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Entry
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- *607608 - SPHINGOMYELIN PHOSPHODIESTERASE 1, ACID LYSOSOMAL; SMPD1
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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">*607608</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<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/607608">Table View</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000166311;t=ENST00000342245" 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=6609" 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=607608" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000166311;t=ENST00000342245" 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_000543,NM_001007593,NM_001318087,NM_001318088,NM_001365135,NR_027400,NR_134502,XM_011520304" 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_000543" 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=607608" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=06353&isoform_id=06353_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/SMPD1" 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/28880,179095,402621,553192,553193,556809,825629,972769,972770,972773,18845013,27370710,55975657,56117840,62089136,119589132,119589133,119589134,119589135,158258208,300795589,320091590,320091592,320091594,320091596,583317726,767966367,969812494,969812496,1435761090,1476413398,2294330687,2462527148,2462527150" 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/P17405" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=6609" 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=ENSG00000166311;t=ENST00000342245" 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=SMPD1" 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=SMPD1" 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+6609" 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/SMPD1" 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:6609" 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/6609" 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=chr11&hgg_gene=ENST00000342245.9&hgg_start=6390474&hgg_end=6394996&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:11120" 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/smpd1" 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=607608[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=607608[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/SMPD1/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000166311" 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=SMPD1" 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=SMPD1" 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=SMPD1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SMPD1&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/PA35969" 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:11120" 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/FBgn0034997.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:98325" 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/SMPD1#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:98325" 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/6609/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/OMIA001795/" 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=6609" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00000211;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00000211 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00000212;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00000212 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00000213;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00000213 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-110411-222" 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:607608" 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:6609" 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=SMPD1&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> 39390005, 52165006<br />
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<strong>ICD10CM:</strong> E75.240, E75.241<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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607608
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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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SPHINGOMYELIN PHOSPHODIESTERASE 1, ACID LYSOSOMAL; SMPD1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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SPHINGOMYELINASE, ACID; ASM
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SMPD1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SMPD1</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/11/126?start=-3&limit=10&highlight=126">11p15.4</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr11:6390474-6394996&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'})">11:6,390,474-6,394,996</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
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Location
|
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</th>
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<th>
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Phenotype
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=257200,607616" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
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</th>
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<th>
|
|
Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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<a href="/geneMap/11/126?start=-3&limit=10&highlight=126">
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11p15.4
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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Niemann-Pick disease, type A
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/257200"> 257200 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</td>
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</tr>
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<tr>
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<span class="mim-font">
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Niemann-Pick disease, type B
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/607616"> 607616 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/607608" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/607608" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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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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</div>
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<div>
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<br />
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div>
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<a id="cloning" class="mim-anchor"></a>
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</h4>
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<div id="mimCloningFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p><a href="#24" class="mim-tip-reference" title="Quintern, L. E., Schuchman, E. H., Levran, O., Suchi, M., Ferlinz, K., Reinke, H., Sandhoff, K., Desnick, R. J. <strong>Isolation of cDNA clones encoding human acid sphingomyelinase: occurrence of alternatively processed transcripts.</strong> EMBO J. 8: 2469-2473, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2555181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2555181</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1989.tb08382.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2555181">Quintern et al. (1989)</a> microsequenced 128 residues from acid sphingomyelinase (<a href="https://enzyme.expasy.org/EC/3.1.4.12" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 3.1.4.12</a>) purified from urine, synthesized oligonucleotide mixtures based on minimal codon redundancy, and used these to screen human fibroblast and placenta cDNA libraries. The findings demonstrated the presence of 2 distinct acid sphingomyelinase transcripts in both human fibroblasts and placenta, suggesting possible alternative processing of the mRNA. both transcripts were approximately 2.5 kb. By screened human placenta, testis, hepatoma, and retina cDNA libraries, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2555181" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Schuchman, E. H., Suchi, M., Takahashi, T., Sandhoff, K., Desnick, R. J. <strong>Human acid sphingomyelinase: isolation, nucleotide sequence, and expression of the full-length and alternatively spliced cDNAs.</strong> J. Biol. Chem. 266: 8531-8539, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1840600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1840600</a>]" pmid="1840600">Schuchman et al. (1991)</a> isolated SMPD1 transcripts, including the previously described type 1 and type 2 cDNAs, as well as a third cDNA. Functional studies showed that only the type 1 transcript encoded catalytically active functional human ASM. The type 1 cDNA encoded a 629-amino acid protein. <a href="#27" class="mim-tip-reference" title="Rodriguez-Pascau, L., Gort, L., Schuchman, E. H., Vilagelui, L., Grinberg, D., Chabas, A. <strong>Identification and characterization of SMPD1 mutations causing Niemann-Pick types A and B in Spanish patients.</strong> Hum. Mutat. 30: 1117-1122, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19405096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19405096</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19405096[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/10.1002/humu.21018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19405096">Rodriguez-Pascau et al. (2009)</a> noted that human ASM protein is synthesized as a 75-kD prepolypeptide, which is converted into a precursor form of 72 kD. The precursor is subject to 2 different processing events. A minor part is cleaved in the ER-Golgi complex, yielding a 57-kD form, whereas a major part is processed to a 70-kD mature form. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19405096+1840600" 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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</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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<a id="geneStructure" class="mim-anchor"></a>
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<h4 href="#mimGeneStructureFold" id="mimGeneStructureToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimGeneStructureToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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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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<div id="mimGeneStructureFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p>Using the SMPD1 cDNA as a probe, <a href="#29" class="mim-tip-reference" title="Schuchman, E. H., Levran, O., Pereira, L. V., Desnick, R. J. <strong>Structural organization and complete nucleotide sequence of the gene encoding human acid sphingomyelinase (SMPD1).</strong> Genomics 12: 197-205, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1740330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1740330</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90366-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1740330">Schuchman et al. (1992)</a> isolated the SMPD1 genomic region and determined the complete nucleotide sequence of the gene including 1,116 and 468 nucleotides upstream and downstream, respectively, from the coding region. They determined that the SMPD1 gene contains 6 exons. Exon 2 is unusually large and encodes 258 amino acids, or about 44% of the mature ASM polypeptide. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1740330" 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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</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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<a id="mapping" class="mim-anchor"></a>
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<h4 href="#mimMappingFold" id="mimMappingToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimMappingToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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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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<div id="mimMappingFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p><a href="#1" class="mim-tip-reference" title="da Veiga Pereira, L., Desnick, R. J., Adler, D. A., Disteche, C. M., Schuchman, E. H. <strong>Regional assignment of the human acid sphingomyelinase gene (SMPD1) by PCR analysis of somatic cell hybrids and in situ hybridization to 11p15.1-p15.4.</strong> Genomics 9: 229-234, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2004772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2004772</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90246-b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2004772">Da Veiga Pereira et al. (1991)</a> demonstrated by Southern blotting of somatic cell hybrids that the SMPD1 gene maps to 11p15.1-p15.4, not to chromosome 17 as had been reported by <a href="#12" class="mim-tip-reference" title="Konrad, R., Wilson, D. <strong>Assignment of the gene for acid lysosomal sphingomyelinase to human chromosome 17. (Abstract)</strong> Cytogenet. Cell Genet. 46: 641, 1987."None>Konrad and Wilson (1987)</a>. By in situ hybridization, <a href="#1" class="mim-tip-reference" title="da Veiga Pereira, L., Desnick, R. J., Adler, D. A., Disteche, C. M., Schuchman, E. H. <strong>Regional assignment of the human acid sphingomyelinase gene (SMPD1) by PCR analysis of somatic cell hybrids and in situ hybridization to 11p15.1-p15.4.</strong> Genomics 9: 229-234, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2004772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2004772</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90246-b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2004772">da Veiga Pereira et al. (1991)</a> refined the localization to 11p15. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2004772" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By PCR-amplification detection assay of a mouse/hamster somatic cell hybrid panel, <a href="#9" class="mim-tip-reference" title="Horinouchi, K., Sakiyama, T., Pereira, L., Lalley, P. A., Schuchman, E. H. <strong>Mouse models of Niemann-Pick disease: mutation analysis and chromosomal mapping rule out the type A and B forms.</strong> Genomics 18: 450-451, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8288255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8288255</a>] [<a href="https://doi.org/10.1006/geno.1993.1497" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8288255">Horinouchi et al. (1993)</a> mapped the orthologous gene in the mouse (Smpd1) to chromosome 7, in a region of well-known homology to distal 11p where the human gene is situated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8288255" 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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<br />
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<div>
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<a id="geneFunction" class="mim-anchor"></a>
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<h4 href="#mimGeneFunctionFold" id="mimGeneFunctionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimGeneFunctionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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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><a href="#34" class="mim-tip-reference" title="Suchi, M., Dinur, T., Desnick, R. J., Gatt, S., Pereira, L., Gilboa, E., Schuchman, E. H. <strong>Retroviral-mediated transfer of the human acid sphingomyelinase cDNA: correction of the metabolic defect in cultured Niemann-Pick disease cells.</strong> Proc. Nat. Acad. Sci. 89: 3227-3231, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1565614/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1565614</a>] [<a href="https://doi.org/10.1073/pnas.89.8.3227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1565614">Suchi et al. (1992)</a> demonstrated that the metabolic defect in cultured Niemann-Pick disease (see <a href="/entry/257200">257200</a>) cells, which lack sphingomyelinase activity, could be corrected by retroviral-mediated transfer of human ASM cDNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1565614" 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>Stress is believed to activate sphingomyelinase to generate ceramide, which serves as a second messenger in initiating the apoptotic response. The first conclusive evidence for this paradigm was provided by <a href="#28" class="mim-tip-reference" title="Santana, P., Pena, L. A., Haimovitz-Friedman, A., Martin, S., Green, D., McLoughlin, M., Cordon-Cardo, C., Schuchman, E. H., Fuks, Z., Kolesnick, R. <strong>Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis.</strong> Cell 86: 189-199, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8706124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8706124</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80091-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8706124">Santana et al. (1996)</a> who showed that lymphoblasts from Niemann-Pick patients failed to respond to ionizing radiation with ceramide generation and apoptosis. These abnormalities could be reversed by restoring acid sphingomyelinase activity by retroviral transfer of human acid sphingomyelinase cDNA. Mice in which the gene had been knocked out also showed defects in radiation-induced ceramide generation and apoptosis in vivo. Comparison with p53 knockout mice suggested to <a href="#28" class="mim-tip-reference" title="Santana, P., Pena, L. A., Haimovitz-Friedman, A., Martin, S., Green, D., McLoughlin, M., Cordon-Cardo, C., Schuchman, E. H., Fuks, Z., Kolesnick, R. <strong>Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis.</strong> Cell 86: 189-199, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8706124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8706124</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80091-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8706124">Santana et al. (1996)</a> that acid sphingomyelinase-mediated apoptosis and p53-mediated apoptosis are probably distinct and independent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8706124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Garcia-Ruiz, C., Colell, A., Mari, M., Morales, A., Calvo, M., Enrich, C., Fernandez-Checa, J. C. <strong>Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice.</strong> J. Clin. Invest. 111: 197-208, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12531875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12531875</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12531875[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI16010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12531875">Garcia-Ruiz et al. (2003)</a> studied the contribution of ASM in TNF-alpha (<a href="/entry/191160">191160</a>)-mediated hepatocellular apoptosis. They showed that selective mGSH (mitochondrial glutathione) depletion sensitized hepatocytes to TNF-alpha-mediated hepatocellular apoptosis by facilitating the onset of mitochondrial permeability transition. Inactivation of endogenous hepatocellular ASM activity protected hepatocytes from TNF-alpha-induced cell death. Similarly, ASM -/- mice were resistant in vivo to endogenous and exogenous TNF-alpha-induced liver damage. Targeting of ganglioside GD3 (<a href="/entry/601123">601123</a>) to mitochondria occurred in ASM +/+ but not in ASM -/- hepatocytes. Treatment of ASM -/- hepatocytes with exogenous ASM induced the colocalization of GD3 and mitochondria. <a href="#6" class="mim-tip-reference" title="Garcia-Ruiz, C., Colell, A., Mari, M., Morales, A., Calvo, M., Enrich, C., Fernandez-Checa, J. C. <strong>Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice.</strong> J. Clin. Invest. 111: 197-208, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12531875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12531875</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12531875[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI16010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12531875">Garcia-Ruiz et al. (2003)</a> concluded that ASM contributes to TNF-alpha-induced hepatocellular apoptosis by promoting the targeting of mitochondria by glycosphingolipids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12531875" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Grassme, H., Gulbins, E., Brenner, B., Ferlinz, K., Sandhoff, K., Harzer, K., Lang, F., Meyer, T. F. <strong>Acidic sphingomyelinase mediates entry of N. gonorrhoeae in nonphagocytic cells.</strong> Cell 91: 605-615, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9393854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9393854</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80448-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9393854">Grassme et al. (1997)</a> provided evidence that acid sphingomyelinase mediates entry of Neisseria gonorrhoeae into nonphagocytic cells. Invasion of human mucosal cells by N. gonorrhoeae via the binding to heparan sulfate proteoglycan receptors is considered a crucial event of the infection. Using different human epithelial cells and primary fibroblasts, <a href="#7" class="mim-tip-reference" title="Grassme, H., Gulbins, E., Brenner, B., Ferlinz, K., Sandhoff, K., Harzer, K., Lang, F., Meyer, T. F. <strong>Acidic sphingomyelinase mediates entry of N. gonorrhoeae in nonphagocytic cells.</strong> Cell 91: 605-615, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9393854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9393854</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80448-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9393854">Grassme et al. (1997)</a> demonstrated an activation of phosphatidylcholine-specific phospholipase C and ASM by N. gonorrhoeae, resulting in the release of diacylglycerol and ceramide. Genetic and/or pharmacologic blockade of ASM and phosphatidylcholine-specific phospholipase C caused inhibition of cellular invasion by N. gonorrhoeae. Complementation of ASM-deficient fibroblasts from Niemann-Pick disease patients restored N. gonorrhoeae-induced signaling and entry processes. <a href="#7" class="mim-tip-reference" title="Grassme, H., Gulbins, E., Brenner, B., Ferlinz, K., Sandhoff, K., Harzer, K., Lang, F., Meyer, T. F. <strong>Acidic sphingomyelinase mediates entry of N. gonorrhoeae in nonphagocytic cells.</strong> Cell 91: 605-615, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9393854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9393854</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80448-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9393854">Grassme et al. (1997)</a> concluded that activation of phosphatidylcholine-specific phospholipase C and ASM is an essential requirement for the entry of N. gonorrhoeae into distinct nonphagocytic human cell types including several epithelial cells and primary fibroblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9393854" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Kirkegaard, T., Roth, A. G., Petersen, N. H. T., Mahalka, A. K., Olsen, O. D., Moilanen, I., Zylicz, A., Knudsen, J., Sandhoff, K., Arenz, C., Kinnunen, P. K. J., Nylandsted, J., Jaattela, M. <strong>Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease-associated lysosomal pathology.</strong> Nature 463: 549-553, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20111001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20111001</a>] [<a href="https://doi.org/10.1038/nature08710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20111001">Kirkegaard et al. (2010)</a> demonstrated that the reduced ASM activity in cells from patients with Niemann-Pick disease A and B is also associated with a marked decrease in lysosomal stability, and that this phenotype could be effectively corrected by treatment with recombinant Hsp70 (<a href="/entry/140550">140550</a>). Hsp70 stabilizes lysosomes by binding to an endolysosomal anionic phospholipid bis(monoacylglycero)phosphate (BMP), an essential cofactor for lysosomal sphingomyelin metabolism. In acidic environments Hsp70 binds with high affinity and specificity to BMP, thereby facilitating the BMP binding and activity of ASM. The inhibition of the Hsp70-BMP interaction by BMP antibodies or a point mutation in Hsp70 (trp90 to phe), as well as the pharmacologic and genetic inhibition of ASM, effectively reverted the Hsp70-mediated stabilization of lysosomes. <a href="#11" class="mim-tip-reference" title="Kirkegaard, T., Roth, A. G., Petersen, N. H. T., Mahalka, A. K., Olsen, O. D., Moilanen, I., Zylicz, A., Knudsen, J., Sandhoff, K., Arenz, C., Kinnunen, P. K. J., Nylandsted, J., Jaattela, M. <strong>Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease-associated lysosomal pathology.</strong> Nature 463: 549-553, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20111001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20111001</a>] [<a href="https://doi.org/10.1038/nature08710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20111001">Kirkegaard et al. (2010)</a> concluded that, taken together, their data opened exciting possibilities for the development of new treatments for lysosomal storage disorders and cancer with compounds that enter the lysosomal lumen by the endocytic delivery pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20111001" 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="#16" class="mim-tip-reference" title="Levran, O., Desnick, R. J., Schuchman, E. H. <strong>Niemann-Pick disease: a frequent missense mutation in the acid sphingomyelinase gene of Ashkenazi Jewish type A and B patients.</strong> Proc. Nat. Acad. Sci. 88: 3748-3752, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2023926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2023926</a>] [<a href="https://doi.org/10.1073/pnas.88.9.3748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2023926">Levran et al. (1991)</a> identified a point mutation in the SMPD1 gene (<a href="#0001">607608.0001</a>) in an Ashkenazi Jewish patient with type A Niemann-Pick disease (<a href="/entry/257200">257200</a>) and <a href="#17" class="mim-tip-reference" title="Levran, O., Desnick, R. J., Schuchman, E. H. <strong>Niemann-Pick type B disease: identification of a single codon deletion in the acid sphingomyelinase gene and genotype/phenotype correlations in type A and B patients.</strong> J. Clin. Invest. 88: 806-810, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1885770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1885770</a>] [<a href="https://doi.org/10.1172/JCI115380" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1885770">Levran et al. (1991)</a> identified a 3-bp deletion in the SMPD1 gene (R608del; <a href="#0002">607608.0002</a>) in an Ashkenazi Jewish patient with type B Niemann-Pick disease (<a href="/entry/607616">607616</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1885770+2023926" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#35" class="mim-tip-reference" title="Takahashi, T., Desnick, R. J., Takada, G., Schuchman, E. H. <strong>Identification of a missense mutation (S436R) in the acid sphingomyelinase gene from a Japanese patient with type B Niemann-Pick disease.</strong> Hum. Mutat. 1: 70-71, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301192</a>] [<a href="https://doi.org/10.1002/humu.1380010111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1301192">Takahashi et al. (1992)</a> characterized 6 Niemann-Pick disease mutations (see <a href="#0004">607608.0004</a>-<a href="#0009">607608.0009</a>) and concluded that small deletions or nonsense mutations that result in a truncated ASM polypeptide and missense mutations that render the enzyme noncatalytic cause type A Niemann-Pick disease, whereas missense mutations that produce a defective enzyme with residual catalytic activity cause the milder nonneuronopathic type B phenotype. <a href="#10" class="mim-tip-reference" title="Ida, H., Rennert, O. M., Maekawa, K., Eto, Y. <strong>Identification of three novel mutations in the acid sphingomyelinase gene of Japanese patients with Niemann-Pick disease type A and B.</strong> Hum. Mutat. 7: 65-67, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8664904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8664904</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1996)7:1<65::AID-HUMU10>3.0.CO;2-Q" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8664904">Ida et al. (1996)</a> identified 3 novel mutations in the SMPD1 gene in Japanese patients with type A and B Niemann-Pick disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8664904+1301192" 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="Lee, C. Y., Krimbou, L., Vincent, J., Bernard, C., Larramee, P., Genest, J., Jr., Marcil, M. <strong>Compound heterozygosity at the sphingomyelin phosphodiesterase-1 (SMPD1) gene is associated with low HDL cholesterol.</strong> Hum. Genet. 112: 552-562, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12607113/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12607113</a>] [<a href="https://doi.org/10.1007/s00439-002-0893-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12607113">Lee et al. (2003)</a> investigated a kindred with type B Niemann-Pick disease resulting from heteroallelic (i.e., compound heterozygous) mutations in the SMPD1 gene (<a href="#0002">607608.0002</a> and <a href="#0014">607608.0014</a>) associated with low levels of HDL cholesterol. Both the index patient, a 47-year-old male, and his sister, who was 2 years younger, had hypertriglyceridemia; the sister also had severe premature coronary artery disease. By studying cellular cholesterol efflux in fibroblasts, <a href="#14" class="mim-tip-reference" title="Lee, C. Y., Krimbou, L., Vincent, J., Bernard, C., Larramee, P., Genest, J., Jr., Marcil, M. <strong>Compound heterozygosity at the sphingomyelin phosphodiesterase-1 (SMPD1) gene is associated with low HDL cholesterol.</strong> Hum. Genet. 112: 552-562, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12607113/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12607113</a>] [<a href="https://doi.org/10.1007/s00439-002-0893-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12607113">Lee et al. (2003)</a> found that, unlike patients with Tangier disease (<a href="/entry/205400">205400</a>), cholesterol efflux was normal under the experimental conditions used. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12607113" 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="#27" class="mim-tip-reference" title="Rodriguez-Pascau, L., Gort, L., Schuchman, E. H., Vilagelui, L., Grinberg, D., Chabas, A. <strong>Identification and characterization of SMPD1 mutations causing Niemann-Pick types A and B in Spanish patients.</strong> Hum. Mutat. 30: 1117-1122, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19405096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19405096</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19405096[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/10.1002/humu.21018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19405096">Rodriguez-Pascau et al. (2009)</a> identified 17 different mutations in the SMPD1 gene, including 10 novel mutations (see, e.g., A482E; <a href="/entry/608607#0016">608607.0016</a> and Y467S; <a href="/entry/608607#0017">608607.0017</a>), in 19 Spanish patients and 2 patients from Maghreb in Northern Africa with Niemann-Pick disease type A (8 patients) or type B (13 patients). The most common mutations were the R608del mutation, found in 38% of alleles, and the A482E mutation, found in 9% of alleles. The R608del mutation was always found in patients with type B disease. Functional expression studies of the mutant proteins in COS-7 cells showed decreased enzyme activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19405096" 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>Imprinting</em></strong></p><p>
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The basis of the variability between type A and type B NPD is poorly understood and does not always correlate with the individual SMPD1 mutations. In addition, some carrier individuals for ASM-deficient NPD have features of the disease (<a href="#14" class="mim-tip-reference" title="Lee, C. Y., Krimbou, L., Vincent, J., Bernard, C., Larramee, P., Genest, J., Jr., Marcil, M. <strong>Compound heterozygosity at the sphingomyelin phosphodiesterase-1 (SMPD1) gene is associated with low HDL cholesterol.</strong> Hum. Genet. 112: 552-562, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12607113/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12607113</a>] [<a href="https://doi.org/10.1007/s00439-002-0893-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12607113">Lee et al., 2003</a>), which is an unusual finding for an autosomal recessive disorder such as this. <a href="#25" class="mim-tip-reference" title="Rethy, L. A., Kalmanchey, R., Klujber, V., Koos, R., Fekete, G. <strong>Acid sphingomyelinase deficiency with Beckwith-Wiedemann syndrome.</strong> Pathol. Oncol. Res. 6: 295-297, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11173664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11173664</a>] [<a href="https://doi.org/10.1007/BF03187335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11173664">Rethy et al. (2000)</a> described a patient with Beckwith-Wiedemann syndrome (BWS; <a href="/entry/130650">130650</a>) who had approximately 30% of normal ASM activity in cultured skin fibroblasts. This 23-month-old child had a normal karyotype, which suggested uniparental disomy of paternal chromosome 11p15. <a href="#25" class="mim-tip-reference" title="Rethy, L. A., Kalmanchey, R., Klujber, V., Koos, R., Fekete, G. <strong>Acid sphingomyelinase deficiency with Beckwith-Wiedemann syndrome.</strong> Pathol. Oncol. Res. 6: 295-297, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11173664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11173664</a>] [<a href="https://doi.org/10.1007/BF03187335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11173664">Rethy et al. (2000)</a> suggested that the SMPD1 gene might be imprinted, on the basis of the reduced ASM activity in this patient, the possibility of 11p15 uniparental disomy, and the fact that the SMPD1 gene has structural features common to other imprinted genes (<a href="#26" class="mim-tip-reference" title="Rethy, L. A. <strong>Growth regulation, acid sphingomyelinase gene and genomic imprinting: lessons from an experiment of nature.</strong> Pathol. Oncol. Res. 6: 298-300, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11310411/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11310411</a>]" pmid="11310411">Rethy, 2000</a>). To assess imprinting at the SMPD1 locus, <a href="#32" class="mim-tip-reference" title="Simonaro, C. M., Park, J.-H., Eliyahu, E., Shtraizent, N., McGovern, M. M., Schuchman, E. H. <strong>Imprinting at the SMPD1 locus: implications for acid sphingomyelinase-deficient Niemann-Pick disease.</strong> Am. J. Hum. Genet. 78: 865-870, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16642440/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16642440</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16642440[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/503750" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16642440">Simonaro et al. (2006)</a> studied several heteroallelic patients with ASM-deficient NPD. They demonstrated that the SMPD1 gene is paternally imprinted and that differential expression of the mutant alleles in patients with ASM-deficient NPD and in carriers influences the disease phenotype. Comparison of the results of genomic sequencing versus RT-PCR sequencing for several patients with NPD revealed preferential expression of 1 mutant allele. Further analysis of one family showed that the expressed allele was maternally inherited and that the distinct clinical presentations of the individual patients were correlated with the amount of residual ASM activity expressed from the maternal mutation. Treatment of NPD cell lines with 5-aza-2-prime-deoxycytidine enhanced the expression of the paternal SMPD1 allele, and bisulfite genomic sequencing identified which CpG dinucleotides within the SMPD1 promoter were methylated. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16642440+11310411+11173664+12607113" 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="Simonaro, C. M., Park, J.-H., Eliyahu, E., Shtraizent, N., McGovern, M. M., Schuchman, E. H. <strong>Imprinting at the SMPD1 locus: implications for acid sphingomyelinase-deficient Niemann-Pick disease.</strong> Am. J. Hum. Genet. 78: 865-870, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16642440/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16642440</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16642440[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/503750" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16642440">Simonaro et al. (2006)</a> identified a carrier individual who had approximately 15% of normal ASM activity and clinical features of ASM-deficient NPD. DNA sequencing confirmed that this individual carried a single SMPD1 mutation and that this mutant allele was preferentially expressed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16642440" 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>Complete sequencing of the Smpd1 gene in 2 mouse models of Niemann-Pick disease by <a href="#9" class="mim-tip-reference" title="Horinouchi, K., Sakiyama, T., Pereira, L., Lalley, P. A., Schuchman, E. H. <strong>Mouse models of Niemann-Pick disease: mutation analysis and chromosomal mapping rule out the type A and B forms.</strong> Genomics 18: 450-451, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8288255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8288255</a>] [<a href="https://doi.org/10.1006/geno.1993.1497" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8288255">Horinouchi et al. (1993)</a> revealed no mutation, indicating that these are not models of either type A or type B Niemann-Pick disease. One of the models, spm/spm, was thought to be a model of type C Niemann-Pick disease (<a href="/entry/257220">257220</a>) and the other may be a model for either type C or type D (see <a href="/entry/257220">257220</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8288255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By homologous recombination in embryonic stem cells, <a href="#21" class="mim-tip-reference" title="Otterbach, B., Stoffel, W. <strong>Acid sphingomyelinase-deficient mice mimic the neurovisceral form of human lysosomal storage disease (Niemann-Pick disease).</strong> Cell 81: 1053-1061, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7600574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7600574</a>] [<a href="https://doi.org/10.1016/s0092-8674(05)80010-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7600574">Otterbach and Stoffel (1995)</a> achieved targeted disruption of the Smpd1 gene in transgenic mice. Homozygous mice accumulated sphingomyelin extensively in the reticuloendothelial system of liver, spleen, bone marrow, and lung, as well as in the brain. Most strikingly, the ganglionic cell layer of Purkinje cells of the cerebellum degenerated completely, leading to severe impairment of neuromotor coordination. The picture resembled that of the neurovisceral form of Niemann-Pick disease (type A). <a href="#8" class="mim-tip-reference" title="Horinouchi, K., Erlich, S., Perl, D. P., Ferlinz, K., Bisgaier, C. L., Sandhoff, K., Desnick, R. J., Stewart, C. L., Schuchman, E. H. <strong>Acid sphingomyelinase deficient mice: a model of types A and B Niemann-Pick disease.</strong> Nature Genet. 10: 288-293, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7670466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7670466</a>] [<a href="https://doi.org/10.1038/ng0795-288" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7670466">Horinouchi et al. (1995)</a> obtained similar results in Asm knockout mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7600574+7670466" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Garcia-Barros, M., Paris, F., Cordon-Cardo, C., Lyden, D., Rafii, S., Haimovitz-Friedman, A., Fuks, Z., Kolesnick, R. <strong>Tumor response to radiotherapy regulated by endothelial cell apoptosis.</strong> Science 300: 1155-1159, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12750523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12750523</a>] [<a href="https://doi.org/10.1126/science.1082504" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12750523">Garcia-Barros et al. (2003)</a> investigated the hypothesis that tumor response to radiation is determined not only by tumor cell type but also by microvascular sensitivity. MCA/129 fibrosarcomas and B16F1 melanomas grown in apoptosis-resistant 'acid sphingomyelinase' (asmase)-deficient or Bax (<a href="/entry/600040">600040</a>)-deficient mice displayed markedly reduced baseline microvascular endothelial apoptosis and grew 200 to 400% faster than tumors on wildtype microvasculature. Thus, <a href="#5" class="mim-tip-reference" title="Garcia-Barros, M., Paris, F., Cordon-Cardo, C., Lyden, D., Rafii, S., Haimovitz-Friedman, A., Fuks, Z., Kolesnick, R. <strong>Tumor response to radiotherapy regulated by endothelial cell apoptosis.</strong> Science 300: 1155-1159, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12750523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12750523</a>] [<a href="https://doi.org/10.1126/science.1082504" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12750523">Garcia-Barros et al. (2003)</a> concluded that endothelial apoptosis is a homeostatic factor regulating angiogenesis-dependent tumor growth. Moreover, these tumors exhibited reduced endothelial apoptosis upon irradiation and, unlike tumors in wildtype mice, they were resistant to single-dose radiation up to 20 Gy. <a href="#5" class="mim-tip-reference" title="Garcia-Barros, M., Paris, F., Cordon-Cardo, C., Lyden, D., Rafii, S., Haimovitz-Friedman, A., Fuks, Z., Kolesnick, R. <strong>Tumor response to radiotherapy regulated by endothelial cell apoptosis.</strong> Science 300: 1155-1159, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12750523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12750523</a>] [<a href="https://doi.org/10.1126/science.1082504" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12750523">Garcia-Barros et al. (2003)</a> concluded that microvascular damage regulates tumor cell response to radiation at the clinically relevant dose range. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12750523" 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="Mari, M., Colell, A., Morales, A., Paneda, C., Varela-Nieto, I., Garcia-Ruiz, C., Fernandez-Checa, J. C. <strong>Acidic sphingomyelinase downregulates the liver-specific methionine adenosyltransferase 1A, contributing to tumor necrosis factor-induced lethal hepatitis.</strong> J. Clin. Invest. 113: 895-904, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15067322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15067322</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15067322[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI19852" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15067322">Mari et al. (2004)</a> demonstrated that levels of methionine adenosyltransferase-1-alpha mRNA as well as MAT I/III protein (see MAT1A, <a href="/entry/250850">250850</a>) decreased in cultured rat hepatocytes by in situ generation of ceramide from exogenous human placenta SMPD1. Hepatocytes lacking the SMPD1 gene were insensitive to TNF-alpha, but were responsive to exogenous SMPD1-induced downregulation of MAT1A. In an in vivo model of lethal hepatitis by TNF-alpha, depletion of S-adenosyl-L-methionine (SAM) preceded activation of caspases 8 and 3, massive liver damage, and death of wildtype mice. In contrast, minimal hepatic SAM depletion, caspase activation, and liver damage were seen in Smpd1 -/- mice. Moreover, therapeutic treatment with SAM abrogated caspase activation and liver injury, thus rescuing Smpd1 +/+ mice from TNF-alpha-induced lethality. <a href="#20" class="mim-tip-reference" title="Mari, M., Colell, A., Morales, A., Paneda, C., Varela-Nieto, I., Garcia-Ruiz, C., Fernandez-Checa, J. C. <strong>Acidic sphingomyelinase downregulates the liver-specific methionine adenosyltransferase 1A, contributing to tumor necrosis factor-induced lethal hepatitis.</strong> J. Clin. Invest. 113: 895-904, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15067322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15067322</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15067322[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI19852" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15067322">Mari et al. (2004)</a> concluded that these findings indicated a new role for SMPD1 in TNF-alpha-induced liver failure through downregulation of MAT1A and suggested that maintenance of SAM might be useful in the treatment of acute and chronic liver disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15067322" 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 mouse hepatocytes, <a href="#13" class="mim-tip-reference" title="Lang, P. A., Schenck, M., Nicolay, J. P., Becker, J. U., Kempe, D. S., Lupescu, A., Koka, S., Eisele, K., Klarl, B. A., Rubben, H., Schmid, K. W., Mann, K., Hildenbrand, S., Hefter, H., Huber, S. M., Wieder, T., Erhardt, A., Haussinger, D., Gulbins, E., Lang, F. <strong>Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide.</strong> Nature Med. 13: 164-170, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17259995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17259995</a>] [<a href="https://doi.org/10.1038/nm1539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17259995">Lang et al. (2007)</a> demonstrated that Cu(2+) induced the secretion of activated Asm from leukocytes, leading to ceramide release in and phosphatidylserine exposure on erythrocytes, which are events prevented by inhibition of Asm. In LEC rats, a model of Wilson disease (<a href="/entry/277900">277900</a>), deficiency in or pharmacologic inhibition of Asm prevented Cu(2+)-induced hepatocyte apoptosis and protected the rats from acute hepatocyte death, liver failure, and early death. Patients with Wilson disease showed elevated plasma levels of ASM, and displayed a constitutive increase of ceramide- and phosphatidylserine-positive erythrocytes. <a href="#13" class="mim-tip-reference" title="Lang, P. A., Schenck, M., Nicolay, J. P., Becker, J. U., Kempe, D. S., Lupescu, A., Koka, S., Eisele, K., Klarl, B. A., Rubben, H., Schmid, K. W., Mann, K., Hildenbrand, S., Hefter, H., Huber, S. M., Wieder, T., Erhardt, A., Haussinger, D., Gulbins, E., Lang, F. <strong>Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide.</strong> Nature Med. 13: 164-170, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17259995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17259995</a>] [<a href="https://doi.org/10.1038/nm1539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17259995">Lang et al. (2007)</a> concluded that Cu(2+) triggers hepatocyte apoptosis through activation of ASM and release of ceramide, suggesting a previously unidentified mechanism for liver cirrhosis and anemia in Wilson disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17259995" 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> rs120074117 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074117;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/rs120074117?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=rs120074117" 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=rs120074117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>Levran et al. (<a href="#15" class="mim-tip-reference" title="Levran, O., Desnick, R. J., Schuchman, E. H. <strong>Identification of the first mutation in Niemann-Pick types A and B disease, a common point mutation in the Ashkenazi Jewish population. (Abstract)</strong> Am. J. Hum. Genet. 47 (suppl.): A162, 1990."None>1990</a>, <a href="#16" class="mim-tip-reference" title="Levran, O., Desnick, R. J., Schuchman, E. H. <strong>Niemann-Pick disease: a frequent missense mutation in the acid sphingomyelinase gene of Ashkenazi Jewish type A and B patients.</strong> Proc. Nat. Acad. Sci. 88: 3748-3752, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2023926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2023926</a>] [<a href="https://doi.org/10.1073/pnas.88.9.3748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2023926">1991</a>) used polymerase chain reaction (PCR) to amplify the coding region from the acid sphingomyelinase gene from an Ashkenazi Jewish patient with Niemann-Pick disease type A (<a href="/entry/257200">257200</a>). Sequence analysis revealed a single G-to-T change at nucleotide 1487 (in a CpG dinucleotide), predicting an arginine-to-leucine amino acid substitution in residue 496. The mutation was found in 5 of 20 (25%) Ashkenazi Jewish type A patients and in 3 of 36 (8.3%) SMPD1 alleles from non-Jewish type A homozygotes. The mutation was found in only 1 of 90 SMPD1 alleles from normal persons of Ashkenazi Jewish descent. The arg496-to-leu mutation was found in one of the mutant alleles in 2 Ashkenazi Jewish patients with type B Niemann-Pick disease and in none of the alleles of 15 non-Jewish type B homozygotes. The R496L mutation was found in about 32% of Ashkenazi Jewish type A Niemann-Pick disease alleles studied. In contrast, only about 5% of the alleles from non-Jewish type A patients had this mutation (<a href="#16" class="mim-tip-reference" title="Levran, O., Desnick, R. J., Schuchman, E. H. <strong>Niemann-Pick disease: a frequent missense mutation in the acid sphingomyelinase gene of Ashkenazi Jewish type A and B patients.</strong> Proc. Nat. Acad. Sci. 88: 3748-3752, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2023926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2023926</a>] [<a href="https://doi.org/10.1073/pnas.88.9.3748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2023926">Levran et al., 1991</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2023926" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In an Ashkenazi Jewish patient with Niemann-Pick disease type B (<a href="/entry/607616">607616</a>), <a href="#17" class="mim-tip-reference" title="Levran, O., Desnick, R. J., Schuchman, E. H. <strong>Niemann-Pick type B disease: identification of a single codon deletion in the acid sphingomyelinase gene and genotype/phenotype correlations in type A and B patients.</strong> J. Clin. Invest. 88: 806-810, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1885770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1885770</a>] [<a href="https://doi.org/10.1172/JCI115380" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1885770">Levran et al. (1991)</a> identified a 3-base deletion at nucleotides 1821-1823 which predicted the removal of an arginine residue from position 608 of the acid sphingomyelinase polypeptide. The other cDNA clone from this patient had the R496L mutation previously identified in type A Niemann-Pick disease patients (<a href="#0001">607608.0001</a>). The delta-R608 mutation was not found in 15 unrelated non-Jewish type B patients, with the notable exception of 1 mildly affected patient of Arab descent who was homoallelic for the delta-R608 mutation. These results indicated that the delta-R608 mutation predicts the type B Niemann-Pick disease phenotype, even in the presence of the R496L type A allele, thereby providing the first genotype/phenotype correlation for this lysosomal storage disease. Although only 2 patients had been studied, it appeared that the delta-R608 mutation was a frequent cause of type B Niemann-Pick disease in Ashkenazi Jews. The terms homoallelic and heteroallelic (for genetic compound) seem to have been used particularly by Desnick and his colleagues, e.g., <a href="#16" class="mim-tip-reference" title="Levran, O., Desnick, R. J., Schuchman, E. H. <strong>Niemann-Pick disease: a frequent missense mutation in the acid sphingomyelinase gene of Ashkenazi Jewish type A and B patients.</strong> Proc. Nat. Acad. Sci. 88: 3748-3752, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2023926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2023926</a>] [<a href="https://doi.org/10.1073/pnas.88.9.3748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2023926">Levran et al. (1991)</a>; they are useful terms for the situations repeatedly encountered as more and more intragenic lesions are identified in mendelian disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1885770+2023926" 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>Niemann-Pick disease type B has a high frequency in the Maghreb region of North Africa, which includes Morocco, Algeria, and Tunisia. In a study of 15 unrelated, non-Jewish North African type B patients, <a href="#37" class="mim-tip-reference" title="Vanier, M. T., Ferlinz, K., Rousson, R., Duthel, S., Louisot, P., Sandhoff, K., Suzuki, K. <strong>Deletion of arginine (608) in acid sphingomyelinase is the prevalent mutation among Niemann-Pick disease type B patients from northern Africa.</strong> Hum. Genet. 92: 325-330, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8225311/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8225311</a>] [<a href="https://doi.org/10.1007/BF01247328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8225311">Vanier et al. (1993)</a> found that 12 were homozygous and 2 compound heterozygous for the arg608-to-del mutation. They found the mutation in only 1 of 16 alleles from type B patients from other geographic areas (France, U.K., Italy, Czechoslovakia). A varying severity of the clinical and enzymatic expression was observed in homozygotes for this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8225311" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The R608 deletion mutation was found in a 55-year-old Belgian woman of Caucasian origin who had had progressive Parkinson disease for the previous 4 years and presented for acute onset of severe back pain, pain in the rib cage due to multiple vertebral fractures, as well as dyspnea due to interstitial lung disease (<a href="#38" class="mim-tip-reference" title="Volders, P., Van Hove, J., Lories, R. J. U., Vandekerckhove, P., Matthijs, G., De Vos, R., Vanier, M. T., Vincent, M. F., Westhovens, R., Luyten, F. P. <strong>Niemann-Pick disease type B: an unusual clinical presentation with multiple vertebral fractures.</strong> Am. J. Med. Genet. 109: 42-51, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11932991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11932991</a>] [<a href="https://doi.org/10.1002/ajmg.10278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11932991">Volders et al., 2002</a>). The patient was short statured as a child and the parents were first cousins. The vertebral fractures were thought to be due to increased physical activity after treatment of Parkinson disease, a genetic predisposition, and worsening disease due to interfering medication. She was treated with cholesterol-lowering drugs such as statins to decrease sphingomyelin synthesis, avoidance of drugs that inhibit sphingomyelinase, and bisphosphonates. No new fractures occurred, but the interstitial lung disease progressed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11932991" 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="Fernandez-Burriel, M., Pena, L., Ramos, J. C., Cabrera, J. C., Marti, M., Rodriguez-Quinones, F., Chabas, A. <strong>The R608del mutation in the acid sphingomyelinase gene (SMPD1) is the most prevalent among patients from Gran Canaria Island with Niemann-Pick disease type B. (Letter)</strong> Clin. Genet. 63: 235-236, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12694237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12694237</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2003.00025.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12694237">Fernandez-Burriel et al. (2003)</a> reported that the R608 deletion was the most prevalent among patients in Gran Canaria Island in patients with Niemann-Pick disease. They estimated the prevalence of the disease as 0.8-1:100,000 in their community; all patients carried the arg608-to-del mutation. Because of the heterogeneity of the clinical phenotype and the high prevalence of the arg608-to-del mutation in their community, they suggested that the mutation be routinely tested for in adults with hepatosplenomegaly of unknown origin before trying more invasive tests such as liver or bone marrow biopsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12694237" 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="#27" class="mim-tip-reference" title="Rodriguez-Pascau, L., Gort, L., Schuchman, E. H., Vilagelui, L., Grinberg, D., Chabas, A. <strong>Identification and characterization of SMPD1 mutations causing Niemann-Pick types A and B in Spanish patients.</strong> Hum. Mutat. 30: 1117-1122, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19405096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19405096</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19405096[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/10.1002/humu.21018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19405096">Rodriguez-Pascau et al. (2009)</a> identified the R608del mutation in 38% of alleles from 21 patients of Spanish origin with Niemann-Pick disease. All patients with the R608del mutation had type B disease. In vitro functional expression studies in COS-7 cells showed that the mutant protein had 21.46% residual activity. Haplotype analysis suggested a founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19405096" 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> rs120074119 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074119;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/rs120074119?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=rs120074119" 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=rs120074119" 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=RCV000003116 OR RCV001248875 OR RCV001851600" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003116, RCV001248875, RCV001851600" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003116...</a>
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<p>By sequence analysis of mRNA and genomic DNA of fibroblasts from a patient with Niemann-Pick disease type A (<a href="/entry/257200">257200</a>), <a href="#2" class="mim-tip-reference" title="Ferlinz, K., Hurwitz, R., Sandhoff, K. <strong>Molecular basis of acid sphingomyelinase deficiency in a patient with Niemann-Pick disease type A.</strong> Biochem. Biophys. Res. Commun. 179: 1187-1191, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1718266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1718266</a>] [<a href="https://doi.org/10.1016/0006-291x(91)91697-b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1718266">Ferlinz et al. (1991)</a> showed a G-to-A transition at nucleotide 1729 resulting in substitution of serine for glycine at position 577. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1718266" 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">rs267607073 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607073;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=rs267607073" 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=rs267607073" 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 19-year-old Japanese female with type B Niemann-Pick disease (<a href="/entry/607616">607616</a>) manifested by moderate hepatosplenomegaly and mild pulmonary involvement and without neuronopathic manifestations, <a href="#35" class="mim-tip-reference" title="Takahashi, T., Desnick, R. J., Takada, G., Schuchman, E. H. <strong>Identification of a missense mutation (S436R) in the acid sphingomyelinase gene from a Japanese patient with type B Niemann-Pick disease.</strong> Hum. Mutat. 1: 70-71, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301192</a>] [<a href="https://doi.org/10.1002/humu.1380010111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1301192">Takahashi et al. (1992)</a> found a ser436-to-arg mutation in homoallelic state. Her affected sister had the same mutation and both parents were heterozygous. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1301192" 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> rs120074120 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074120;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/rs120074120?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=rs120074120" 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=rs120074120" 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=RCV000003118 OR RCV001248867 OR RCV001390954" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003118, RCV001248867, RCV001390954" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003118...</a>
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<p>In a type A Niemann-Pick disease (<a href="/entry/257200">257200</a>) patient of Asian Indian ancestry, <a href="#35" class="mim-tip-reference" title="Takahashi, T., Desnick, R. J., Takada, G., Schuchman, E. H. <strong>Identification of a missense mutation (S436R) in the acid sphingomyelinase gene from a Japanese patient with type B Niemann-Pick disease.</strong> Hum. Mutat. 1: 70-71, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301192</a>] [<a href="https://doi.org/10.1002/humu.1380010111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1301192">Takahashi et al. (1992)</a> found homoallelism for a T-to-A transversion in exon 2, predicting a premature stop at codon leucine-261. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1301192" 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">rs786204694 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786204694;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=rs786204694" 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=rs786204694" 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=RCV000169504 OR RCV001067762 OR RCV001248975" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000169504, RCV001067762, RCV001248975" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000169504...</a>
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<p><a href="#35" class="mim-tip-reference" title="Takahashi, T., Desnick, R. J., Takada, G., Schuchman, E. H. <strong>Identification of a missense mutation (S436R) in the acid sphingomyelinase gene from a Japanese patient with type B Niemann-Pick disease.</strong> Hum. Mutat. 1: 70-71, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301192</a>] [<a href="https://doi.org/10.1002/humu.1380010111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1301192">Takahashi et al. (1992)</a> found that a type A Niemann-Pick disease (<a href="/entry/257200">257200</a>) patient of European ancestry was heteroallelic for a 2-base (TT) deletion in exon 2, which caused a frameshift mutation at SMPD1 codon 178, leading to a premature stop at codon 190. The mutation on the other chromosome was a G-to-A transition in exon 3 which caused a methionine-to-isoleucine substitution at codon 382 (M382I). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1301192" 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">rs120074121 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074121;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=rs120074121" 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=rs120074121" 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=RCV000003120 OR RCV000596113 OR RCV004799730" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003120, RCV000596113, RCV004799730" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003120...</a>
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<p>See <a href="#0006">607608.0006</a>. Transient expression of the L261X (<a href="#0005">607608.0005</a>), L178FS (<a href="#0006">607608.0006</a>), and M382I mutations in COS-1 cells demonstrated that these lesions did not produce catalytically active enzyme, consistent with the severe neuronopathic type A Niemann-Pick disease (<a href="/entry/257200">257200</a>) phenotype.</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> rs120074122 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074122;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/rs120074122?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=rs120074122" 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=rs120074122" 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=RCV000003121 OR RCV000723418 OR RCV001248871 OR RCV001851601 OR RCV002468958 OR RCV003472960" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003121, RCV000723418, RCV001248871, RCV001851601, RCV002468958, RCV003472960" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003121...</a>
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<p><a href="#35" class="mim-tip-reference" title="Takahashi, T., Desnick, R. J., Takada, G., Schuchman, E. H. <strong>Identification of a missense mutation (S436R) in the acid sphingomyelinase gene from a Japanese patient with type B Niemann-Pick disease.</strong> Hum. Mutat. 1: 70-71, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301192</a>] [<a href="https://doi.org/10.1002/humu.1380010111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1301192">Takahashi et al. (1992)</a> found that a type B Niemann-Pick disease (<a href="/entry/607616">607616</a>) patient of European descent was heteroallelic for 2 missense mutations: a G-to-A transition in exon 2 which predicted a glycine-to-arginine substitution at codon 242 (G242R), and an A-to-G transition in exon 3 which resulted in an asparagine-to-serine substitution at codon 383 (N383S). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1301192" 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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SMPD1, ASN383SER
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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> rs120074123 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074123;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/rs120074123?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=rs120074123" 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=rs120074123" 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=RCV000003122 OR RCV001248870 OR RCV002512692" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003122, RCV001248870, RCV002512692" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003122...</a>
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<p>See <a href="#0008">607608.0008</a>. <a href="#35" class="mim-tip-reference" title="Takahashi, T., Desnick, R. J., Takada, G., Schuchman, E. H. <strong>Identification of a missense mutation (S436R) in the acid sphingomyelinase gene from a Japanese patient with type B Niemann-Pick disease.</strong> Hum. Mutat. 1: 70-71, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301192</a>] [<a href="https://doi.org/10.1002/humu.1380010111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1301192">Takahashi et al. (1992)</a> found that the G242R allele (<a href="#0008">607608.0008</a>) produced enzyme activity in COS-1 cells at levels about 40% of that expressed by the normal allele, thereby explaining the mild Niemann-Pick disease type B (<a href="/entry/607616">607616</a>) phenotype of the patient and the high residual activity (approximately 15% of normal) in cultured lymphoblasts. In contrast, the other allele, N383S, did not produce catalytically active enzyme. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1301192" 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>.0010 NIEMANN-PICK DISEASE, TYPE A</strong>
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SMPD1, LEU302PRO
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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> rs120074124 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074124;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/rs120074124?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=rs120074124" 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=rs120074124" 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=RCV000003123 OR RCV000175622 OR RCV000192222 OR RCV000984009 OR RCV001380607" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003123, RCV000175622, RCV000192222, RCV000984009, RCV001380607" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003123...</a>
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<p><a href="#18" class="mim-tip-reference" title="Levran, O., Desnick, R. J., Schuchman, E. H. <strong>Identification and expression of a common missense mutation (L302P) in the acid sphingomyelinase gene of Ashkenazi Jewish type A Niemann-Pick disease patients.</strong> Blood 80: 2081-2087, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1391960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1391960</a>]" pmid="1391960">Levran et al. (1992)</a> reported a T-to-C transition at nucleotide 905, predicting a leucine-to-proline substitution at SMPD1 codon 302 in 8 of 34 (23.5%) Ashkenazi type A Niemann-Pick disease (<a href="/entry/257200">257200</a>) alleles studied. In contrast, it was not found in any of the SMPD1 alleles from non-Jewish type A patients or in alleles from type B patients or in 100 SMPD1 alleles from normal Ashkenazi Jewish persons. The authenticity of the frequent R496L (<a href="#0001">607608.0001</a>) and L302P mutations was confirmed by separately introducing each nucleotide change into the full-length SMPD1 cDNA by site-directed mutagenesis and transient expression in COS-1 cells. Neither mutation expressed SMPD1 catalytic activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1391960" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 NIEMANN-PICK DISEASE, TYPE A</strong>
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SMPD1, 1-BP DEL, PRO330FS
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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> rs387906289 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906289;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/rs387906289?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=rs387906289" 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=rs387906289" 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=RCV000003124 OR RCV000192223 OR RCV000723827 OR RCV000817028 OR RCV000984010" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003124, RCV000192223, RCV000723827, RCV000817028, RCV000984010" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003124...</a>
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<p><a href="#19" class="mim-tip-reference" title="Levran, O., Desnick, R. J., Schuchman, E. H. <strong>Type A Niemann-Pick disease: a frameshift mutation in the acid sphingomyelinase gene (fsP330) occurs in Ashkenazi Jewish patients.</strong> Hum. Mutat. 2: 317-319, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8401540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8401540</a>] [<a href="https://doi.org/10.1002/humu.1380020414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8401540">Levran et al. (1993)</a> described a new mutation that causes type A Niemann-Pick disease (<a href="/entry/257200">257200</a>) in Ashkenazi Jewish patients. Deletion of a single cytosine in codon 330 of the SMPD1 cDNA (which normally encodes a proline residue) caused a frameshift that led to the formation of a premature stop (TGA) at codon 382. The mutation occurred in 4 of 52 SMPD1 alleles analyzed from unrelated Ashkenazi Jewish type A patients or obligate heterozygotes. In contrast, the mutation was not found in non-Jewish type A patients or in any Jewish or non-Jewish type B patients. Three mutations, R496L (<a href="#0001">607608.0001</a>), L302P (<a href="#0010">607608.0010</a>), and this mutation, account for about 65% of the mutant SMPD1 alleles in Ashkenazi Jewish type A Niemann-Pick disease patients. The single base deletion causing the pro330FS mutation was in a region of the gene where 9 of the 10 residues were cytosines. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8401540" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 NIEMANN-PICK DISEASE, INTERMEDIATE, PROTRACTED NEUROVISCERAL</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> rs120074125 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074125;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/rs120074125?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=rs120074125" 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=rs120074125" 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=RCV000003125 OR RCV000410490 OR RCV000797253 OR RCV001248981 OR RCV004546410" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003125, RCV000410490, RCV000797253, RCV001248981, RCV004546410" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003125...</a>
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<p>In a kindred with its roots in a small village of Serbia, <a href="#33" class="mim-tip-reference" title="Sperl, W., Bart, G., Vanier, M. T., Christomanou, H., Baldissera, I., Steichensdorf, E., Paschke, E. <strong>A family with visceral course of Niemann-Pick disease, macular halo syndrome and low sphingomyelin degradation rate.</strong> J. Inherit. Metab. Dis. 17: 93-103, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8051942/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8051942</a>] [<a href="https://doi.org/10.1007/BF00735404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8051942">Sperl et al. (1994)</a> described 6 members affected by an atypical intermediate form of Niemann-Pick disease (see <a href="/entry/257200">257200</a>) with a visceral course and additional retinal changes, namely macular halos, indicative of neuronal storage. A very low degradation rate of sphingomyelin was demonstrated in skin fibroblasts. <a href="#3" class="mim-tip-reference" title="Ferlinz, K., Hurwitz, R., Weiler, M., Suzuki, K., Sandhoff, K., Vanier, M. T. <strong>Molecular analysis of the acid sphingomyelinase deficiency in a family with an intermediate form of Niemann-Pick disease.</strong> Am. J. Hum. Genet. 56: 1343-1349, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7762557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7762557</a>]" pmid="7762557">Ferlinz et al. (1995)</a> demonstrated a novel mutation, a T-to-G transversion at nucleotide 1171 (nucleotides counted from the A of the first putative initiation codon, ATG), resulting in a substitution of glycine (GGG) for the normal tryptophan (TGG) at amino acid position 391. Northern analysis did not show significant aberration in quantity and size of the mRNA compared with normals. The family contained an example of pseudodominance resulting from the marriage of a homozygote with a heterozygote. Three of 4 children were homozygotes. <a href="#3" class="mim-tip-reference" title="Ferlinz, K., Hurwitz, R., Weiler, M., Suzuki, K., Sandhoff, K., Vanier, M. T. <strong>Molecular analysis of the acid sphingomyelinase deficiency in a family with an intermediate form of Niemann-Pick disease.</strong> Am. J. Hum. Genet. 56: 1343-1349, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7762557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7762557</a>]" pmid="7762557">Ferlinz et al. (1995)</a> concluded that instability and rapid breakdown of the mature mutant enzyme protein due to the mutation was the primary mechanism for deficiency of sphingomyelinase activity in these patients, rather than direct inactivation of catalytic activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7762557+8051942" 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>.0013 NIEMANN-PICK DISEASE, TYPE B</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">rs120074126 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074126;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=rs120074126" 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=rs120074126" 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=RCV000003126 OR RCV000192225 OR RCV000411474 OR RCV000634570 OR RCV000723415" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003126, RCV000192225, RCV000411474, RCV000634570, RCV000723415" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003126...</a>
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<p>In 28 Saudi Arabian cases of type B Niemann-Pick disease (<a href="/entry/607616">607616</a>), <a href="#31" class="mim-tip-reference" title="Simonaro, C. M., Desnick, R. J., McGovern, M. M., Wasserstein, M. P., Schuchman, E. H. <strong>The demographics and distribution of type B Niemann-Pick disease: novel mutations lead to new genotype/phenotype correlations.</strong> Am. J. Hum. Genet. 71: 1413-1419, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12369017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12369017</a>] [<a href="https://doi.org/10.1086/345074" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12369017">Simonaro et al. (2002)</a> found that his421-to-tyr (H421Y) was the most frequent mutation, accounting for 71.4% of mutant alleles. The mutation occurs within the putative active-site region of the enzyme and at a histidine residue that might be involved in zinc binding. The mutation was associated with an early onset and a more severe form of type B Niemann-Pick disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12369017" 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>.0014 NIEMANN-PICK DISEASE, TYPE B</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> rs120074127 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074127;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/rs120074127?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=rs120074127" 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=rs120074127" 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=RCV000003127 OR RCV000193674 OR RCV000372224 OR RCV000634567 OR RCV000780732 OR RCV001248934" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003127, RCV000193674, RCV000372224, RCV000634567, RCV000780732, RCV001248934" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003127...</a>
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<p><a href="#14" class="mim-tip-reference" title="Lee, C. Y., Krimbou, L., Vincent, J., Bernard, C., Larramee, P., Genest, J., Jr., Marcil, M. <strong>Compound heterozygosity at the sphingomyelin phosphodiesterase-1 (SMPD1) gene is associated with low HDL cholesterol.</strong> Hum. Genet. 112: 552-562, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12607113/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12607113</a>] [<a href="https://doi.org/10.1007/s00439-002-0893-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12607113">Lee et al. (2003)</a> studied a family in which a brother and sister were compound heterozygotes for the R608 deletion (<a href="#0002">607608.0002</a>) and an arg441-to-ter (R441X) mutation in the SMPD1 gene. The proband, a 47-year-old man, had been admitted to a pediatric hospital at the age of 3 years for failure to thrive and hepatosplenomegaly. Patchy pulmonary infiltrates were found without obvious infectious cause, and splenectomy was performed. The diagnosis of type B Niemann-Pick disease (<a href="/entry/607616">607616</a>) was made on the basis of lipid-laden histiocytes on histopathology. Subsequent physical and neurologic development were normal and he worked as a mechanic. His sister, who was 2 years younger, was also diagnosed with type B Niemann-Pick disease on the basis of splenectomy. Her physical and intellectual development proceeded normally. At age 41 years, she was found to have severe coronary artery disease and underwent coronary artery bypass. <a href="#14" class="mim-tip-reference" title="Lee, C. Y., Krimbou, L., Vincent, J., Bernard, C., Larramee, P., Genest, J., Jr., Marcil, M. <strong>Compound heterozygosity at the sphingomyelin phosphodiesterase-1 (SMPD1) gene is associated with low HDL cholesterol.</strong> Hum. Genet. 112: 552-562, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12607113/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12607113</a>] [<a href="https://doi.org/10.1007/s00439-002-0893-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12607113">Lee et al. (2003)</a> concluded that compound heterozygosity for the 2 mutations was associated with low HDL cholesterol and premature coronary artery disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12607113" 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>.0015 NIEMANN-PICK DISEASE, TYPE B</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> rs120074128 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074128;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/rs120074128?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=rs120074128" 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=rs120074128" 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=RCV000003128 OR RCV000003129 OR RCV000169297 OR RCV000781865 OR RCV000812595 OR RCV001248931 OR RCV002512693 OR RCV003333947" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003128, RCV000003129, RCV000169297, RCV000781865, RCV000812595, RCV001248931, RCV002512693, RCV003333947" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003128...</a>
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<p>In 2 unrelated patients with Niemann-Pick disease type B (<a href="/entry/607616">607616</a>), <a href="#22" class="mim-tip-reference" title="Pavlu, H., Elleder, M. <strong>Two novel mutations in patients with atypical phenotypes of acid sphingomyelinase deficiency.</strong> J. Inherit. Metab. Dis. 20: 615-616, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9266408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9266408</a>] [<a href="https://doi.org/10.1023/a:1005387932546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9266408">Pavlu and Elleder (1997)</a> identified a homozygous 874C-A transversion in exon 2 of the SMPD1 gene, resulting in a gln292-to-lys (Q292K) substitution. Both patients had progressive visceral manifestations, and 1 developed neurologic symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9266408" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Pavlu-Pereira, H., Asfaw, B., Poupetova, H., Ledvinova, J., Sikora, J., Vanier, M. T., Sandhoff, K., Zeman, J., Novotna, Z., Chudoba, D., Elleder, M. <strong>Acid sphinogomyelinase deficiency. Phenotype variability with prevalence of intermediate phenotype in a series of twenty-five Czech and Slovak patients. A multi-approach study.</strong> J. Inherit. Metab. Dis. 28: 203-227, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15877209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15877209</a>] [<a href="https://doi.org/10.1007/s10545-005-5671-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15877209">Pavlu-Pereira et al. (2005)</a> found that the Q292K mutation was associated with an intermediate form of Niemann-Pick disease characterized by a protracted neurovisceral phenotype (see <a href="/entry/257200">257200</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15877209" 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 NIEMANN-PICK DISEASE, TYPE 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> rs267607075 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607075;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/rs267607075?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=rs267607075" 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=rs267607075" 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=RCV000003130 OR RCV000780737 OR RCV001249038 OR RCV001824114 OR RCV001851602" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003130, RCV000780737, RCV001249038, RCV001824114, RCV001851602" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003130...</a>
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<p>In a Spanish patient with Niemann-Pick disease type A (<a href="/entry/257200">257200</a>), <a href="#27" class="mim-tip-reference" title="Rodriguez-Pascau, L., Gort, L., Schuchman, E. H., Vilagelui, L., Grinberg, D., Chabas, A. <strong>Identification and characterization of SMPD1 mutations causing Niemann-Pick types A and B in Spanish patients.</strong> Hum. Mutat. 30: 1117-1122, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19405096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19405096</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19405096[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/10.1002/humu.21018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19405096">Rodriguez-Pascau et al. (2009)</a> identified a homozygous 1445C-A transversion in exon 5 of the SMPD1 gene, resulting in an ala482-to-glu (A482E) substitution. Two additional patients were compound heterozygous for this mutation and another pathogenic mutation. In vitro functional expression studies in COS-7 cells showed that the mutant protein had less than 5% residual activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19405096" 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">rs267607074 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607074;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=rs267607074" 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=rs267607074" 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=RCV000003131 OR RCV001379382" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003131, RCV001379382" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003131...</a>
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<p>In a Spanish patient with Niemann-Pick disease type A (<a href="/entry/257200">257200</a>), <a href="#27" class="mim-tip-reference" title="Rodriguez-Pascau, L., Gort, L., Schuchman, E. H., Vilagelui, L., Grinberg, D., Chabas, A. <strong>Identification and characterization of SMPD1 mutations causing Niemann-Pick types A and B in Spanish patients.</strong> Hum. Mutat. 30: 1117-1122, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19405096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19405096</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19405096[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/10.1002/humu.21018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19405096">Rodriguez-Pascau et al. (2009)</a> identified a homozygous 1400A-C transversion in exon 5 of the SMPD1 gene, resulting in a tyr467-to-ser (Y467S) substitution. In vitro functional expression studies in COS-7 cells showed that the mutant protein had less than 5% residual activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19405096" 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>See Also:</strong>
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<a href="#Takahashi1992" class="mim-tip-reference" title="Takahashi, T., Suchi, M., Desnick, R. J., Takada, G., Schuchman, E. H. <strong>Identification and expression of five mutations in the human acid sphingomyelinase gene causing types A and B Niemann-Pick disease: molecular evidence for genetic heterogeneity in the neuronopathic and non-neuronopathic forms.</strong> J. Biol. Chem. 267: 12552-12558, 1992.">Takahashi et al. (1992)</a>; <a href="#Wilson1987" class="mim-tip-reference" title="Wilson, D. E., Konrad, R. <strong>Assignment of the gene for acid lysosomal sphingomyelinase to human chromosome 17. (Abstract)</strong> Am. J. Hum. Genet. 41: A191, 1987.">Wilson and Konrad (1987)</a>
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<strong>REFERENCES</strong>
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<a id="da Veiga Pereira1991" class="mim-anchor"></a>
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da Veiga Pereira, L., Desnick, R. J., Adler, D. A., Disteche, C. M., Schuchman, E. H.
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<strong>Regional assignment of the human acid sphingomyelinase gene (SMPD1) by PCR analysis of somatic cell hybrids and in situ hybridization to 11p15.1-p15.4.</strong>
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Genomics 9: 229-234, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2004772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2004772</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2004772" 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/10.1016/0888-7543(91)90246-b" target="_blank">Full Text</a>]
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Ferlinz, K., Hurwitz, R., Sandhoff, K.
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<strong>Molecular basis of acid sphingomyelinase deficiency in a patient with Niemann-Pick disease type A.</strong>
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Biochem. Biophys. Res. Commun. 179: 1187-1191, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1718266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1718266</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1718266" 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/10.1016/0006-291x(91)91697-b" target="_blank">Full Text</a>]
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Ferlinz, K., Hurwitz, R., Weiler, M., Suzuki, K., Sandhoff, K., Vanier, M. T.
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<strong>Molecular analysis of the acid sphingomyelinase deficiency in a family with an intermediate form of Niemann-Pick disease.</strong>
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Am. J. Hum. Genet. 56: 1343-1349, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7762557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7762557</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7762557" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Fernandez-Burriel, M., Pena, L., Ramos, J. C., Cabrera, J. C., Marti, M., Rodriguez-Quinones, F., Chabas, A.
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<strong>The R608del mutation in the acid sphingomyelinase gene (SMPD1) is the most prevalent among patients from Gran Canaria Island with Niemann-Pick disease type B. (Letter)</strong>
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Clin. Genet. 63: 235-236, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12694237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12694237</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12694237" 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/10.1034/j.1399-0004.2003.00025.x" target="_blank">Full Text</a>]
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Garcia-Barros, M., Paris, F., Cordon-Cardo, C., Lyden, D., Rafii, S., Haimovitz-Friedman, A., Fuks, Z., Kolesnick, R.
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<strong>Tumor response to radiotherapy regulated by endothelial cell apoptosis.</strong>
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Science 300: 1155-1159, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12750523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12750523</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12750523" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1082504" target="_blank">Full Text</a>]
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Garcia-Ruiz, C., Colell, A., Mari, M., Morales, A., Calvo, M., Enrich, C., Fernandez-Checa, J. C.
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<strong>Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice.</strong>
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J. Clin. Invest. 111: 197-208, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12531875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12531875</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12531875[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12531875" 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/JCI16010" target="_blank">Full Text</a>]
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Grassme, H., Gulbins, E., Brenner, B., Ferlinz, K., Sandhoff, K., Harzer, K., Lang, F., Meyer, T. F.
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<strong>Acidic sphingomyelinase mediates entry of N. gonorrhoeae in nonphagocytic cells.</strong>
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Cell 91: 605-615, 1997.
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<strong>Acid sphingomyelinase deficiency with Beckwith-Wiedemann syndrome.</strong>
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[<a href="https://doi.org/10.1007/BF03187335" target="_blank">Full Text</a>]
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Rethy, L. A.
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<strong>Growth regulation, acid sphingomyelinase gene and genomic imprinting: lessons from an experiment of nature.</strong>
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<a id="Rodriguez-Pascau2009" class="mim-anchor"></a>
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Rodriguez-Pascau, L., Gort, L., Schuchman, E. H., Vilagelui, L., Grinberg, D., Chabas, A.
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<strong>Identification and characterization of SMPD1 mutations causing Niemann-Pick types A and B in Spanish patients.</strong>
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[<a href="https://doi.org/10.1002/humu.21018" target="_blank">Full Text</a>]
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Santana, P., Pena, L. A., Haimovitz-Friedman, A., Martin, S., Green, D., McLoughlin, M., Cordon-Cardo, C., Schuchman, E. H., Fuks, Z., Kolesnick, R.
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[<a href="https://doi.org/10.1016/s0092-8674(00)80091-4" target="_blank">Full Text</a>]
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<strong>Structural organization and complete nucleotide sequence of the gene encoding human acid sphingomyelinase (SMPD1).</strong>
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[<a href="https://doi.org/10.1016/0888-7543(92)90366-z" target="_blank">Full Text</a>]
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<a id="Schuchman1991" class="mim-anchor"></a>
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<strong>Human acid sphingomyelinase: isolation, nucleotide sequence, and expression of the full-length and alternatively spliced cDNAs.</strong>
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Simonaro, C. M., Desnick, R. J., McGovern, M. M., Wasserstein, M. P., Schuchman, E. H.
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<strong>The demographics and distribution of type B Niemann-Pick disease: novel mutations lead to new genotype/phenotype correlations.</strong>
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Am. J. Hum. Genet. 71: 1413-1419, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12369017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12369017</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12369017" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/345074" target="_blank">Full Text</a>]
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Simonaro, C. M., Park, J.-H., Eliyahu, E., Shtraizent, N., McGovern, M. M., Schuchman, E. H.
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<strong>Imprinting at the SMPD1 locus: implications for acid sphingomyelinase-deficient Niemann-Pick disease.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16642440/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16642440</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16642440[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16642440" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/503750" target="_blank">Full Text</a>]
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Sperl, W., Bart, G., Vanier, M. T., Christomanou, H., Baldissera, I., Steichensdorf, E., Paschke, E.
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<strong>A family with visceral course of Niemann-Pick disease, macular halo syndrome and low sphingomyelin degradation rate.</strong>
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J. Inherit. Metab. Dis. 17: 93-103, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8051942/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8051942</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8051942" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF00735404" target="_blank">Full Text</a>]
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Suchi, M., Dinur, T., Desnick, R. J., Gatt, S., Pereira, L., Gilboa, E., Schuchman, E. H.
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<strong>Retroviral-mediated transfer of the human acid sphingomyelinase cDNA: correction of the metabolic defect in cultured Niemann-Pick disease cells.</strong>
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Proc. Nat. Acad. Sci. 89: 3227-3231, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1565614/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1565614</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1565614" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.89.8.3227" target="_blank">Full Text</a>]
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Takahashi, T., Desnick, R. J., Takada, G., Schuchman, E. H.
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<strong>Identification of a missense mutation (S436R) in the acid sphingomyelinase gene from a Japanese patient with type B Niemann-Pick disease.</strong>
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Hum. Mutat. 1: 70-71, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301192</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1301192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.1380010111" target="_blank">Full Text</a>]
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Takahashi, T., Suchi, M., Desnick, R. J., Takada, G., Schuchman, E. H.
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<strong>Identification and expression of five mutations in the human acid sphingomyelinase gene causing types A and B Niemann-Pick disease: molecular evidence for genetic heterogeneity in the neuronopathic and non-neuronopathic forms.</strong>
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J. Biol. Chem. 267: 12552-12558, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1618760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1618760</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1618760" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Vanier, M. T., Ferlinz, K., Rousson, R., Duthel, S., Louisot, P., Sandhoff, K., Suzuki, K.
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<strong>Deletion of arginine (608) in acid sphingomyelinase is the prevalent mutation among Niemann-Pick disease type B patients from northern Africa.</strong>
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Hum. Genet. 92: 325-330, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8225311/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8225311</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8225311" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF01247328" target="_blank">Full Text</a>]
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Volders, P., Van Hove, J., Lories, R. J. U., Vandekerckhove, P., Matthijs, G., De Vos, R., Vanier, M. T., Vincent, M. F., Westhovens, R., Luyten, F. P.
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<strong>Niemann-Pick disease type B: an unusual clinical presentation with multiple vertebral fractures.</strong>
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Am. J. Med. Genet. 109: 42-51, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11932991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11932991</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11932991" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.10278" target="_blank">Full Text</a>]
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Wilson, D. E., Konrad, R.
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<strong>Assignment of the gene for acid lysosomal sphingomyelinase to human chromosome 17. (Abstract)</strong>
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Am. J. Hum. Genet. 41: A191, 1987.
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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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Ada Hamosh - updated : 03/11/2010
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Cassandra L. Kniffin - updated : 11/11/2009<br>Cassandra L. Kniffin - updated : 1/7/2009<br>Marla J. F. O'Neill - updated : 4/12/2007<br>Victor A. McKusick - updated : 4/14/2006<br>Marla J. F. O'Neill - updated : 5/20/2004<br>Victor A. McKusick - updated : 5/8/2003<br>Victor A. McKusick - updated : 4/23/2003<br>Denise L. M. Goh - updated : 4/18/2003
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Cassandra L. Kniffin : 3/7/2003
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carol : 06/25/2021
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carol : 06/24/2021<br>alopez : 03/11/2010<br>wwang : 12/3/2009<br>ckniffin : 11/11/2009<br>wwang : 1/21/2009<br>carol : 1/16/2009<br>ckniffin : 1/7/2009<br>carol : 6/16/2008<br>terry : 9/14/2007<br>wwang : 4/17/2007<br>terry : 4/12/2007<br>carol : 11/10/2006<br>alopez : 4/18/2006<br>terry : 4/14/2006<br>carol : 5/25/2004<br>terry : 5/20/2004<br>alopez : 6/11/2003<br>terry : 6/10/2003<br>terry : 5/27/2003<br>carol : 5/13/2003<br>tkritzer : 5/9/2003<br>terry : 5/8/2003<br>cwells : 4/25/2003<br>terry : 4/23/2003<br>carol : 4/21/2003<br>terry : 4/18/2003<br>carol : 3/13/2003<br>ckniffin : 3/13/2003<br>ckniffin : 3/10/2003
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<span class="mim-font">
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<strong>*</strong> 607608
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</h3>
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<h3>
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SPHINGOMYELIN PHOSPHODIESTERASE 1, ACID LYSOSOMAL; SMPD1
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</h3>
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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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<h4>
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<span class="mim-font">
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SPHINGOMYELINASE, ACID; ASM
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SMPD1</em></strong>
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<strong>SNOMEDCT:</strong> 39390005, 52165006;
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<strong>ICD10CM:</strong> E75.240, E75.241;
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<strong>
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<em>
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Cytogenetic location: 11p15.4
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Genomic coordinates <span class="small">(GRCh38)</span> : 11:6,390,474-6,394,996 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<tbody>
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<td rowspan="2">
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<span class="mim-font">
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11p15.4
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<span class="mim-font">
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Niemann-Pick disease, type A
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<span class="mim-font">
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257200
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Autosomal recessive
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<span class="mim-font">
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3
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<span class="mim-font">
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Niemann-Pick disease, type B
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<span class="mim-font">
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607616
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<h4>
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<strong>Cloning and Expression</strong>
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<p>Quintern et al. (1989) microsequenced 128 residues from acid sphingomyelinase (EC 3.1.4.12) purified from urine, synthesized oligonucleotide mixtures based on minimal codon redundancy, and used these to screen human fibroblast and placenta cDNA libraries. The findings demonstrated the presence of 2 distinct acid sphingomyelinase transcripts in both human fibroblasts and placenta, suggesting possible alternative processing of the mRNA. both transcripts were approximately 2.5 kb. By screened human placenta, testis, hepatoma, and retina cDNA libraries, </p><p>Schuchman et al. (1991) isolated SMPD1 transcripts, including the previously described type 1 and type 2 cDNAs, as well as a third cDNA. Functional studies showed that only the type 1 transcript encoded catalytically active functional human ASM. The type 1 cDNA encoded a 629-amino acid protein. Rodriguez-Pascau et al. (2009) noted that human ASM protein is synthesized as a 75-kD prepolypeptide, which is converted into a precursor form of 72 kD. The precursor is subject to 2 different processing events. A minor part is cleaved in the ER-Golgi complex, yielding a 57-kD form, whereas a major part is processed to a 70-kD mature form. </p>
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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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</h4>
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<span class="mim-text-font">
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<p>Using the SMPD1 cDNA as a probe, Schuchman et al. (1992) isolated the SMPD1 genomic region and determined the complete nucleotide sequence of the gene including 1,116 and 468 nucleotides upstream and downstream, respectively, from the coding region. They determined that the SMPD1 gene contains 6 exons. Exon 2 is unusually large and encodes 258 amino acids, or about 44% of the mature ASM polypeptide. </p>
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</span>
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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>Da Veiga Pereira et al. (1991) demonstrated by Southern blotting of somatic cell hybrids that the SMPD1 gene maps to 11p15.1-p15.4, not to chromosome 17 as had been reported by Konrad and Wilson (1987). By in situ hybridization, da Veiga Pereira et al. (1991) refined the localization to 11p15. </p><p>By PCR-amplification detection assay of a mouse/hamster somatic cell hybrid panel, Horinouchi et al. (1993) mapped the orthologous gene in the mouse (Smpd1) to chromosome 7, in a region of well-known homology to distal 11p where the human gene is situated. </p>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Suchi et al. (1992) demonstrated that the metabolic defect in cultured Niemann-Pick disease (see 257200) cells, which lack sphingomyelinase activity, could be corrected by retroviral-mediated transfer of human ASM cDNA. </p><p>Stress is believed to activate sphingomyelinase to generate ceramide, which serves as a second messenger in initiating the apoptotic response. The first conclusive evidence for this paradigm was provided by Santana et al. (1996) who showed that lymphoblasts from Niemann-Pick patients failed to respond to ionizing radiation with ceramide generation and apoptosis. These abnormalities could be reversed by restoring acid sphingomyelinase activity by retroviral transfer of human acid sphingomyelinase cDNA. Mice in which the gene had been knocked out also showed defects in radiation-induced ceramide generation and apoptosis in vivo. Comparison with p53 knockout mice suggested to Santana et al. (1996) that acid sphingomyelinase-mediated apoptosis and p53-mediated apoptosis are probably distinct and independent. </p><p>Garcia-Ruiz et al. (2003) studied the contribution of ASM in TNF-alpha (191160)-mediated hepatocellular apoptosis. They showed that selective mGSH (mitochondrial glutathione) depletion sensitized hepatocytes to TNF-alpha-mediated hepatocellular apoptosis by facilitating the onset of mitochondrial permeability transition. Inactivation of endogenous hepatocellular ASM activity protected hepatocytes from TNF-alpha-induced cell death. Similarly, ASM -/- mice were resistant in vivo to endogenous and exogenous TNF-alpha-induced liver damage. Targeting of ganglioside GD3 (601123) to mitochondria occurred in ASM +/+ but not in ASM -/- hepatocytes. Treatment of ASM -/- hepatocytes with exogenous ASM induced the colocalization of GD3 and mitochondria. Garcia-Ruiz et al. (2003) concluded that ASM contributes to TNF-alpha-induced hepatocellular apoptosis by promoting the targeting of mitochondria by glycosphingolipids. </p><p>Grassme et al. (1997) provided evidence that acid sphingomyelinase mediates entry of Neisseria gonorrhoeae into nonphagocytic cells. Invasion of human mucosal cells by N. gonorrhoeae via the binding to heparan sulfate proteoglycan receptors is considered a crucial event of the infection. Using different human epithelial cells and primary fibroblasts, Grassme et al. (1997) demonstrated an activation of phosphatidylcholine-specific phospholipase C and ASM by N. gonorrhoeae, resulting in the release of diacylglycerol and ceramide. Genetic and/or pharmacologic blockade of ASM and phosphatidylcholine-specific phospholipase C caused inhibition of cellular invasion by N. gonorrhoeae. Complementation of ASM-deficient fibroblasts from Niemann-Pick disease patients restored N. gonorrhoeae-induced signaling and entry processes. Grassme et al. (1997) concluded that activation of phosphatidylcholine-specific phospholipase C and ASM is an essential requirement for the entry of N. gonorrhoeae into distinct nonphagocytic human cell types including several epithelial cells and primary fibroblasts. </p><p>Kirkegaard et al. (2010) demonstrated that the reduced ASM activity in cells from patients with Niemann-Pick disease A and B is also associated with a marked decrease in lysosomal stability, and that this phenotype could be effectively corrected by treatment with recombinant Hsp70 (140550). Hsp70 stabilizes lysosomes by binding to an endolysosomal anionic phospholipid bis(monoacylglycero)phosphate (BMP), an essential cofactor for lysosomal sphingomyelin metabolism. In acidic environments Hsp70 binds with high affinity and specificity to BMP, thereby facilitating the BMP binding and activity of ASM. The inhibition of the Hsp70-BMP interaction by BMP antibodies or a point mutation in Hsp70 (trp90 to phe), as well as the pharmacologic and genetic inhibition of ASM, effectively reverted the Hsp70-mediated stabilization of lysosomes. Kirkegaard et al. (2010) concluded that, taken together, their data opened exciting possibilities for the development of new treatments for lysosomal storage disorders and cancer with compounds that enter the lysosomal lumen by the endocytic delivery pathway. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</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>Levran et al. (1991) identified a point mutation in the SMPD1 gene (607608.0001) in an Ashkenazi Jewish patient with type A Niemann-Pick disease (257200) and Levran et al. (1991) identified a 3-bp deletion in the SMPD1 gene (R608del; 607608.0002) in an Ashkenazi Jewish patient with type B Niemann-Pick disease (607616). </p><p>Takahashi et al. (1992) characterized 6 Niemann-Pick disease mutations (see 607608.0004-607608.0009) and concluded that small deletions or nonsense mutations that result in a truncated ASM polypeptide and missense mutations that render the enzyme noncatalytic cause type A Niemann-Pick disease, whereas missense mutations that produce a defective enzyme with residual catalytic activity cause the milder nonneuronopathic type B phenotype. Ida et al. (1996) identified 3 novel mutations in the SMPD1 gene in Japanese patients with type A and B Niemann-Pick disease. </p><p>Lee et al. (2003) investigated a kindred with type B Niemann-Pick disease resulting from heteroallelic (i.e., compound heterozygous) mutations in the SMPD1 gene (607608.0002 and 607608.0014) associated with low levels of HDL cholesterol. Both the index patient, a 47-year-old male, and his sister, who was 2 years younger, had hypertriglyceridemia; the sister also had severe premature coronary artery disease. By studying cellular cholesterol efflux in fibroblasts, Lee et al. (2003) found that, unlike patients with Tangier disease (205400), cholesterol efflux was normal under the experimental conditions used. </p><p>Rodriguez-Pascau et al. (2009) identified 17 different mutations in the SMPD1 gene, including 10 novel mutations (see, e.g., A482E; 608607.0016 and Y467S; 608607.0017), in 19 Spanish patients and 2 patients from Maghreb in Northern Africa with Niemann-Pick disease type A (8 patients) or type B (13 patients). The most common mutations were the R608del mutation, found in 38% of alleles, and the A482E mutation, found in 9% of alleles. The R608del mutation was always found in patients with type B disease. Functional expression studies of the mutant proteins in COS-7 cells showed decreased enzyme activity. </p><p><strong><em>Imprinting</em></strong></p><p>
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The basis of the variability between type A and type B NPD is poorly understood and does not always correlate with the individual SMPD1 mutations. In addition, some carrier individuals for ASM-deficient NPD have features of the disease (Lee et al., 2003), which is an unusual finding for an autosomal recessive disorder such as this. Rethy et al. (2000) described a patient with Beckwith-Wiedemann syndrome (BWS; 130650) who had approximately 30% of normal ASM activity in cultured skin fibroblasts. This 23-month-old child had a normal karyotype, which suggested uniparental disomy of paternal chromosome 11p15. Rethy et al. (2000) suggested that the SMPD1 gene might be imprinted, on the basis of the reduced ASM activity in this patient, the possibility of 11p15 uniparental disomy, and the fact that the SMPD1 gene has structural features common to other imprinted genes (Rethy, 2000). To assess imprinting at the SMPD1 locus, Simonaro et al. (2006) studied several heteroallelic patients with ASM-deficient NPD. They demonstrated that the SMPD1 gene is paternally imprinted and that differential expression of the mutant alleles in patients with ASM-deficient NPD and in carriers influences the disease phenotype. Comparison of the results of genomic sequencing versus RT-PCR sequencing for several patients with NPD revealed preferential expression of 1 mutant allele. Further analysis of one family showed that the expressed allele was maternally inherited and that the distinct clinical presentations of the individual patients were correlated with the amount of residual ASM activity expressed from the maternal mutation. Treatment of NPD cell lines with 5-aza-2-prime-deoxycytidine enhanced the expression of the paternal SMPD1 allele, and bisulfite genomic sequencing identified which CpG dinucleotides within the SMPD1 promoter were methylated. </p><p>Simonaro et al. (2006) identified a carrier individual who had approximately 15% of normal ASM activity and clinical features of ASM-deficient NPD. DNA sequencing confirmed that this individual carried a single SMPD1 mutation and that this mutant allele was preferentially expressed. </p>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</h4>
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<span class="mim-text-font">
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<p>Complete sequencing of the Smpd1 gene in 2 mouse models of Niemann-Pick disease by Horinouchi et al. (1993) revealed no mutation, indicating that these are not models of either type A or type B Niemann-Pick disease. One of the models, spm/spm, was thought to be a model of type C Niemann-Pick disease (257220) and the other may be a model for either type C or type D (see 257220). </p><p>By homologous recombination in embryonic stem cells, Otterbach and Stoffel (1995) achieved targeted disruption of the Smpd1 gene in transgenic mice. Homozygous mice accumulated sphingomyelin extensively in the reticuloendothelial system of liver, spleen, bone marrow, and lung, as well as in the brain. Most strikingly, the ganglionic cell layer of Purkinje cells of the cerebellum degenerated completely, leading to severe impairment of neuromotor coordination. The picture resembled that of the neurovisceral form of Niemann-Pick disease (type A). Horinouchi et al. (1995) obtained similar results in Asm knockout mice. </p><p>Garcia-Barros et al. (2003) investigated the hypothesis that tumor response to radiation is determined not only by tumor cell type but also by microvascular sensitivity. MCA/129 fibrosarcomas and B16F1 melanomas grown in apoptosis-resistant 'acid sphingomyelinase' (asmase)-deficient or Bax (600040)-deficient mice displayed markedly reduced baseline microvascular endothelial apoptosis and grew 200 to 400% faster than tumors on wildtype microvasculature. Thus, Garcia-Barros et al. (2003) concluded that endothelial apoptosis is a homeostatic factor regulating angiogenesis-dependent tumor growth. Moreover, these tumors exhibited reduced endothelial apoptosis upon irradiation and, unlike tumors in wildtype mice, they were resistant to single-dose radiation up to 20 Gy. Garcia-Barros et al. (2003) concluded that microvascular damage regulates tumor cell response to radiation at the clinically relevant dose range. </p><p>Mari et al. (2004) demonstrated that levels of methionine adenosyltransferase-1-alpha mRNA as well as MAT I/III protein (see MAT1A, 250850) decreased in cultured rat hepatocytes by in situ generation of ceramide from exogenous human placenta SMPD1. Hepatocytes lacking the SMPD1 gene were insensitive to TNF-alpha, but were responsive to exogenous SMPD1-induced downregulation of MAT1A. In an in vivo model of lethal hepatitis by TNF-alpha, depletion of S-adenosyl-L-methionine (SAM) preceded activation of caspases 8 and 3, massive liver damage, and death of wildtype mice. In contrast, minimal hepatic SAM depletion, caspase activation, and liver damage were seen in Smpd1 -/- mice. Moreover, therapeutic treatment with SAM abrogated caspase activation and liver injury, thus rescuing Smpd1 +/+ mice from TNF-alpha-induced lethality. Mari et al. (2004) concluded that these findings indicated a new role for SMPD1 in TNF-alpha-induced liver failure through downregulation of MAT1A and suggested that maintenance of SAM might be useful in the treatment of acute and chronic liver disease. </p><p>In mouse hepatocytes, Lang et al. (2007) demonstrated that Cu(2+) induced the secretion of activated Asm from leukocytes, leading to ceramide release in and phosphatidylserine exposure on erythrocytes, which are events prevented by inhibition of Asm. In LEC rats, a model of Wilson disease (277900), deficiency in or pharmacologic inhibition of Asm prevented Cu(2+)-induced hepatocyte apoptosis and protected the rats from acute hepatocyte death, liver failure, and early death. Patients with Wilson disease showed elevated plasma levels of ASM, and displayed a constitutive increase of ceramide- and phosphatidylserine-positive erythrocytes. Lang et al. (2007) concluded that Cu(2+) triggers hepatocyte apoptosis through activation of ASM and release of ceramide, suggesting a previously unidentified mechanism for liver cirrhosis and anemia in Wilson disease. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>17 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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<h4>
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<span class="mim-font">
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<strong>.0001 NIEMANN-PICK DISEASE, TYPE A</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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SMPD1, ARG496LEU
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<br />
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SNP: rs120074117,
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gnomAD: rs120074117,
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ClinVar: RCV000003114, RCV000192227, RCV000413382, RCV000526587, RCV000984008, RCV004018542, RCV004742209
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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>Levran et al. (1990, 1991) used polymerase chain reaction (PCR) to amplify the coding region from the acid sphingomyelinase gene from an Ashkenazi Jewish patient with Niemann-Pick disease type A (257200). Sequence analysis revealed a single G-to-T change at nucleotide 1487 (in a CpG dinucleotide), predicting an arginine-to-leucine amino acid substitution in residue 496. The mutation was found in 5 of 20 (25%) Ashkenazi Jewish type A patients and in 3 of 36 (8.3%) SMPD1 alleles from non-Jewish type A homozygotes. The mutation was found in only 1 of 90 SMPD1 alleles from normal persons of Ashkenazi Jewish descent. The arg496-to-leu mutation was found in one of the mutant alleles in 2 Ashkenazi Jewish patients with type B Niemann-Pick disease and in none of the alleles of 15 non-Jewish type B homozygotes. The R496L mutation was found in about 32% of Ashkenazi Jewish type A Niemann-Pick disease alleles studied. In contrast, only about 5% of the alleles from non-Jewish type A patients had this mutation (Levran et al., 1991). </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 NIEMANN-PICK DISEASE, TYPE B</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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SMPD1, ARG608DEL
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<br />
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SNP: rs120074118,
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ClinVar: RCV000179325, RCV000192229, RCV000413544, RCV000539031, RCV000781864, RCV001004371, RCV003967439
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an Ashkenazi Jewish patient with Niemann-Pick disease type B (607616), Levran et al. (1991) identified a 3-base deletion at nucleotides 1821-1823 which predicted the removal of an arginine residue from position 608 of the acid sphingomyelinase polypeptide. The other cDNA clone from this patient had the R496L mutation previously identified in type A Niemann-Pick disease patients (607608.0001). The delta-R608 mutation was not found in 15 unrelated non-Jewish type B patients, with the notable exception of 1 mildly affected patient of Arab descent who was homoallelic for the delta-R608 mutation. These results indicated that the delta-R608 mutation predicts the type B Niemann-Pick disease phenotype, even in the presence of the R496L type A allele, thereby providing the first genotype/phenotype correlation for this lysosomal storage disease. Although only 2 patients had been studied, it appeared that the delta-R608 mutation was a frequent cause of type B Niemann-Pick disease in Ashkenazi Jews. The terms homoallelic and heteroallelic (for genetic compound) seem to have been used particularly by Desnick and his colleagues, e.g., Levran et al. (1991); they are useful terms for the situations repeatedly encountered as more and more intragenic lesions are identified in mendelian disorders. </p><p>Niemann-Pick disease type B has a high frequency in the Maghreb region of North Africa, which includes Morocco, Algeria, and Tunisia. In a study of 15 unrelated, non-Jewish North African type B patients, Vanier et al. (1993) found that 12 were homozygous and 2 compound heterozygous for the arg608-to-del mutation. They found the mutation in only 1 of 16 alleles from type B patients from other geographic areas (France, U.K., Italy, Czechoslovakia). A varying severity of the clinical and enzymatic expression was observed in homozygotes for this mutation. </p><p>The R608 deletion mutation was found in a 55-year-old Belgian woman of Caucasian origin who had had progressive Parkinson disease for the previous 4 years and presented for acute onset of severe back pain, pain in the rib cage due to multiple vertebral fractures, as well as dyspnea due to interstitial lung disease (Volders et al., 2002). The patient was short statured as a child and the parents were first cousins. The vertebral fractures were thought to be due to increased physical activity after treatment of Parkinson disease, a genetic predisposition, and worsening disease due to interfering medication. She was treated with cholesterol-lowering drugs such as statins to decrease sphingomyelin synthesis, avoidance of drugs that inhibit sphingomyelinase, and bisphosphonates. No new fractures occurred, but the interstitial lung disease progressed. </p><p>Fernandez-Burriel et al. (2003) reported that the R608 deletion was the most prevalent among patients in Gran Canaria Island in patients with Niemann-Pick disease. They estimated the prevalence of the disease as 0.8-1:100,000 in their community; all patients carried the arg608-to-del mutation. Because of the heterogeneity of the clinical phenotype and the high prevalence of the arg608-to-del mutation in their community, they suggested that the mutation be routinely tested for in adults with hepatosplenomegaly of unknown origin before trying more invasive tests such as liver or bone marrow biopsy. </p><p>Rodriguez-Pascau et al. (2009) identified the R608del mutation in 38% of alleles from 21 patients of Spanish origin with Niemann-Pick disease. All patients with the R608del mutation had type B disease. In vitro functional expression studies in COS-7 cells showed that the mutant protein had 21.46% residual activity. Haplotype analysis suggested a founder effect. </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 NIEMANN-PICK DISEASE, TYPE A</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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SMPD1, GLY577SER
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<br />
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SNP: rs120074119,
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gnomAD: rs120074119,
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ClinVar: RCV000003116, RCV001248875, RCV001851600
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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>By sequence analysis of mRNA and genomic DNA of fibroblasts from a patient with Niemann-Pick disease type A (257200), Ferlinz et al. (1991) showed a G-to-A transition at nucleotide 1729 resulting in substitution of serine for glycine at position 577. </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 NIEMANN-PICK DISEASE, TYPE B</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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SMPD1, SER436ARG
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<br />
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SNP: rs267607073,
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ClinVar: RCV000003117
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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 19-year-old Japanese female with type B Niemann-Pick disease (607616) manifested by moderate hepatosplenomegaly and mild pulmonary involvement and without neuronopathic manifestations, Takahashi et al. (1992) found a ser436-to-arg mutation in homoallelic state. Her affected sister had the same mutation and both parents were heterozygous. </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>.0005 NIEMANN-PICK DISEASE, TYPE A</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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SMPD1, LEU261TER
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<br />
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SNP: rs120074120,
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gnomAD: rs120074120,
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ClinVar: RCV000003118, RCV001248867, RCV001390954
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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 type A Niemann-Pick disease (257200) patient of Asian Indian ancestry, Takahashi et al. (1992) found homoallelism for a T-to-A transversion in exon 2, predicting a premature stop at codon leucine-261. </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 NIEMANN-PICK DISEASE, TYPE A</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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SMPD1, 2-BP DEL, LEU178FS
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<br />
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SNP: rs786204694,
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ClinVar: RCV000169504, RCV001067762, RCV001248975
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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>Takahashi et al. (1992) found that a type A Niemann-Pick disease (257200) patient of European ancestry was heteroallelic for a 2-base (TT) deletion in exon 2, which caused a frameshift mutation at SMPD1 codon 178, leading to a premature stop at codon 190. The mutation on the other chromosome was a G-to-A transition in exon 3 which caused a methionine-to-isoleucine substitution at codon 382 (M382I). </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>.0007 NIEMANN-PICK DISEASE, TYPE A</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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SMPD1, MET382ILE
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<br />
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SNP: rs120074121,
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ClinVar: RCV000003120, RCV000596113, RCV004799730
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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>See 607608.0006. Transient expression of the L261X (607608.0005), L178FS (607608.0006), and M382I mutations in COS-1 cells demonstrated that these lesions did not produce catalytically active enzyme, consistent with the severe neuronopathic type A Niemann-Pick disease (257200) phenotype.</p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0008 NIEMANN-PICK DISEASE, TYPE B</strong>
|
|
</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">
|
|
|
|
SMPD1, GLY242ARG
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<br />
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|
SNP: rs120074122,
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|
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gnomAD: rs120074122,
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|
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ClinVar: RCV000003121, RCV000723418, RCV001248871, RCV001851601, RCV002468958, RCV003472960
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|
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</span>
|
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</div>
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|
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<div>
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<span class="mim-text-font">
|
|
<p>Takahashi et al. (1992) found that a type B Niemann-Pick disease (607616) patient of European descent was heteroallelic for 2 missense mutations: a G-to-A transition in exon 2 which predicted a glycine-to-arginine substitution at codon 242 (G242R), and an A-to-G transition in exon 3 which resulted in an asparagine-to-serine substitution at codon 383 (N383S). </p>
|
|
</span>
|
|
</div>
|
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<div>
|
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<br />
|
|
</div>
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|
|
</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 NIEMANN-PICK DISEASE, TYPE B</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
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SMPD1, ASN383SER
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|
<br />
|
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|
|
SNP: rs120074123,
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|
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|
|
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gnomAD: rs120074123,
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|
|
|
|
|
ClinVar: RCV000003122, RCV001248870, RCV002512692
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>See 607608.0008. Takahashi et al. (1992) found that the G242R allele (607608.0008) produced enzyme activity in COS-1 cells at levels about 40% of that expressed by the normal allele, thereby explaining the mild Niemann-Pick disease type B (607616) phenotype of the patient and the high residual activity (approximately 15% of normal) in cultured lymphoblasts. In contrast, the other allele, N383S, did not produce catalytically active enzyme. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
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<div>
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 NIEMANN-PICK DISEASE, TYPE A</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMPD1, LEU302PRO
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<br />
|
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|
|
SNP: rs120074124,
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|
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gnomAD: rs120074124,
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|
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ClinVar: RCV000003123, RCV000175622, RCV000192222, RCV000984009, RCV001380607
|
|
|
|
|
|
</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Levran et al. (1992) reported a T-to-C transition at nucleotide 905, predicting a leucine-to-proline substitution at SMPD1 codon 302 in 8 of 34 (23.5%) Ashkenazi type A Niemann-Pick disease (257200) alleles studied. In contrast, it was not found in any of the SMPD1 alleles from non-Jewish type A patients or in alleles from type B patients or in 100 SMPD1 alleles from normal Ashkenazi Jewish persons. The authenticity of the frequent R496L (607608.0001) and L302P mutations was confirmed by separately introducing each nucleotide change into the full-length SMPD1 cDNA by site-directed mutagenesis and transient expression in COS-1 cells. Neither mutation expressed SMPD1 catalytic activity. </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>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 NIEMANN-PICK DISEASE, TYPE A</strong>
|
|
</span>
|
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</h4>
|
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</div>
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|
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<div>
|
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<span class="mim-text-font">
|
|
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|
SMPD1, 1-BP DEL, PRO330FS
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<br />
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|
|
SNP: rs387906289,
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gnomAD: rs387906289,
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ClinVar: RCV000003124, RCV000192223, RCV000723827, RCV000817028, RCV000984010
|
|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Levran et al. (1993) described a new mutation that causes type A Niemann-Pick disease (257200) in Ashkenazi Jewish patients. Deletion of a single cytosine in codon 330 of the SMPD1 cDNA (which normally encodes a proline residue) caused a frameshift that led to the formation of a premature stop (TGA) at codon 382. The mutation occurred in 4 of 52 SMPD1 alleles analyzed from unrelated Ashkenazi Jewish type A patients or obligate heterozygotes. In contrast, the mutation was not found in non-Jewish type A patients or in any Jewish or non-Jewish type B patients. Three mutations, R496L (607608.0001), L302P (607608.0010), and this mutation, account for about 65% of the mutant SMPD1 alleles in Ashkenazi Jewish type A Niemann-Pick disease patients. The single base deletion causing the pro330FS mutation was in a region of the gene where 9 of the 10 residues were cytosines. </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>.0012 NIEMANN-PICK DISEASE, INTERMEDIATE, PROTRACTED NEUROVISCERAL</strong>
|
|
</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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SMPD1, TRP391GLY
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|
|
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<br />
|
|
|
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SNP: rs120074125,
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gnomAD: rs120074125,
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ClinVar: RCV000003125, RCV000410490, RCV000797253, RCV001248981, RCV004546410
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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 kindred with its roots in a small village of Serbia, Sperl et al. (1994) described 6 members affected by an atypical intermediate form of Niemann-Pick disease (see 257200) with a visceral course and additional retinal changes, namely macular halos, indicative of neuronal storage. A very low degradation rate of sphingomyelin was demonstrated in skin fibroblasts. Ferlinz et al. (1995) demonstrated a novel mutation, a T-to-G transversion at nucleotide 1171 (nucleotides counted from the A of the first putative initiation codon, ATG), resulting in a substitution of glycine (GGG) for the normal tryptophan (TGG) at amino acid position 391. Northern analysis did not show significant aberration in quantity and size of the mRNA compared with normals. The family contained an example of pseudodominance resulting from the marriage of a homozygote with a heterozygote. Three of 4 children were homozygotes. Ferlinz et al. (1995) concluded that instability and rapid breakdown of the mature mutant enzyme protein due to the mutation was the primary mechanism for deficiency of sphingomyelinase activity in these patients, rather than direct inactivation of catalytic activity. </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>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0013 NIEMANN-PICK DISEASE, TYPE B</strong>
|
|
</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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SMPD1, HIS421TYR
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<br />
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SNP: rs120074126,
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ClinVar: RCV000003126, RCV000192225, RCV000411474, RCV000634570, RCV000723415
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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 28 Saudi Arabian cases of type B Niemann-Pick disease (607616), Simonaro et al. (2002) found that his421-to-tyr (H421Y) was the most frequent mutation, accounting for 71.4% of mutant alleles. The mutation occurs within the putative active-site region of the enzyme and at a histidine residue that might be involved in zinc binding. The mutation was associated with an early onset and a more severe form of type B Niemann-Pick disease. </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>.0014 NIEMANN-PICK DISEASE, TYPE B</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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SMPD1, ARG441TER
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<br />
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SNP: rs120074127,
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gnomAD: rs120074127,
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ClinVar: RCV000003127, RCV000193674, RCV000372224, RCV000634567, RCV000780732, RCV001248934
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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>Lee et al. (2003) studied a family in which a brother and sister were compound heterozygotes for the R608 deletion (607608.0002) and an arg441-to-ter (R441X) mutation in the SMPD1 gene. The proband, a 47-year-old man, had been admitted to a pediatric hospital at the age of 3 years for failure to thrive and hepatosplenomegaly. Patchy pulmonary infiltrates were found without obvious infectious cause, and splenectomy was performed. The diagnosis of type B Niemann-Pick disease (607616) was made on the basis of lipid-laden histiocytes on histopathology. Subsequent physical and neurologic development were normal and he worked as a mechanic. His sister, who was 2 years younger, was also diagnosed with type B Niemann-Pick disease on the basis of splenectomy. Her physical and intellectual development proceeded normally. At age 41 years, she was found to have severe coronary artery disease and underwent coronary artery bypass. Lee et al. (2003) concluded that compound heterozygosity for the 2 mutations was associated with low HDL cholesterol and premature coronary artery disease. </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>.0015 NIEMANN-PICK DISEASE, TYPE B</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">
|
|
NIEMANN-PICK DISEASE, INTERMEDIATE, PROTRACTED NEUROVISCERAL, 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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SMPD1, GLN292LYS
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<br />
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SNP: rs120074128,
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gnomAD: rs120074128,
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ClinVar: RCV000003128, RCV000003129, RCV000169297, RCV000781865, RCV000812595, RCV001248931, RCV002512693, RCV003333947
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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 2 unrelated patients with Niemann-Pick disease type B (607616), Pavlu and Elleder (1997) identified a homozygous 874C-A transversion in exon 2 of the SMPD1 gene, resulting in a gln292-to-lys (Q292K) substitution. Both patients had progressive visceral manifestations, and 1 developed neurologic symptoms. </p><p>Pavlu-Pereira et al. (2005) found that the Q292K mutation was associated with an intermediate form of Niemann-Pick disease characterized by a protracted neurovisceral phenotype (see 257200). </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>.0016 NIEMANN-PICK DISEASE, TYPE A</strong>
|
|
</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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SMPD1, ALA482GLU
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<br />
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SNP: rs267607075,
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gnomAD: rs267607075,
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ClinVar: RCV000003130, RCV000780737, RCV001249038, RCV001824114, RCV001851602
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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 Spanish patient with Niemann-Pick disease type A (257200), Rodriguez-Pascau et al. (2009) identified a homozygous 1445C-A transversion in exon 5 of the SMPD1 gene, resulting in an ala482-to-glu (A482E) substitution. Two additional patients were compound heterozygous for this mutation and another pathogenic mutation. In vitro functional expression studies in COS-7 cells showed that the mutant protein had less than 5% residual activity. </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>.0017 NIEMANN-PICK DISEASE, TYPE A</strong>
|
|
</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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SMPD1, TYR467SER
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<br />
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SNP: rs267607074,
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ClinVar: RCV000003131, RCV001379382
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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 Spanish patient with Niemann-Pick disease type A (257200), Rodriguez-Pascau et al. (2009) identified a homozygous 1400A-C transversion in exon 5 of the SMPD1 gene, resulting in a tyr467-to-ser (Y467S) substitution. In vitro functional expression studies in COS-7 cells showed that the mutant protein had less than 5% residual activity. </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>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Takahashi et al. (1992); Wilson and Konrad (1987)
|
|
</span>
|
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<div>
|
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<br />
|
|
</div>
|
|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
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<p />
|
|
</div>
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<div>
|
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<ol>
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<li>
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<p class="mim-text-font">
|
|
da Veiga Pereira, L., Desnick, R. J., Adler, D. A., Disteche, C. M., Schuchman, E. H.
|
|
<strong>Regional assignment of the human acid sphingomyelinase gene (SMPD1) by PCR analysis of somatic cell hybrids and in situ hybridization to 11p15.1-p15.4.</strong>
|
|
Genomics 9: 229-234, 1991.
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[PubMed: 2004772]
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[Full Text: https://doi.org/10.1016/0888-7543(91)90246-b]
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<li>
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<p class="mim-text-font">
|
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Ferlinz, K., Hurwitz, R., Sandhoff, K.
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<strong>Molecular basis of acid sphingomyelinase deficiency in a patient with Niemann-Pick disease type A.</strong>
|
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Biochem. Biophys. Res. Commun. 179: 1187-1191, 1991.
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[PubMed: 1718266]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Ferlinz, K., Hurwitz, R., Weiler, M., Suzuki, K., Sandhoff, K., Vanier, M. T.
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<strong>Molecular analysis of the acid sphingomyelinase deficiency in a family with an intermediate form of Niemann-Pick disease.</strong>
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Am. J. Hum. Genet. 56: 1343-1349, 1995.
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[PubMed: 7762557]
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<li>
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<p class="mim-text-font">
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Fernandez-Burriel, M., Pena, L., Ramos, J. C., Cabrera, J. C., Marti, M., Rodriguez-Quinones, F., Chabas, A.
|
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<strong>The R608del mutation in the acid sphingomyelinase gene (SMPD1) is the most prevalent among patients from Gran Canaria Island with Niemann-Pick disease type B. (Letter)</strong>
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Clin. Genet. 63: 235-236, 2003.
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[PubMed: 12694237]
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[Full Text: https://doi.org/10.1034/j.1399-0004.2003.00025.x]
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</p>
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<li>
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<p class="mim-text-font">
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Garcia-Barros, M., Paris, F., Cordon-Cardo, C., Lyden, D., Rafii, S., Haimovitz-Friedman, A., Fuks, Z., Kolesnick, R.
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<strong>Tumor response to radiotherapy regulated by endothelial cell apoptosis.</strong>
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Science 300: 1155-1159, 2003.
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[PubMed: 12750523]
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[Full Text: https://doi.org/10.1126/science.1082504]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Garcia-Ruiz, C., Colell, A., Mari, M., Morales, A., Calvo, M., Enrich, C., Fernandez-Checa, J. C.
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<strong>Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice.</strong>
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J. Clin. Invest. 111: 197-208, 2003.
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[PubMed: 12531875]
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[Full Text: https://doi.org/10.1172/JCI16010]
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<li>
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<p class="mim-text-font">
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Grassme, H., Gulbins, E., Brenner, B., Ferlinz, K., Sandhoff, K., Harzer, K., Lang, F., Meyer, T. F.
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<strong>Acidic sphingomyelinase mediates entry of N. gonorrhoeae in nonphagocytic cells.</strong>
|
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Cell 91: 605-615, 1997.
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[PubMed: 9393854]
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[Full Text: https://doi.org/10.1016/s0092-8674(00)80448-1]
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</li>
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<li>
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<p class="mim-text-font">
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Horinouchi, K., Erlich, S., Perl, D. P., Ferlinz, K., Bisgaier, C. L., Sandhoff, K., Desnick, R. J., Stewart, C. L., Schuchman, E. H.
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<strong>Acid sphingomyelinase deficient mice: a model of types A and B Niemann-Pick disease.</strong>
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Nature Genet. 10: 288-293, 1995.
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[PubMed: 7670466]
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[Full Text: https://doi.org/10.1038/ng0795-288]
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</p>
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<li>
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<p class="mim-text-font">
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Horinouchi, K., Sakiyama, T., Pereira, L., Lalley, P. A., Schuchman, E. H.
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<strong>Mouse models of Niemann-Pick disease: mutation analysis and chromosomal mapping rule out the type A and B forms.</strong>
|
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Genomics 18: 450-451, 1993.
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[PubMed: 8288255]
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[Full Text: https://doi.org/10.1006/geno.1993.1497]
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<p class="mim-text-font">
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Ida, H., Rennert, O. M., Maekawa, K., Eto, Y.
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<strong>Identification of three novel mutations in the acid sphingomyelinase gene of Japanese patients with Niemann-Pick disease type A and B.</strong>
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Hum. Mutat. 7: 65-67, 1996.
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[PubMed: 8664904]
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[Full Text: https://doi.org/10.1002/(SICI)1098-1004(1996)7:1<65::AID-HUMU10>3.0.CO;2-Q]
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</p>
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<li>
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<p class="mim-text-font">
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Kirkegaard, T., Roth, A. G., Petersen, N. H. T., Mahalka, A. K., Olsen, O. D., Moilanen, I., Zylicz, A., Knudsen, J., Sandhoff, K., Arenz, C., Kinnunen, P. K. J., Nylandsted, J., Jaattela, M.
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<strong>Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease-associated lysosomal pathology.</strong>
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Nature 463: 549-553, 2010.
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[PubMed: 20111001]
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[Full Text: https://doi.org/10.1038/nature08710]
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</p>
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<li>
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<p class="mim-text-font">
|
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Konrad, R., Wilson, D.
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<strong>Assignment of the gene for acid lysosomal sphingomyelinase to human chromosome 17. (Abstract)</strong>
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Cytogenet. Cell Genet. 46: 641, 1987.
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|
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Lang, P. A., Schenck, M., Nicolay, J. P., Becker, J. U., Kempe, D. S., Lupescu, A., Koka, S., Eisele, K., Klarl, B. A., Rubben, H., Schmid, K. W., Mann, K., Hildenbrand, S., Hefter, H., Huber, S. M., Wieder, T., Erhardt, A., Haussinger, D., Gulbins, E., Lang, F.
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<strong>Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide.</strong>
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Nature Med. 13: 164-170, 2007.
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[PubMed: 17259995]
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[Full Text: https://doi.org/10.1038/nm1539]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Lee, C. Y., Krimbou, L., Vincent, J., Bernard, C., Larramee, P., Genest, J., Jr., Marcil, M.
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<strong>Compound heterozygosity at the sphingomyelin phosphodiesterase-1 (SMPD1) gene is associated with low HDL cholesterol.</strong>
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Hum. Genet. 112: 552-562, 2003.
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[PubMed: 12607113]
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[Full Text: https://doi.org/10.1007/s00439-002-0893-1]
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</p>
|
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</li>
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<li>
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|
<p class="mim-text-font">
|
|
Levran, O., Desnick, R. J., Schuchman, E. H.
|
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<strong>Identification of the first mutation in Niemann-Pick types A and B disease, a common point mutation in the Ashkenazi Jewish population. (Abstract)</strong>
|
|
Am. J. Hum. Genet. 47 (suppl.): A162, 1990.
|
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|
|
</p>
|
|
</li>
|
|
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<li>
|
|
<p class="mim-text-font">
|
|
Levran, O., Desnick, R. J., Schuchman, E. H.
|
|
<strong>Niemann-Pick disease: a frequent missense mutation in the acid sphingomyelinase gene of Ashkenazi Jewish type A and B patients.</strong>
|
|
Proc. Nat. Acad. Sci. 88: 3748-3752, 1991.
|
|
|
|
|
|
[PubMed: 2023926]
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|
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[Full Text: https://doi.org/10.1073/pnas.88.9.3748]
|
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Levran, O., Desnick, R. J., Schuchman, E. H.
|
|
<strong>Niemann-Pick type B disease: identification of a single codon deletion in the acid sphingomyelinase gene and genotype/phenotype correlations in type A and B patients.</strong>
|
|
J. Clin. Invest. 88: 806-810, 1991.
|
|
|
|
|
|
[PubMed: 1885770]
|
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|
|
[Full Text: https://doi.org/10.1172/JCI115380]
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Levran, O., Desnick, R. J., Schuchman, E. H.
|
|
<strong>Identification and expression of a common missense mutation (L302P) in the acid sphingomyelinase gene of Ashkenazi Jewish type A Niemann-Pick disease patients.</strong>
|
|
Blood 80: 2081-2087, 1992.
|
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|
|
|
|
[PubMed: 1391960]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Levran, O., Desnick, R. J., Schuchman, E. H.
|
|
<strong>Type A Niemann-Pick disease: a frameshift mutation in the acid sphingomyelinase gene (fsP330) occurs in Ashkenazi Jewish patients.</strong>
|
|
Hum. Mutat. 2: 317-319, 1993.
|
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|
|
|
[PubMed: 8401540]
|
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|
|
[Full Text: https://doi.org/10.1002/humu.1380020414]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Suchi, M., Dinur, T., Desnick, R. J., Gatt, S., Pereira, L., Gilboa, E., Schuchman, E. H.
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<strong>Retroviral-mediated transfer of the human acid sphingomyelinase cDNA: correction of the metabolic defect in cultured Niemann-Pick disease cells.</strong>
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Takahashi, T., Desnick, R. J., Takada, G., Schuchman, E. H.
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<strong>Identification of a missense mutation (S436R) in the acid sphingomyelinase gene from a Japanese patient with type B Niemann-Pick disease.</strong>
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Takahashi, T., Suchi, M., Desnick, R. J., Takada, G., Schuchman, E. H.
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<strong>Identification and expression of five mutations in the human acid sphingomyelinase gene causing types A and B Niemann-Pick disease: molecular evidence for genetic heterogeneity in the neuronopathic and non-neuronopathic forms.</strong>
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<strong>Deletion of arginine (608) in acid sphingomyelinase is the prevalent mutation among Niemann-Pick disease type B patients from northern Africa.</strong>
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Volders, P., Van Hove, J., Lories, R. J. U., Vandekerckhove, P., Matthijs, G., De Vos, R., Vanier, M. T., Vincent, M. F., Westhovens, R., Luyten, F. P.
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<strong>Assignment of the gene for acid lysosomal sphingomyelinase to human chromosome 17. (Abstract)</strong>
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