>John A. Phillips, III - updated : 12/20/1996
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/2/1986
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 10/30/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 04/14/2015<br>mcolton : 4/9/2015<br>carol : 4/12/2012<br>carol : 1/13/2010<br>carol : 8/12/2009<br>terry : 8/3/2009<br>alopez : 6/9/2009<br>wwang : 3/26/2009<br>wwang : 11/6/2008<br>wwang : 10/17/2008<br>carol : 9/17/2008<br>carol : 3/24/2008<br>alopez : 7/24/2007<br>alopez : 10/18/2004<br>carol : 6/17/2004<br>carol : 6/1/2004<br>tkritzer : 10/24/2003<br>tkritzer : 10/6/2003<br>tkritzer : 10/6/2003<br>tkritzer : 10/1/2003<br>alopez : 9/22/2003<br>tkritzer : 1/2/2003<br>mcapotos : 10/15/2001<br>mcapotos : 10/10/2001<br>terry : 10/5/2001<br>mcapotos : 9/17/2001<br>mcapotos : 9/10/2001<br>mcapotos : 5/19/2000<br>mcapotos : 5/16/2000<br>terry : 4/19/2000<br>mgross : 12/20/1999<br>mgross : 12/15/1999<br>carol : 9/14/1999<br>carol : 8/3/1999<br>carol : 6/16/1999<br>carol : 6/16/1999<br>jlewis : 6/15/1999<br>terry : 6/8/1999<br>jlewis : 6/7/1999<br>terry : 6/1/1999<br>mgross : 3/10/1999<br>mgross : 2/17/1999<br>terry : 2/15/1999<br>carol : 10/7/1998<br>terry : 10/2/1998<br>carol : 5/13/1998<br>joanna : 5/13/1998<br>jenny : 5/21/1997<br>jenny : 5/21/1997<br>terry : 9/11/1995<br>mark : 8/31/1995<br>mimadm : 4/14/1994<br>warfield : 4/12/1994<br>carol : 7/19/1993<br>carol : 2/5/1993
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
|
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<strong>*</strong> 171760
|
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</span>
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</h3>
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</div>
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<div>
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<h3>
|
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<span class="mim-font">
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|
|
ALKALINE PHOSPHATASE, LIVER; ALPL
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
ALKALINE PHOSPHATASE, LIVER/BONE/KIDNEY TYPE<br />
|
|
ALKALINE PHOSPHATASE, TISSUE-NONSPECIFIC; TNSALP; TNAP
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: ALPL</em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
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<p>
|
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<span class="mim-text-font">
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|
|
<strong>SNOMEDCT:</strong> 20756002, 30174008, 55236002, 708672004;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 1p36.12
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 1:21,508,984-21,578,410 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
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</p>
|
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed 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="4">
|
|
<span class="mim-font">
|
|
1p36.12
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Hypophosphatasia, adult
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
146300
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant; Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
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</tr>
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hypophosphatasia, childhood
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
241510
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hypophosphatasia, infantile
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
241500
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Odontohypophosphatasia
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
146300
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant; Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
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|
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|
<div>
|
|
<br />
|
|
</div>
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|
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|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Alkaline phosphatases are membrane-bound glycoproteins that hydrolyze various monophosphate esters at a high pH optimum (Weiss et al., 1986). Liver/bone/kidney alkaline phosphatase, also known as tissue-nonspecific alkaline phosphatase, acts physiologically as a lipid-anchored phosphoethanolamine (PEA) and pyridoxal-5-prime-phosphate (PLP) ectophosphatase (Fedde and Whyte, 1990). </p><p>See ALPQTL1 (171720) for information on quantitative trait loci influencing the plasma level of alkaline phosphatase.</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using quantitative inhibition and thermostability studies, Goldstein et al. (1980) presented evidence for the existence of at least 3 distinct forms of human alkaline phosphatase (EC 3.1.3.1): intestinal (ALPI; 171740), placental (ALPP; 171800), and liver/bone/kidney (ALPL). Harris et al. (1974) found no genetic variants by electrophoretic means. </p><p>Weiss et al. (1986) cloned a cDNA for liver/bone/kidney alkaline phosphatase from a human osteosarcoma cell line. The deduced 524-amino acid ALPL protein has a presumed signal peptide of 17 amino acids and a predicted molecular mass of 57.2 kD. The ALPL protein shares 52% sequence identity with placental alkaline phosphatase. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Fedde and Whyte (1990) demonstrated that the alkaline phosphatase of skin fibroblasts is ALPL, the tissue-nonspecific type, and that it is active toward millimolar concentrations of the putative natural substrates phosphoethanolamine and pyridoxal-5-prime-phosphate. Both activities were deficient in hypophosphatasia (see 241500) fibroblasts. They presented evidence that normal fibroblast ALP is linked to the outside of the plasma membrane; thus, the enzyme acts physiologically as a lipid-anchored PEA and PLP ectophosphatase. </p>
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</span>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Weiss et al. (1988) and Matsuura et al. (1990) found that the ALPL gene exists in single copy in the haploid genome and contains 12 exons distributed over more than 50 kb. As compared with the gene isolated using a bone-type ALPL cDNA (Weiss et al., 1988), liver-type ALPL mRNA was found to have another leader exon about 3.4 kb upstream from exon 2 and alternative splicing in the first exon was indicated (Matsuura et al., 1990). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using human-rodent somatic cell hybrids, Swallow et al. (1985, 1986) mapped the gene for liver/bone/kidney alkaline phosphatase to chromosome 1. Mouse Akp2, which is homologous, is on chromosome 4 between Pgm2 and Pgd. Thus, ALPL might be located on 1p between PGM1 (171900) and PGD (172200). </p><p>Using a DNA polymorphism of the ALPL gene, Ardinger et al. (1987) found linkage to Rh (theta = 0.08; lod = 5.50). Multipoint analysis indicated the following order: Rh--3--ALPL--12--GLUT--23--PGM1, with the interlocus intervals as percent recombination in males (the female rate about 2.8 times the male rate).</p><p>Weiss et al. (1987) assigned the ALPL locus to 1p36.1-p34 by demonstrating linkage to Rh (maximum lod score = 5.50, theta = 0.10). In the full report, Smith et al. (1988) established the location in 1p36.1-p34 by a combination of Southern blot analysis of hybrid cell DNA, in situ hybridization, and genetic linkage analysis. Linkage to Rh was indicated by a maximum lod score of 15.66 at a recombination fraction of 0.10 and to alpha-L-fucosidase (FUCA1; 612280) by a maximum lod score of 8.24 at a recombination fraction of 0.02. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Hypophosphatasia</em></strong></p><p>
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In a male infant with infantile hypophosphatasia (HPPI; 241500) who was born of second-cousin parents and died at 3 months of age, Weiss et al. (1988) identified homozygosity for a mutation in the ALPL gene (A162T; 171760.0001). Functional studies demonstrated that the mutation abolished the expression of active enzyme. </p><p>In studies of fibroblasts from 4 unrelated patients with severe (perinatal or infantile) hypophosphatasia (see 241500), Henthorn et al. (1992) identified compound heterozygosity for 8 different mutations in the ALPL gene (171760.0002-171760.0009). </p><p>Henthorn and Whyte (1992) reviewed 9 missense mutations in the ALPL gene found in hypophosphatasia. They showed that the 9 amino acid residues affected in these mutations are identical in all mammals examined, indicating evolutionary conservation. Indeed, 3 of the mutations resulted in amino acid substitutions in regions of the polypeptide that are conserved throughout evolution, being identical in mammals, yeast, and bacteria. Four of the mutations were observed in a single patient and the others in only a few. The asp378-to-val mutation (171760.0009) had the highest frequency, being found in 9 of 42 patients and none of 63 controls. Thus, the experience is similar to that in so many other disorders in which many different allelic mutations can produce the same or a similar phenotype. </p><p>Mornet et al. (1998) characterized tissue-nonspecific alkaline phosphatase gene mutations in 13 European families affected by perinatal, infantile, or childhood hypophosphatasia (HPPC; 241510). Eighteen distinct mutations were found, only 3 of which had previously been reported, in North American and Japanese populations. Most of the 15 newly identified mutations were missense mutations, but 2 mutations affected donor splice sites and 1 was a nonsense mutation. A missense mutation in the last codon of the putative signal peptide probably affected the final maturation of the protein. Despite extensive sequencing of the gene and its promoter region, only 1 mutation was identified in 2 cases, 1 of which was compatible with a possible dominant effect of certain mutations and the putative role of polymorphisms of the ALPL gene. In 12 of the 13 tested families, genetic diagnosis was possible by characterization of the mutations or by use of polymorphisms as genetic markers. In 2 families where clinical, laboratory, and radiographic data were unclear, the diagnosis of hypophosphatasia could be made, and prenatal diagnosis was performed in 1 case. Thus, severe hypophosphatasia is due to a very large spectrum of mutations in European populations with no prevalent mutation; genetic diagnosis must be performed by extensive analysis of the gene. Combined with previous reports, a total of 43 ALPL mutations had been identified. </p><p>Zurutuza et al. (1999) used clinical data, site-directed mutagenesis, and computer-assisted modeling to propose a classification of 32 ALPL gene mutations found in 23 European patients (17 with lethal hypophosphatasia and 6 with nonlethal hypophosphatasia). Transfection studies of the missense mutations found in nonlethal hypophosphatasia showed that 6 of them allowed significant residual in vitro enzymatic activity, suggesting that these mutations corresponded to moderate alleles. Each of the 6 patients with nonlethal hypophosphatasia carried at least 1 of these alleles. The 3-dimensional model study showed that moderate mutations were not found in the active site, and that most of the severe missense mutations were localized in crucial domains such as the active site, the vicinity of the active site, and homodimer interface. Some mutations appeared to be organized in clusters on the surface of the molecule that may represent candidates for regions interacting with the C-terminal end involved in glycosylphosphatidylinositol (GPI) attachment or with other dimers to form tetramers. The results of these studies showed a good correlation between clinical forms of the disease, mutagenesis experiments, and the 3-dimensional structure study, and allowed the authors to distinguish moderate alleles from severe alleles. They also confirmed that the extremely high phenotypic heterogeneity observed in patients with hypophosphatasia was due mainly to variable residual enzymatic activities allowed by missense mutations in the gene. </p><p>Mornet (1999) studied 2 large families with adult hypophosphatasia (HPPA; 146300). In 1 family, hypophosphatasia was dominantly inherited and was due to a missense mutation in the ALPL gene. In the other family, hypophosphatasia was recessively transmitted and was due to compound heterozygosity of a missense mutation and a splicing mutation in the ALPL gene. Thus, adult hypophosphatasia can be transmitted as either a dominant or recessive trait.</p><p>Mornet (2000) stated that most of the 65 distinct mutations that had been described to that time were missense mutations. Correlations of genotype and phenotype had been established on the basis of clinical data exhibited by the patients, transfection studies, computer-assisted modeling, and examination of biochemical properties of alkaline phosphatase in cultured fibroblasts of patients. Mornet (2000) also discussed the dominantly inherited form of adult hypophosphatasia. It appeared that dominant and recessive hypophosphatasia could in some instances be due to the same mutations. The findings also suggested that parents of patients affected with severe recessive forms of the disease may show, in addition to the well-known hypophosphatasemia, undiagnosed mild symptoms corresponding to adult hypophosphatasia or odontohypophosphatasia (HPPO; see 146300). </p><p>Lia-Baldini et al. (2001) stated that in approximately 14% of patients tested in their laboratories, only 1 ALPL gene mutation was found, despite exhaustive sequencing of the gene, suggesting that missing mutations are harbored in intron or regulatory sequences or that the disease is dominantly transmitted. The distinction between these 2 situations is of obvious importance to genetic counseling. Lia-Baldini et al. (2001) studied 8 point mutations found in patients with no other detectable mutation. Three of these mutations, G46V, S164L, and I473F, had not previously been described; the others were A99T (171760.0015), R167W, R206W, G232V (171760.0021), and N461I. By means of site-directed mutagenesis, transfections in COS-1 cells, and 3-dimensional modeling, Lia-Baldini et al. (2001) evaluated the possible dominant effect of these 8 mutations. Four exhibited dominant-negative effect by inhibiting the enzymatic activity of the heterodimer, whereas the other 4 did not show such inhibition. Strong inhibition resulted in severe hypophosphatasia, whereas partial inhibition resulted in milder forms of the disease. Analysis of the 3D model of the enzyme showed that mutations exhibiting a dominant-negative effect were clustered in 2 regions, namely, the active site and an area probably interacting with a region having a particular biologic function such as dimerization, tetramerization, or membrane anchoring. </p><p>In a patient with lethal perinatal hypophosphatasia with a unique clinical presentation of convulsions that responded to pyridoxine, Litmanovitz et al. (2002) identified 2 mutations in the ALPL gene. One mutation was considered to be moderate (Zurutuza et al., 1999); the other was novel. </p><p>According to Herasse et al. (2002), the glu174-to-lys (E174K; 171760.0008) mutation in the ALPL gene is common in Caucasians, widely distributed geographically, and present in 31% of patients with mild hypophosphatasia. </p><p>Herasse et al. (2003) reported 3 patients with odontohypophosphatasia (see 146300) resulting from heterozygosity for a mutation in the ALPL gene; 2 of the mutations had previously been reported (see A99T; 171760.0015), whereas the third, pro91 to leu, was novel (P91L; 171760.0018). The proband with the P91L mutation was 9 years old and the other 2 were 2 years old. The 39-year-old mother of the proband with the P91L mutation had lost her permanent teeth and had hypophosphatasia. The 38-year-old mother of the proband with the A99T mutation had an unusual number of dental caries, numerous treatments of dental root canals, and low serum ALP. </p><p>Whyte et al. (2015) evaluated clinical and molecular features in 173 patients with hypophosphatasia, including 64 patients with odontohypophosphatasia, 38 with mild childhood HPP, 58 with severe childhood HPP, and 13 with infantile HPP. Sequencing of the ALPL gene was performed in 105 patients, of whom 63 had a single heterozygous mutation consistent with autosomal dominant HPP and 42 had compound heterozygous mutations consistent with autosomal recessive HPP. No homozygotes were identified. An autosomal recessive inheritance pattern predominated in infantile- and severe childhood-onset HPP. </p><p>Mornet et al. (2021) evaluated mutations in the ALPL gene in a cohort of 424 European patients with HPP. The patient phenotypes were categorized into perinatal HPP, infantile HPP, childhood HPP, odontoHPP, and adult HPP, and the mutations in ALPL were categorized as normal (N), severe with no dominant effect (s), severe with a dominant-negative effect (Sd), moderate (m), and not classifiable (NC) based on prior functional testing. In the cohort, 166 patients had heterozygous mutations and 258 patients had compound heterozygous or homozygous mutations, comprising 682 mutant alleles and 249 distinct mutations. Some mutations were found to be anchored to specific geographic regions (e.g., R184Q was more common in France), indicating likely founder effects as opposed to individual mutational events. Patients with perinatal HPP had s/s, s/Sd, and Sd/Sd genotypes; patients with infantile HPP had s/s, Sd/m, s/m, and m/m genotypes; patients with childhood HPP had Sd/m, s/m and Sd/N genotypes; patients with adult HPP had Sd/N, Sd/m, s/m, m/N, and s/N genotypes; and patients with odontoHPP had mostly Sd/N genotypes. A subset of mutations identified in patients with autosomal recessive disease were also seen in patients with autosomal dominant disease, which had implications for genetic counseling in families. Notably, a newly recognized cohort of patients with adult HPP had a heterozygous mutation in ALPL without a dominant-negative effect. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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---Vitamin B6 Levels</p><p>For discussion of a possible association between variation in the ALPL gene and plasma levels of vitamin B6, see 612957.</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using homologous recombination in embryonic stem cells to generate null mutant mice, Waymire et al. (1995) found that mice lacking ALPL (which they referred to as tissue-nonspecific alkaline phosphatase) have normal skeletal development. However, at approximately 2 weeks after birth, homozygous mutant mice developed seizures that were subsequently fatal. Defective metabolism of PLP, characterized by elevated serum PLP levels, resulted in reduced levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the brain. The mutant seizure phenotype could be rescued by the administration of pyridoxal and a semisolid diet. Waymire et al. (1995) observed at about 3 weeks of age both a color difference and malformation of the incisor teeth in the TNAP mutant mice who were administered pyridoxal. Significantly, TNAP is expressed in the tissues within which incisor development takes place. At the growth level, the teeth of the mutants were unusually white and brittle, suggestive of hypocalcification. Between 25 and 60 days of age, mutant animals that responded to pyridoxal injections and were fed a high-fat solid diet started to display signs of paralysis. This progressed to complete inability of the animals to move and death presumably from respiratory and/or cardiac failure. During the time that pyridoxal was being administered, the incisors became progressively more deformed and often broke. (The feeding of a semisolid diet was intended to maximize their food intake.) None of the mutants fed this diet developed symptoms of paralysis; however, if pyridoxal supplementation was withdrawn, all died from seizures within 72 hours. As in humans, mouse TNAP functions as an ectoenzyme to convert PLP to pyridoxal. Waymire et al. (1995) suggested that the fact that pyridoxal is undetectable in the plasma of only rare cases of the severe perinatal form of human hypophosphatasia is probably a reflection of the type of mutation and the degree of residual alkaline phosphatase activity. Some of the TNAP mutants administered pyridoxine responded to the treatment, but the effect on longevity was minimal and mutants succumbed to seizure-related death within 2 weeks. Whyte et al. (1988) observed essentially the same progression in an infant with severe neonatal hypophosphatemia who presented with seizures, had undetectable levels of plasma pyridoxal, and was administered pyridoxine. In mammals, following uptake, the majority of pyridoxine is phosphorylated to form pyridoxine phosphate before being oxidized to yield pyridoxal 5-prime phosphate. The PLP is subsequently converted to pyridoxal by alkaline phosphatase. Very little, if any, pyridoxine is converted directly to pyridoxal. Individuals with hypophosphatasia would not be expected to interconvert pyridoxine to pyridoxal with any degree of efficiency and, based on the findings in the knockout mice by Waymire et al. (1995), administration of pyridoxal would theoretically be more appropriate. It is noteworthy that Waymire et al. (1995) found that pyridoxal administration was relatively ineffective in mice with certain genetic backgrounds. This suggested the existence of genetic modifiers specific to some backgrounds that lead to variable expressivity within the mutants on that background. Macfarlane et al. (1992) found a similar phenomenon in human sibs with hypoplasia. Humans and rodents fed a diet with a high-fat content have elevated levels of circulating alkaline phosphatase whose source is the intestinal isozyme, IAP (ALPI; 171740). Extrapolation from the mouse model suggested to Waymire et al. (1995) that, in those rare cases of hypophosphatasia associated with seizures, it would be better to substitute pyridoxal for pyridoxine, and to administer a high-fat diet to maximize IAP expression which might compensate at least partially for loss of function of the TNAP isozyme. However, because of the high dose of pyridoxal and the paralysis observed in the 'knockout' mice, such treatment would need to be carefully monitored. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>23 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 HYPOPHOSPHATASIA, INFANTILE</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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ALPL, ALA162THR
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<br />
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SNP: rs121918000,
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gnomAD: rs121918000,
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ClinVar: RCV000014648, RCV001093406, RCV001582482, RCV002496361, RCV003466856
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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 infant with hypophosphatasia (241500) who was born of second-cousin parents and died at 3 months of age, Weiss et al. (1988) identified homozygosity for a 711G-A transition in exon 6 of the ALPL gene, resulting in an ala162-to-thr (A162T) substitution. Introduction of this mutation into an otherwise normal cDNA by site-directed mutagenesis abolished the expression of active enzyme. The parents and other clinically unaffected relatives were found to be heterozygous for A162T, and the mutation cosegregated with levels of liver/bone/kidney alkaline phosphatase activity that were below the normal range. </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 HYPOPHOSPHATASIA, INFANTILE</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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ALPL, ARG54CYS
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<br />
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SNP: rs121918001,
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ClinVar: RCV000014649, RCV001851857, RCV003466857, RCV004700234, RCV004739304
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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 fibroblasts from a 5-month-old boy with hypophosphatasia (241500) who died at 6 months of age, Henthorn et al. (1992) identified compound heterozygosity for 2 mutations in the ALPL gene: a 387C-T transition in exon 4, resulting in an arg54-to-cys (R54C) substitution, and a 1057A-C transversion in exon 9, resulting in an asp277-to-ala (D277A) substitution (171760.0003). </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 HYPOPHOSPHATASIA, INFANTILE</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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HYPOPHOSPHATASIA, CHILDHOOD, INCLUDED<br />
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HYPOPHOSPHATASIA, ADULT, INCLUDED
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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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ALPL, ASP277ALA
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<br />
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SNP: rs121918002,
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gnomAD: rs121918002,
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ClinVar: RCV000014650, RCV000014651, RCV000014652, RCV000224505, RCV000589324, RCV002276545, RCV002496362, RCV004549362
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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>For discussion of the asp277-to-ala (D277A) mutation in the ALPL gene that was found in compound heterozygous state in a patient with infantile hypophosphatasia (241500) by Henthorn et al. (1992), see 171760.0002. </p><p>In 2 sibs with the mild childhood form of hypophosphatasia and in a 65-year-old woman with adult hypophosphatasia (146300), Henthorn et al. (1992) identified compound heterozygosity for 2 mutations in the ALPL gene: a D277A mutation, and 747G-A transition, resulting in a glu174-to-lys (E174K) substitution (171760.0008). </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 HYPOPHOSPHATASIA, INFANTILE</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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ALPL, ARG54PRO
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<br />
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SNP: rs121918003,
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gnomAD: rs121918003,
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ClinVar: RCV000014653, RCV001362179, RCV003460473, RCV003486545
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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 fibroblasts from a girl with hypophosphatasia (241500) who died 3 hours after birth, Henthorn et al. (1992) identified compound heterozygosity for 2 mutations in the ALPL gene: a 388G-C transversion in exon 4, resulting in an arg54-to-pro (R54P) substitution, and a 796A-C transversion in exon 6, resulting in a gln190-to-pro (Q190P) substitution (171760.0005). </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 HYPOPHOSPHATASIA, INFANTILE</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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ALPL, GLN190PRO
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<br />
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SNP: rs121918004,
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ClinVar: RCV000014654, RCV000224906, RCV003230364
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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>For discussion of the gln190-to-pro (Q190P) mutation in the ALPL gene that was found in compound heterozygous state in a patient with infantile hypophosphatasia (241500) by Henthorn et al. (1992), see 171760.0004. </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>.0006 HYPOPHOSPHATASIA, INFANTILE</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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ALPL, ALA16VAL
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<br />
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SNP: rs121918005,
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gnomAD: rs121918005,
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ClinVar: RCV000014655, RCV001042961, RCV001273156, RCV001333468, RCV003473099, RCV005016263
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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 cell line designated MW10 from a patient with hypophosphatasia (241500), Henthorn et al. (1992) found compound heterozygosity for an ala16-to-val (A16V) mutation and a tyr419-to-his mutation (Y419H; 171760.0007). </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 HYPOPHOSPHATASIA, INFANTILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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ALPL, TYR419HIS
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<br />
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SNP: rs121918006,
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ClinVar: RCV000014656
|
|
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|
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the tyr419-to-his (Y419H) mutation in the ALPL gene that was found in compound heterozygous state in a patient with infantile hypophosphatasia (241500) by Henthorn et al. (1992), see 171760.0006. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 HYPOPHOSPHATASIA, INFANTILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
HYPOPHOSPHATASIA, CHILDHOOD, INCLUDED<br />
|
|
HYPOPHOSPHATASIA, ADULT
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
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|
ALPL, GLU174LYS
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<br />
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|
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SNP: rs121918007,
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gnomAD: rs121918007,
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|
|
ClinVar: RCV000014658, RCV000014659, RCV000014660, RCV000207183, RCV000224962, RCV000763300, RCV001250150, RCV002276546, RCV002513051, RCV004584327, RCV004739305
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In fibroblasts from a girl who presented at 2 months of age with severe hypophosphatasia (241500) and died at age 8 months, Henthorn et al. (1992) identified compound heterozygosity for 2 mutations in the ALPL gene: a 747G-A transition in exon 6, resulting in a glu174-to-lys (E174K) substitution, and a 1309A-T transversion in exon 10, resulting in an asp361-to-val (D361V) substitution (171760.0009). </p><p>For discussion of the asp378-to-val (D378V) mutation found in compound heterozygous state in the ALPL gene in patients with childhood (241510) or adult (146300) hypophosphatasia by Henthorn et al. (1992), see 171760.0003. </p><p>Herasse et al. (2002) investigated whether the E174K mutation had a unique origin or multiple origins arising from de novo mutations by genotyping 3 intragenic polymorphisms in patients with E174K and unaffected related individuals. Because all of the E174K mutations were found on a common ancestral haplotype, the authors suggested that a founder mutation occurred on a single chromosome in northwestern Europe and spread by human migration. </p>
|
|
</span>
|
|
</div>
|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 HYPOPHOSPHATASIA, INFANTILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
HYPOPHOSPHATASIA, ADULT, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALPL, ASP378VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918008,
|
|
|
|
|
|
gnomAD: rs121918008,
|
|
|
|
|
|
ClinVar: RCV000014661, RCV000014662, RCV000207084, RCV000224520, RCV000763302, RCV001847606, RCV004549364, RCV004984641
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Whyte et al. (2007) stated that the ASP361VAL designation has been changed to ASP378VAL. </p><p>For discussion of the asp378-to-val (D378V) mutation in the ALPL gene that was found in compound heterozygous state in a patient with infantile hypophosphatasia (241500) by Henthorn et al. (1992), see 171760.0008. </p><p>Moore et al. (1999) described a family with mild hypophosphatasia, apparently transmitted as an autosomal dominant trait, in which ultrasonography detected an affected fetus with severe long bone bowing. In contrast to the progressive deterioration typical of both the perinatal and infantile forms of hypophosphatasia, these skeletal defects improved spontaneously during infancy and early childhood. Biochemical evidence of hypophosphatasia was present in this family, and Moore et al. (1999) identified the D378V mutation in the ALPL gene of all affected members. </p><p>Whyte et al. (2007) identified heterozygosity for the D378V mutation in a middle-aged woman with adult hypophosphatasia (146300) who was successfully treated with teriparatide. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 HYPOPHOSPHATASIA, INFANTILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALPL, GLY317ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918009,
|
|
|
|
|
|
|
|
ClinVar: RCV000014663, RCV000207270, RCV000224376, RCV000763301, RCV000786923, RCV002276547, RCV004549365
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In individuals with the Mennonite perinatal, lethal form of hypophosphatasia (241500), Greenberg et al. (1993) demonstrated a homoallelic G-to-A transition in exon 10 of the ALPL gene at position 1177, changing a polar glycine to an acidic aspartate (gly317-to-asp, or G317D). A patient with a juvenile form of hypophosphatasia, with a Mennonite mother and a non-Mennonite father, was found to be heteroallelic for a maternally inherited G317D allele and a paternally inherited glu174-to-lys (E174K; 171760.0008) allele. The authors reported finding the same 2 mutations present as a genetic compound in other late-onset hypophosphatasia patients. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 HYPOPHOSPHATASIA, INFANTILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALPL, PHE310LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918010,
|
|
|
|
|
|
gnomAD: rs121918010,
|
|
|
|
|
|
ClinVar: RCV000014664, RCV000207096, RCV000380876, RCV000724148, RCV002504786, RCV004549366
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In fibroblasts of a neonate with hypophosphatasia (241500), Ozono et al. (1996) identified compound heterozygosity for 2 mutations in the ALPL gene: a 1155T-C transition, resulting in a phe3101-to-leu (F3101L) substitution, and a 1542G-A transition, resulting in a gly439-to-arg (G439R) substitution (171760.0019). The F3101L mutant exhibited an ALPL activity level 65% of normal, while the G439R mutant had no activity. Each parent was heterozygous for 1 of the mutations. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 HYPOPHOSPHATASIA, INFANTILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALPL, 1-BP DEL, 1735T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906525,
|
|
|
|
|
|
gnomAD: rs387906525,
|
|
|
|
|
|
ClinVar: RCV000014665, RCV000207209, RCV000346130, RCV003460475
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese patient with infantile hypophosphatasia (241500), Orimo et al. (1994) identified compound heterozygosity for 2 mutations in the ALPL gene. One mutation, inherited from the mother, was a 1-bp deletion in exon 12 (1735delT). The deletion caused a frameshift downstream from codon 503 (leu), and the normal termination codon at 508 was eliminated. Since a new in-frame termination codon appeared at codon 588 in the mutant DNA, the resultant protein was predicted to have 80 additional amino acids. The other mutation, inherited from the father, was a 1068G-A transition in exon 9, resulting in a glu281-to-lys (E281K; 171760.0020) substitution. </p><p>Goseki-Sone et al. (1998) studied expression of the mutant 1735delT ALPL cDNA in COS-1 cells. They found that the protein translated from the mutant gene had undetectable ALPL activity, and its molecular size was larger than the wildtype protein. Detection of the mutant protein in cells transfected with the 1735delT mutation with an immunofluorescent method exhibited only a faint signal on the cell surface, but an intense intracellular fluorescence after permeabilization. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 HYPOPHOSPHATASIA, CHILDHOOD</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALPL, ARG119HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918011,
|
|
|
|
|
|
gnomAD: rs121918011,
|
|
|
|
|
|
ClinVar: RCV000014666, RCV000169168, RCV000364426, RCV000767525, RCV000770988, RCV002276548, RCV002490366, RCV004798728
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Zurutuza et al. (1999) divided hypophosphatasia into lethal and nonlethal types. They studied 32 ALPL mutations found in 23 European patients, 17 with lethal hypophosphatasia (see 241500) and 6 with nonlethal hypophosphatasia (241510). They identified 6 mutations which on transfection studies were shown to allow significant residual in vitro enzymatic activity. The oldest patient in their study, aged 11 years, was a compound heterozygote for arg119 to his (R119H) and gly145 to val (G145V; 171760.0014). The former was apparently a 'moderate' allele, whereas the latter was a 'severe' allele. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 HYPOPHOSPHATASIA, CHILDHOOD</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALPL, GLY145VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918012,
|
|
|
|
|
|
|
|
ClinVar: RCV000014667, RCV000670940, RCV001239346
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the gly145-to-val (G145V) mutation in the ALPL gene that was found in compound heterozygous state in a patient with childhood-onset hypophosphatasia (241510) by Zurutuza et al. (1999), see 171760.0013. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 HYPOPHOSPHATASIA, CHILDHOOD</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
HYPOPHOSPHATASIA, ADULT, INCLUDED<br />
|
|
ODONTOHYPOPHOSPHATASIA, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALPL, ALA99THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918013,
|
|
|
|
|
|
|
|
ClinVar: RCV000014668, RCV000014669, RCV000014670, RCV000169426, RCV000224118, RCV000590781, RCV004549367
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 13 affected members of a 4-generation Texas family segregating autosomal dominant hypophosphatasia in both children (241510) and adults (146300), Hu et al. (2000) identified heterozygosity for an ala99-to-thr (A99T) substitution in the ALPL gene. The mutation was also found in 1 clinically unaffected individual who had an elevated urinary phosphoethanolamine (PEA) level. Lia-Baldini et al. (2001) performed functional studies of the A99T mutation and observed a moderate dominant negative effect. Complete sequencing of the gene in the brother and sister twin probands from the Texas family, including the untranslated exon 1 and intron/exon borders, revealed no mutation other than the heterozygous 346G-A transition in exon 5 of the ALPL gene that results in the A99T substitution. </p><p>Herasse et al. (2003) identified the A99T mutation in heterozygous state in a 2-year-old male and his mother; the former had only dental manifestations and low serum alkaline phosphatase and the latter did not have odontohypophosphatasia (146300) but had an unusual number of dental caries and had had numerous treatments of dental root canals. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 HYPOPHOSPHATASIA, PERINATAL LETHAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALPL, IVS6DS, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs749544042,
|
|
|
|
|
|
gnomAD: rs749544042,
|
|
|
|
|
|
ClinVar: RCV000014671, RCV000710058, RCV001227927, RCV001553715, RCV003466858, RCV004549368, RCV005016264
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Sergi et al. (2001) made a postmortem diagnosis of perinatal lethal hypophosphatasia (see 241500) on the basis of radiologic and pathologic changes of a generalized bone mineralization defect including asymmetry of the cervical vertebral arches. The parents were nonconsanguineous. The fetus was found to be a compound heterozygote: the first nucleotide of intron 6 of the ALPL gene was changed from G to A; the other chromosome carried an asn400-to-ser missense mutation in exon 11 (N400S; 171760.0017). The former was of maternal origin and the latter of paternal origin. DNA-based prenatal testing in a subsequent pregnancy following a chorionic villus sampling performed at 10 weeks of gestation showed no mutation and a healthy baby was born at term. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 HYPOPHOSPHATASIA, PERINATAL LETHAL</strong>
|
|
</span>
|
|
</h4>
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|
</div>
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<div>
|
|
<span class="mim-text-font">
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ALPL, ASN400SER
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<br />
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|
|
SNP: rs121918014,
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gnomAD: rs121918014,
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|
|
ClinVar: RCV000014672, RCV000169778, RCV000710510, RCV001194283, RCV001253058, RCV004719646, RCV004739306, RCV005016265
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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>For discussion of the asn400-to-ser (N400S) mutation in the ALPL gene that was found in compound heterozygous state in a fetus with perinatal lethal hypophosphatasia (see 241500) by Sergi et al. (2001), see 171760.0016. </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>.0018 ODONTOHYPOPHOSPHATASIA</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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ALPL, PRO91LEU
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<br />
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SNP: rs121918015,
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ClinVar: RCV000014673
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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 9-year-old boy with Down syndrome (190685) and odontohypophosphatasia (146300) and his 39-year-old mother, Herasse et al. (2003) identified heterozygosity for a 323C-T transition in the ALPL gene, resulting in a pro91-to-leu (P91L) change. The boy had lost 7 deciduous teeth, mostly incisors, beginning at the age of 2 years and had low serum alkaline phosphatase, and his mother had lost her permanent teeth and had a low alkaline phosphatase level, indicating that the findings could not be attributed to Down syndrome. </p>
|
|
</span>
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</div>
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<div>
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<br />
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|
</div>
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</div>
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<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 HYPOPHOSPHATASIA, INFANTILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
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|
|
|
ALPL, GLY439ARG
|
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|
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<br />
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|
|
SNP: rs121918016,
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|
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gnomAD: rs121918016,
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|
|
ClinVar: RCV000014674, RCV001387538, RCV003448247, RCV004786260
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|
|
</span>
|
|
</div>
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the gly439-to-arg (G439R) mutation in the ALPL gene that was found in compound heterozygous state in a patient with infantile hypophosphatasia (241500) by Ozono et al. (1996), see 171760.0011. </p>
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|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 HYPOPHOSPHATASIA, INFANTILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
ALPL, GLU281LYS
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<br />
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|
|
SNP: rs121918017,
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|
|
gnomAD: rs121918017,
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|
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|
|
|
ClinVar: RCV000014657, RCV001549327, RCV001582483, RCV002504785, RCV003460474, RCV004549363
|
|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the glu281-to-lys (E281K) mutation in the ALPL gene that was found in compound heterozygous state in a patient with infantile hypophosphatasia (241500) by Orimo et al. (1994), see 171760.0012. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 HYPOPHOSPHATASIA, CHILDHOOD</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
ODONTOHYPOPHOSPHATASIA, INCLUDED
|
|
</span>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALPL, GLY232VAL
|
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<br />
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|
|
SNP: rs121918018,
|
|
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|
|
gnomAD: rs121918018,
|
|
|
|
|
|
ClinVar: RCV000014675, RCV000014676, RCV000668001, RCV000723607, RCV001826462, RCV003335039, RCV003466859
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 15-month-old girl with a phenotype suggestive of childhood hypophosphatasia (241510), Lia-Baldini et al. (2001) identified heterozygosity for a 746G-T transversion in exon 7 of the ALPL gene, resulting in a gly232-to-val (G232V) substitution. The mutation was inherited from her father, who had recurrent dental caries in his 3rd decade despite being raised with fluoridated water; the authors suggested that this represented odontohypophosphatasia (146300). </p><p>Lia-Baldini et al. (2008) performed functional analysis of the G232V mutation in the ALPL gene and demonstrated that the mutant protein sequestrates some of the wildtype protein in the cells and prevents it from reaching the membrane. These results suggested a new mechanism for dominance in hypophosphatasia, involving mutated homodimers and heterodimers that are sequestrated in the cells with only wildtype homodimers (approximately 25% of the total dimers) able to play a physiologic role in the cell. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 HYPOPHOSPHATASIA, INFANTILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
HYPOPHOSPHATASIA, CHILDHOOD, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALPL, ALA176THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918019,
|
|
|
|
|
|
gnomAD: rs121918019,
|
|
|
|
|
|
ClinVar: RCV000014677, RCV000014678, RCV000763299, RCV000808101, RCV001275108, RCV002276549, RCV002288490, RCV004549369
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Stevenson et al. (2008) described a boy with prenatal presentation of hypophosphatasia (241500) manifesting as long bone deformity detected in utero by sonography at 18 weeks' gestation who had spontaneous pre- and postnatal improvement. He was compound heterozygous for missense mutations in the ALPL gene, one in exon 6 (526G-A, ala176 to thr, A176T) and the other in exon 8 (814C-T, arg272 to cys, R272C). His affected older brother, who carried the same mutations, had childhood hypophosphatasia (241510). His sonography at 20 weeks was reported as normal, and he was first evaluated at 19 months of age for premature tooth loss. At 18 weeks' gestation, the proband presented with sharp angulation of the midshaft of the right humerus, radius, and ulna. All major long bones were subjectively of slightly narrow diameter and poorly ossified. At birth there was bowing of the right arm with dimpling of the skin near the apex of the bowing, but the physical examination was otherwise unremarkable. Evidence of healing and healed fractures in the right humerus, radius, and ulna was seen on radiographs at birth and 6 months of age. At age 17 months he was evaluated for premature tooth loss, and at that time bowing of the right upper arm was present. The female twin of the proband carried neither mutation and was clinically unaffected. Each parent was heterozygous for one of the mutations. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 HYPOPHOSPHATASIA, INFANTILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
HYPOPHOSPHATASIA, CHILDHOOD, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ALPL, ARG272CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918020,
|
|
|
|
|
|
gnomAD: rs121918020,
|
|
|
|
|
|
ClinVar: RCV000014679, RCV000169779, RCV000817506, RCV001804731, RCV003473100, RCV004549370, RCV005007851
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the arg272-to-cys (R272C) mutation in the ALPL gene that was found in compound heterozygous state in brothers, one with infantile hypophosphatasia (241500) and the other with childhood hypophosphatasia (241510) by Stevenson et al. (2008), see 171760.0022. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Hua et al. (1986)
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ardinger, R. H., Jr., Buetow, K. H., Weiss, M. J., Nemer, M., DeHaven, C. R., Murray, J. C.
|
|
<strong>Multipoint linkage relationships of 6 loci on 1p (ALPL, GLUT, PGD, PGM1, PND, RH). (Abstract)</strong>
|
|
Am. J. Hum. Genet. 41: A154 only, 1987.
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Fedde, K. N., Whyte, M. P.
|
|
<strong>Alkaline phosphatase (tissue-nonspecific isoenzyme) is a phosphoethanolamine and pyridoxal-5-prime-phosphate ectophosphatase: normal and hypophosphatasia fibroblast study.</strong>
|
|
Am. J. Hum. Genet. 47: 767-775, 1990.
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|
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|
|
[PubMed: 2220817]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Goldstein, D. J., Rogers, C. E., Harris, H.
|
|
<strong>Expression of alkaline phosphatase loci in mammalian tissues.</strong>
|
|
Proc. Nat. Acad. Sci. 77: 2857-2860, 1980.
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[PubMed: 6930672]
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[Full Text: https://doi.org/10.1073/pnas.77.5.2857]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Goseki-Sone, M., Orimo, H., Iimura, T., Miyazaki, H., Oda, K., Shibata, H., Yanagishita, M., Takagi, Y., Watanabe, H., Shimada, T., Oida, S.
|
|
<strong>Expression of the mutant (1735T-DEL) tissue-nonspecific alkaline phosphatase gene from hypophosphatasia patients.</strong>
|
|
J. Bone Miner. Res. 13: 1827-1834, 1998.
|
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[PubMed: 9844100]
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[Full Text: https://doi.org/10.1359/jbmr.1998.13.12.1827]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Greenberg, C. R., Taylor, C. L. D., Haworth, J. C., Seargeant, L. E., Philipps, S., Triggs-Raine, B., Chodirker, B. N.
|
|
<strong>A homoallelic gly317-to-asp mutation in ALPL causes the perinatal (lethal) form of hypophosphatasia in Canadian Mennonites.</strong>
|
|
Genomics 17: 215-217, 1993.
|
|
|
|
|
|
[PubMed: 8406453]
|
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|
|
[Full Text: https://doi.org/10.1006/geno.1993.1305]
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Harris, H., Hopkinson, D. A., Robson, E. B.
|
|
<strong>The incidence of rare alleles determining electrophoretic variants: data on 43 enzyme loci in man.</strong>
|
|
Ann. Hum. Genet. 37: 237-253, 1974.
|
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|
|
[PubMed: 4812947]
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|
|
[Full Text: https://doi.org/10.1111/j.1469-1809.1974.tb01832.x]
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</p>
|
|
</li>
|
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Henthorn, P. S., Raducha, M., Fedde, K. N., Lafferty, M. A., Whyte, M. P.
|
|
<strong>Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia.</strong>
|
|
Proc. Nat. Acad. Sci. 89: 9924-9928, 1992.
|
|
|
|
|
|
[PubMed: 1409720]
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|
|
[Full Text: https://doi.org/10.1073/pnas.89.20.9924]
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Henthorn, P. S., Whyte, M. P.
|
|
<strong>Missense mutations of the tissue-nonspecific alkaline phosphatase gene in hypophosphatasia.</strong>
|
|
Clin. Chem. 38: 2501-2505, 1992.
|
|
|
|
|
|
[PubMed: 1360878]
|
|
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Herasse, M., Spentchian, M., Taillandier, A., Keppler-Noreuil, K., Fliorito, A. N. M., Bergoffen, J., Wallerstein, R., Muti, C., Simon-Bouy, B., Mornet, E.
|
|
<strong>Molecular study of three cases of odontohypophosphatasia resulting from heterozygosity for mutations in the tissue non-specific alkaline phosphatase gene.</strong>
|
|
J. Med. Genet. 40: 605-609, 2003.
|
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|
|
|
|
[PubMed: 12920074]
|
|
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|
|
[Full Text: https://doi.org/10.1136/jmg.40.8.605]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Herasse, M., Spentchian, M., Taillandier, A., Mornet, E.
|
|
<strong>Evidence of a founder effect for the tissue-nonspecific alkaline phosphatase (TNSALP) gene E174K mutation in hypophosphatasia patients.</strong>
|
|
Europ. J. Hum. Genet. 10: 666-668, 2002.
|
|
|
|
|
|
[PubMed: 12357339]
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|
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|
|
[Full Text: https://doi.org/10.1038/sj.ejhg.5200857]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hu, J. C.-C., Plaetke, R., Mornet, E., Zhang, C., Sun, X., Thomas, H. F., Simmer, J. P.
|
|
<strong>Characterization of a family with dominant hypophosphatasia.</strong>
|
|
Europ. J. Oral Sci. 108: 189-194, 2000.
|
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|
|
|
|
[PubMed: 10872988]
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|
|
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|
|
[Full Text: https://doi.org/10.1034/j.1600-0722.2000.108003189.x]
|
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|
|
</p>
|
|
</li>
|
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Hua, J.-C., Berger, J., Pan, Y.-C. E., Hulmes, J. D., Udenfriend, S.
|
|
<strong>Partial sequencing of human adult, human fetal, and bovine intestinal alkaline phosphatases: comparison with the human placental and liver isozymes.</strong>
|
|
Proc. Nat. Acad. Sci. 83: 2368-2372, 1986.
|
|
|
|
|
|
[PubMed: 3458202]
|
|
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|
|
[Full Text: https://doi.org/10.1073/pnas.83.8.2368]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
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Contributors:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 10/30/2024<br>Ada Hamosh - updated : 8/3/2009<br>John A. Phillips, III - updated : 6/9/2009<br>Marla J. F. O'Neill - updated : 10/17/2008<br>Carol A. Bocchini - updated : 9/17/2008<br>John A. Phillips, III - updated : 3/24/2008<br>Natalie E. Krasikov - updated : 6/1/2004<br>Victor A. McKusick - updated : 10/1/2003<br>Ada Hamosh - updated : 9/22/2003<br>Victor A. McKusick - updated : 10/5/2001<br>Victor A. McKusick - updated : 9/10/2001<br>Victor A. McKusick - updated : 4/19/2000<br>Sonja A. Rasmussen - updated : 12/15/1999<br>Victor A. McKusick - updated : 6/8/1999<br>Victor A. McKusick - updated : 6/1/1999<br>Victor A. McKusick - updated : 2/15/1999<br>John A. Phillips, III - updated : 12/20/1996
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<span class="mim-text-font">
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Victor A. McKusick : 6/2/1986
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carol : 10/30/2024<br>carol : 04/14/2015<br>mcolton : 4/9/2015<br>carol : 4/12/2012<br>carol : 1/13/2010<br>carol : 8/12/2009<br>terry : 8/3/2009<br>alopez : 6/9/2009<br>wwang : 3/26/2009<br>wwang : 11/6/2008<br>wwang : 10/17/2008<br>carol : 9/17/2008<br>carol : 3/24/2008<br>alopez : 7/24/2007<br>alopez : 10/18/2004<br>carol : 6/17/2004<br>carol : 6/1/2004<br>tkritzer : 10/24/2003<br>tkritzer : 10/6/2003<br>tkritzer : 10/6/2003<br>tkritzer : 10/1/2003<br>alopez : 9/22/2003<br>tkritzer : 1/2/2003<br>mcapotos : 10/15/2001<br>mcapotos : 10/10/2001<br>terry : 10/5/2001<br>mcapotos : 9/17/2001<br>mcapotos : 9/10/2001<br>mcapotos : 5/19/2000<br>mcapotos : 5/16/2000<br>terry : 4/19/2000<br>mgross : 12/20/1999<br>mgross : 12/15/1999<br>carol : 9/14/1999<br>carol : 8/3/1999<br>carol : 6/16/1999<br>carol : 6/16/1999<br>jlewis : 6/15/1999<br>terry : 6/8/1999<br>jlewis : 6/7/1999<br>terry : 6/1/1999<br>mgross : 3/10/1999<br>mgross : 2/17/1999<br>terry : 2/15/1999<br>carol : 10/7/1998<br>terry : 10/2/1998<br>carol : 5/13/1998<br>joanna : 5/13/1998<br>jenny : 5/21/1997<br>jenny : 5/21/1997<br>terry : 9/11/1995<br>mark : 8/31/1995<br>mimadm : 4/14/1994<br>warfield : 4/12/1994<br>carol : 7/19/1993<br>carol : 2/5/1993
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