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- *606869 - HEXOSAMINIDASE A; HEXA
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- OMIM
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<p>
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<span class="h4">*606869</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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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#nomenclature">Nomenclature</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/606869">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>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div id="mimFloatingLinksMenu">
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<div class="panel 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=ENSG00000213614;t=ENST00000268097" 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=3073" 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=606869" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000213614;t=ENST00000268097" 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_000520,NM_001318825,NR_134869" 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_000520" 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=606869" 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=06040&isoform_id=06040_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/HEXA" 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/179458,179460,912778,4261627,4261632,4261942,4261943,4261946,17511941,33876034,50949867,54261591,62896563,119598308,189181666,194375013,194375235,194383206,194387350,311033393,353351766,353351768,353351770,353351772,353351774,353351776,353351778,353351780,354697080,957949525,957949528,957949531,957949534,957949537,974005364" 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/P06865" 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=3073" 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=ENSG00000213614;t=ENST00000268097" 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=HEXA" 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=HEXA" 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+3073" 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/HEXA" 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:3073" 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/3073" 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=chr15&hgg_gene=ENST00000268097.10&hgg_start=72340924&hgg_end=72376014&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:4878" 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/hexa" 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=606869[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
|
|
</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=606869[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/HEXA/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/ENSG00000213614" 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=HEXA" 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=HEXA" 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=HEXA" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.hexdb.mcgill.ca" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=HEXA&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/PA29256" 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:4878" 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/FBgn0041629.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:96073" 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/HEXA#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:96073" 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/3073/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/OMIA001461/" 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=3073" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00020509;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-050417-283" 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:606869" 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:3073" 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=HEXA&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> 111385000, 238024005, 9537004<br />
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<strong>ICD10CM:</strong> E75.02, E75.09<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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606869
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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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|
|
HEXOSAMINIDASE A; HEXA
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</span>
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</h3>
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</div>
|
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
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<p>
|
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
BETA-HEXOSAMINIDASE A
|
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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>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=HEXA" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">HEXA</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/15/353?start=-3&limit=10&highlight=353">15q23</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr15:72340924-72376014&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'})">15:72,340,924-72,376,014</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
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|
|
</span>
|
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</p>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
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<th>
|
|
Phenotype
|
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</th>
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
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|
<tr>
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<span class="mim-font">
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<a href="/geneMap/15/353?start=-3&limit=10&highlight=353">
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15q23
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[Hex A pseudodeficiency]
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<span class="mim-font">
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<a href="/entry/272800"> 272800 </a>
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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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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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GM2-gangliosidosis, several forms
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<span class="mim-font">
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<a href="/entry/272800"> 272800 </a>
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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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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<a href="/entry/272800"> 272800 </a>
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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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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<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/606869" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/606869" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<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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<p>The HEXA gene encodes the alpha subunit of hexosaminidase A (<a href="https://enzyme.expasy.org/EC/3.2.1.52" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 3.2.1.52</a>), a lysosomal enzyme involved in the breakdown of gangliosides. There are 2 isoenzymes of hexosaminidase: Hex-A and Hex-B (HEXB; <a href="/entry/606873">606873</a>). <a href="#8" class="mim-tip-reference" title="Beutler, E., Kuhl, W., Comings, D. <strong>Hexosaminidase isozyme in type O Gm2 gangliosidosis (Sandhoff-Jatzkewitz disease).</strong> Am. J. Hum. Genet. 27: 628-638, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/808963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">808963</a>]" pmid="808963">Beutler et al. (1975)</a> concluded that Hex-A has the structure alpha-beta, while Hex-B has the structure beta-beta. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=808963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="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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<strong>Cloning and Expression</strong>
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<p><a href="#50" class="mim-tip-reference" title="Myerowitz, R., Piekarz, R., Neufeld, E. F., Shows, T. B., Suzuki, K. <strong>Human beta-hexosaminidase alpha chain: coding sequence and homology with the beta chain.</strong> Proc. Nat. Acad. Sci. 82: 7830-7834, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2933746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2933746</a>] [<a href="https://doi.org/10.1073/pnas.82.23.7830" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2933746">Myerowitz et al. (1985)</a> cloned the alpha chain of Hex-A from an adult human liver library and found an open reading frame corresponding to 529 amino acids, with a molecular weight of approximately 60 kD. The first 17 to 22 amino acids satisfied the requirements of a signal sequence. They noted striking sequence homology with the amino acid sequence for the beta chain, and suggested that both chains evolved from a common ancestor. <a href="#36" class="mim-tip-reference" title="Korneluk, R. G., Mahuran, D. J., Neote, K., Klavins, M. H., O'Dowd, B. F., Tropak, M., Willard, H. F., Anderson, M.-J., Lowden, J. A., Gravel, R. A. <strong>Isolation of cDNA clones coding for the alpha-subunit of human beta-hexosaminidase: extensive homology between the alpha- and beta-subunits and studies on Tay-Sachs disease.</strong> J. Biol. Chem. 261: 8407-8413, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3013851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3013851</a>]" pmid="3013851">Korneluk et al. (1986)</a> found 57% amino acid homology between Hex-A and Hex-B. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3013851+2933746" 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>
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<br />
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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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<strong>Gene Structure</strong>
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</h4>
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<span class="mim-text-font">
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<p><a href="#75" class="mim-tip-reference" title="Proia, R. L., Soravia, E. <strong>Organization of the gene encoding the human beta-hexosaminidase alpha-chain.</strong> J. Biol. Chem. 262: 5677-5681, 1987. Note: Erratum: J. Biol. Chem. 262: 15322 only, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2952641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2952641</a>]" pmid="2952641">Proia and Soravia (1987)</a> studied the structure of the HEXA gene by restriction endonuclease mapping, Southern blotting, and DNA sequencing. The alpha-chain gene is about 35 kb long and contains 14 exons. Differential transcription of processing of the most 3-prime exon of the gene resulted in 2 alpha-chain mRNAs with different 3-prime untranslated regions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2952641" 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>
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<br />
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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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<strong>Mapping</strong>
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</h4>
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<span class="mim-text-font">
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<p>By study of somatic cell hybrids, <a href="#37" class="mim-tip-reference" title="Lalley, P. A., Rattazzi, M. C., Shows, T. B. <strong>Human beta-D-N-acetylhexosaminidases A and B: expression and linkage relationships in somatic cell hybrids.</strong> Proc. Nat. Acad. Sci. 71: 1569-1573, 1974.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4524661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4524661</a>] [<a href="https://doi.org/10.1073/pnas.71.4.1569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4524661">Lalley et al. (1974)</a> suggested that a locus determining hexosaminidase A is on chromosome 7. Subsequently, <a href="#94" class="mim-tip-reference" title="Van Heyningen, V., Bobrow, M., Bodmer, W. F., Gardiner, S. E., Povey, S., Hopkinson, D. A. <strong>Chromosome assignment of some human enzyme loci: mitochondrial malate dehydrogenase to 7, mannosephosphate isomerase and pyruvate kinase to 15 and probably, esterase D to 13.</strong> Ann. Hum. Genet. 38: 295-303, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1137344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1137344</a>] [<a href="https://doi.org/10.1111/j.1469-1809.1975.tb00613.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1137344">Van Heyningen et al. (1975)</a> found that the MPI (<a href="/entry/154550">154550</a>) and PK3 (<a href="/entry/179050">179050</a>) loci are on chromosome 15, and <a href="#23" class="mim-tip-reference" title="Gilbert, F., Kucherlapati, R. S., Creagan, R. P., Murnane, M. J., Darlington, G. J., Ruddle, F. H. <strong>Tay-Sachs' and Sandhoff's diseases: the assignment of genes for hexosaminidase A and B to individual human chromosomes.</strong> Proc. Nat. Acad. Sci. 72: 263-267, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1054503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1054503</a>] [<a href="https://doi.org/10.1073/pnas.72.1.263" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1054503">Gilbert et al. (1975)</a> concluded that MPI, PK3 and HEXA are syntenic. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1054503+4524661+1137344" 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="Chern, C. J., Beutler, E., Kuhl, W., Gilbert, F., Mellman, W. J., Croce, C. M. <strong>Characterization of heteropolymeric hexosaminidase A in human x mouse hybrid cells.</strong> Proc. Nat. Acad. Sci. 73: 3637-3640, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/62363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">62363</a>] [<a href="https://doi.org/10.1073/pnas.73.10.3637" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="62363">Chern et al. (1976)</a> studied heteropolymeric hexosaminidase A formed by human-mouse hybrid cells that contained an X;15 translocation chromosome but lacked human chromosome 5. Tests with specific antisera suggested that the hybrid molecule had human alpha units and mouse beta units. The findings are consistent with hexosaminidase A being composed of alpha and beta subunits coded by genes on chromosomes 15 and 5, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=62363" 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="#12" class="mim-tip-reference" title="Chern, C. J., Kennett, R., Engel, E., Mellman, W. J., Croce, C. M. <strong>Assignment of the structural genes for the alpha subunit of hexosaminidase A, mannosephosphate isomerase and pyruvate kinase to the region q22-qter of human chromosome 15.</strong> Somat. Cell Genet. 3: 553-560, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/341373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">341373</a>] [<a href="https://doi.org/10.1007/BF01539065" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="341373">Chern et al. (1977)</a> mapped the HEXA gene to chromosome 15q22-qter by somatic cell hybrid analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=341373" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Formiga, L. de F., Poenaru, L., Couronne, F., Flori, E., Eibel, J. L., Deminatti, M. M., Savary, J. B., Lai, J. L., Gilgenkrantz, S., Pierson, M. <strong>Interstitial deletion of chromosome 15: two cases.</strong> Hum. Genet. 80: 401-404, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3198122/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3198122</a>] [<a href="https://doi.org/10.1007/BF00273663" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3198122">Formiga et al. (1988)</a> reported 2 cases of interstitial deletion of chromosome 15. Assay of hexosaminidase A in 1 case enabled them to confirm that the structural gene is located between 15q22 and 15q25 and is included in the deletion. By high resolution in situ hybridization, <a href="#81" class="mim-tip-reference" title="Takeda, K., Nakai, H., Hagiwara, H., Tada, K., Shows, T. B., Byers, M. G., Myerowitz, R. <strong>Fine assignment of beta-hexosaminidase A alpha-subunit on 15q23-q24 by high resolution in situ hybridization.</strong> Tohoku J. Exp. Med. 160: 203-211, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2141199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2141199</a>] [<a href="https://doi.org/10.1620/tjem.160.203" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2141199">Takeda et al. (1990)</a> narrowed the assignment to 15q23-q24. Using a cDNA clone for in situ hybridization, <a href="#55" class="mim-tip-reference" title="Nakai, H., Byers, M. G., Nowak, N. J., Shows, T. B. <strong>Assignment of beta-hexosaminidase A alpha-subunit to human chromosomal region 15q23-q24.</strong> Cytogenet. Cell Genet. 56: 164, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1829032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1829032</a>] [<a href="https://doi.org/10.1159/000133077" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1829032">Nakai et al. (1991)</a> assigned the HEXA gene to 15q23-q24. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3198122+2141199+1829032" 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="#77" class="mim-tip-reference" title="Seldin, M. F., Saunders, A. M., Rochelle, J. M., Howard, T. A. <strong>A proximal mouse chromosome 9 linkage map that further defines linkage groups homologous with segments of human chromosomes 11, 15, and 19.</strong> Genomics 9: 678-685, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1674729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1674729</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90361-h" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1674729">Seldin et al. (1991)</a> demonstrated that the HEXA homolog in the mouse is located on chromosome 9. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1674729" 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="#70" class="mim-tip-reference" title="Pennybacker, M., Liessem, B., Moczall, H., Tifft, C. J., Sandhoff, K., Proia, R. L. <strong>Identification of domains in human beta-hexosaminidase that determine substrate specificity.</strong> J. Biol. Chem. 271: 17377-17382, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8663217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8663217</a>] [<a href="https://doi.org/10.1074/jbc.271.29.17377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8663217">Pennybacker et al. (1996)</a> identified domains in human hexosaminidase that confer distinctive substrate specificity to Hex-A (alpha-beta), Hex-B (beta-beta), and Hex-S (alpha-alpha) isozymes. The active site on the beta subunit primarily degrades neutral substrates, whereas the alpha-subunit site is active against sulfated substrates. Only Hex-A, together with the GM2 activator protein, can degrade GM2 ganglioside. <a href="#70" class="mim-tip-reference" title="Pennybacker, M., Liessem, B., Moczall, H., Tifft, C. J., Sandhoff, K., Proia, R. L. <strong>Identification of domains in human beta-hexosaminidase that determine substrate specificity.</strong> J. Biol. Chem. 271: 17377-17382, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8663217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8663217</a>] [<a href="https://doi.org/10.1074/jbc.271.29.17377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8663217">Pennybacker et al. (1996)</a> generated chimeric hexosaminidase subunits by interchanging analogous regions of the alpha and beta subunits. Chimeric constructs were expressed in HeLa cells and selected constructs were produced in the baculovirus expression system to determine their ability to degrade GM2 ganglioside in the presence of GM2 activator protein. Their results allowed them to define 2 noncontiguous sequences in the alpha subunit (amino acids 1-191 and 403-529) which, when substituted into analogous positions in the beta subunit, conferred activity against the sulfated substrate. <a href="#70" class="mim-tip-reference" title="Pennybacker, M., Liessem, B., Moczall, H., Tifft, C. J., Sandhoff, K., Proia, R. L. <strong>Identification of domains in human beta-hexosaminidase that determine substrate specificity.</strong> J. Biol. Chem. 271: 17377-17382, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8663217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8663217</a>] [<a href="https://doi.org/10.1074/jbc.271.29.17377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8663217">Pennybacker et al. (1996)</a> also found that amino acids 225-556 in the beta subunit are required for activator-dependent GM2 ganglioside degradation by HexA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8663217" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#41" class="mim-tip-reference" title="Lemieux, M. J., Mark, B. L., Cherney, M. M., Withers, S. G., Mahuran, D. J., James, M. N. G. <strong>Crystallographic structure of human beta-hexosaminidase A: interpretation of Tay-Sachs mutations and loss of GM2 ganglioside hydrolysis.</strong> J. Molec. Biol. 359: 913-929, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16698036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16698036</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16698036[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/10.1016/j.jmb.2006.04.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16698036">Lemieux et al. (2006)</a> reported that the 2.8-angstrom resolution x-ray crystallographic structure of Hex-A revealed an alpha/beta heterodimer, with each subunit having a functional active site. Only the alpha subunit active site can hydrolyze GM2 gangliosides due to a flexible loop structure that is removed posttranslationally from the beta subunit. The beta subunit lacks certain key residues and therefore cleaves only neutral substrates efficiently. The alpha subunit contains 2 domains. Domain I is an N-terminal domain with 2 parallel alpha-helices sandwiched between a 6-stranded antiparallel beta-sheet. Domain II is a C-terminal domain comprising a beta-alpha (8)-barrel structure with an active site pocket. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16698036" 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="#8" class="mim-tip-reference" title="Beutler, E., Kuhl, W., Comings, D. <strong>Hexosaminidase isozyme in type O Gm2 gangliosidosis (Sandhoff-Jatzkewitz disease).</strong> Am. J. Hum. Genet. 27: 628-638, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/808963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">808963</a>]" pmid="808963">Beutler et al. (1975)</a> concluded that Tay-Sachs disease (<a href="/entry/272800">272800</a>) is caused by mutation in the alpha subunit of hexosaminidase, causing a dysfunctional Hex-A enzyme, whereas Sandhoff disease (<a href="/entry/268800">268800</a>) is caused by mutation in the beta subunit (HEXB; <a href="/entry/606873">606873</a>), causing dysfunctional Hex-A and Hex-B enzymes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=808963" 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="#53" class="mim-tip-reference" title="Myerowitz, R. <strong>Tay-Sachs disease-causing mutations and neutral polymorphisms in the Hex A gene.</strong> Hum. Mutat. 9: 195-208, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9090523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9090523</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)9:3<195::AID-HUMU1>3.0.CO;2-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9090523">Myerowitz (1997)</a> stated that 78 mutations in the HEXA gene had been described, including 65 single-base substitutions, 1 large and 10 small deletions, and 2 small insertions. Of the single-base substitutions, 45 caused missense mutations; 39 of these were disease-causing, 3 were benign but caused a change in phenotype, and 3 were neutral polymorphisms. Six nonsense mutations and 14 splice site lesions resulted from single-base substitutions; all but 1 of the splice site lesions caused a severe form of Tay-Sachs disease. Eight frameshift mutations arose from 6 deletion- and 2 insertion-type lesions. One of the insertions, consisting of 4 bp within exon 11 (<a href="#0001">606869.0001</a>), is found in 80% of the carriers of Tay-Sachs disease from the Ashkenazi Jewish population. A very large deletion of 7.5 kb, including all of exon 1 and portions of DNA upstream and downstream from that exon (<a href="#0003">606869.0003</a>), is the major mutation found in Tay-Sachs disease carriers from the French Canadian population. Most of the other mutations are confined to single pedigrees. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9090523" 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="#44" class="mim-tip-reference" title="McGinniss, M. J., Brown, D. H., Fulwiler, A., Marten, M., Lim-Steele, J. S. T., Kaback, M. M. <strong>Eight novel mutations in the HEXA gene.</strong> Genet. Med. 4: 158-161, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12180151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12180151</a>] [<a href="https://doi.org/10.1097/00125817-200205000-00010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12180151">McGinniss et al. (2002)</a> identified 8 novel mutations in the HEXA gene, as well as 31 previously described mutations in 49 subjects (47 enzymatically defined carriers and 2 disease afflicted) who were negative for the 4 common disease-associated and the 2 pseudodeficient mutations. Six novel mutations were found in non-Jewish carriers, and 2 were found in 2 patients with infantile Tay-Sachs disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12180151" 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>B1 Variant</em></strong></p><p>
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<a href="#83" class="mim-tip-reference" title="Tanaka, A., Ohno, K., Sandhoff, K., Maire, I., Kolodny, E. H., Brown, A., Suzuki, K. <strong>GM2-gangliosidosis B1 variant: analysis of beta-hexosaminidase alpha gene abnormalities in seven patients.</strong> Am. J. Hum. Genet. 46: 329-339, 1990. Note: Erratum: Am. J. Hum. Genet. 48: 176 only, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2137287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2137287</a>]" pmid="2137287">Tanaka et al. (1990)</a> studied 7 patients with the enzymologic characteristics of the B1 variant of Tay-Sachs disease. The variant was characterized by normal catalytic activity on certain artificial substrates, but defective catalytic activity against natural substrates, including GM2 gangliosides. All of the patients, except 1 from Czechoslovakia, carried the same arg178-to-his mutation referred to as DN (see <a href="#0006">606869.0006</a>). The Czechoslovakian patient had a mutation in the same codon: a change of nucleotide 532 from C to T resulting in an arg178-to-cys change in the protein (see <a href="#0007">606869.0007</a>). Site-directed mutagenesis and expression studies in COS-1 cells demonstrated that either of the point mutations abolished catalytic activity of the alpha subunit. The HEXA gene has 1 intron that is exceptionally large. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2137287" 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 homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability, <a href="#54" class="mim-tip-reference" title="Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others. <strong>Deep sequencing reveals 50 novel genes for recessive cognitive disorders.</strong> Nature 478: 57-63, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21937992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21937992</a>] [<a href="https://doi.org/10.1038/nature10423" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21937992">Najmabadi et al. (2011)</a> identified a missense mutation in the HEXA gene (<a href="#0058">606869.0058</a>) in a family (M165) in which the first-cousin parents had 5 healthy children and 3 children with moderate intellectual disability and seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21937992" 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="#63" class="mim-tip-reference" title="Ohno, K., Saito, S., Sugawara, K., Sakuraba, H. <strong>Structural consequences of amino acid substitutions causing Tay-Sachs disease.</strong> Molec. Genet. Metab. 94: 462-468, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18490185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18490185</a>] [<a href="https://doi.org/10.1016/j.ymgme.2008.04.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18490185">Ohno et al. (2008)</a> performed structural analysis of 33 missense mutations in the HEXA gene, including 24 associated with infantile onset and 9 associated with later onset. The authors used structural modeling of the mutant alpha subunits by calculating the number of atoms affected and determining the solvent-accessible surface area of the corresponding residue in the wildtype enzyme. Nineteen (79%) of the 24 mutations associated with the infantile form of the disease influenced 40 atoms or more (see, e.g., E482K; <a href="#0004">606869.0004</a>). Four (80%) of the other 5 infantile cases involving less than 39 atoms affected 1 or more atoms in a functionally important region, such as the active site pocket and/or dimer interface. In contrast, 7 (78%) of 9 late-onset cases influenced less than 39 atoms, and 5 (56%) did not influence any atoms in the functionally important region (see, e.g., G269S; <a href="#0008">606869.0008</a>). These results suggested that structural changes responsible for infantile TSD are generally large and/or located in the functionally important region, whereas those responsible for late-onset TSD are generally small. The findings showed that the structural changes significantly correlated with severity of the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18490185" 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="#62" class="mim-tip-reference" title="O'Brien, J. S. <strong>Suggestions for a nomenclature for the GM2-gangliosidoses making certain (possibly unwarranted) assumptions. (Comments).</strong> Am. J. Hum. Genet. 30: 672-675, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/747190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">747190</a>]" pmid="747190">O'Brien (1978)</a> made suggestions for nomenclature of the various hexosaminidase A and B mutations. Three loci were postulated: alpha, responsible for the alpha subunit, mapped to chromosome 15; beta, responsible for the beta subunit, mapped to chromosome 5; and an activator locus (GM2A; <a href="/entry/613109">613109</a>) or loci determining the structure of one or more proteins that stimulate Hex-A to cleave GM2 and GA2 gangliosides. Hex-A is assumed to have the structure alpha-2-beta-2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=747190" 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> rs387906309 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906309;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/rs387906309?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=rs387906309" 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=rs387906309" 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=RCV000004093 OR RCV000224443 OR RCV000623223 OR RCV001250227 OR RCV001252517 OR RCV004755708" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004093, RCV000224443, RCV000623223, RCV001250227, RCV001252517, RCV004755708" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004093...</a>
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<p><a href="#47" class="mim-tip-reference" title="Myerowitz, R., Costigan, F. C. <strong>The major defect in Ashkenazi Jews with Tay-Sachs disease is an insertion in the gene for the alpha-chain of beta-hexosaminidase.</strong> J. Biol. Chem. 263: 18587-18589, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2848800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2848800</a>]" pmid="2848800">Myerowitz and Costigan (1988)</a> demonstrated that the most frequent DNA lesion in Tay-Sachs disease (<a href="/entry/272800">272800</a>) of Ashkenazi Jews is a homozygous 4-bp insertion in exon 11. This mutation introduces a premature termination signal in exon 11, resulting in a deficiency of mRNA. Using a dot-blot assay to screen patients and heterozygous carriers for the insertion mutation, <a href="#47" class="mim-tip-reference" title="Myerowitz, R., Costigan, F. C. <strong>The major defect in Ashkenazi Jews with Tay-Sachs disease is an insertion in the gene for the alpha-chain of beta-hexosaminidase.</strong> J. Biol. Chem. 263: 18587-18589, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2848800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2848800</a>]" pmid="2848800">Myerowitz and Costigan (1988)</a> found the lesion in about 70% of carriers tested, thus identifying it as the most frequent defect underlying Tay-Sachs disease in the Ashkenazi Jewish population. <a href="#90" class="mim-tip-reference" title="Triggs-Raine, B. L., Gravel, R. A. <strong>Diagnostic heteroduplexes: simple detection of carriers of a 4-bp insertion mutation in Tay-Sachs disease.</strong> Am. J. Hum. Genet. 46: 183-184, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2294750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2294750</a>]" pmid="2294750">Triggs-Raine and Gravel (1990)</a> showed that this insertion mutation of only 4 bp can be detected by the formation of heteroduplexes. This mutation causes a frameshift and a termination codon 9 nucleotides downstream. By site-directed mutagenesis, <a href="#61" class="mim-tip-reference" title="Nishimoto, J., Tanaka, A., Nanba, E., Suzuki, K. <strong>Expression of the beta-hexosaminidase alpha subunit gene with the four-base insertion of infantile Jewish Tay-Sachs disease.</strong> J. Biol. Chem. 266: 14306-14309, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1830584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1830584</a>]" pmid="1830584">Nishimoto et al. (1991)</a> examined the basis of the paradox that the mutant gene with the 4-base insertion in exon 11 is transcribed normally but the mRNA is essentially undetectable. They found no evidence of interference with normal splicing of the transcript and the mutation did not destabilize properly spliced mRNA. Thus, the studies left open the question of the mechanism of the mutation. The possibility was mentioned that another still unidentified abnormality in the same allele may be responsible for the nearly complete absence of mRNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1830584+2848800+2294750" 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>There appears to be an increased frequency of TSD in the Cajun population of southwest Louisiana which numbers less than one million persons. <a href="#42" class="mim-tip-reference" title="McDowell, G. A., Mules, E. H., Fabacher, P., Shapira, E., Blitzer, M. G. <strong>The presence of two different infantile Tay-Sachs disease mutations in a Cajun population.</strong> Am. J. Hum. Genet. 51: 1071-1077, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1307230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1307230</a>]" pmid="1307230">McDowell et al. (1992)</a> reported that in the previous 3 decades, at least 8 infants from 6 apparently unrelated Cajun families had been identified. They found that the mutation in 11 of 12 of the TSD alleles in these 6 families was the exon 11 insertion present in approximately 70% of Ashkenazi Jewish TSD heterozygotes. The remaining allele was a single-base transition in the donor splice site of intron 9 (<a href="#0033">606869.0033</a>). To trace the origins of these 2 mutations in the Cajun population, the TSD carrier status was determined enzymatically in 90 members of 4 of the 6 families, and extensive pedigrees were constructed for all carriers. A single ancestral couple from France was found to be common to most of the carriers of the exon 11 insertion. Pedigree data suggested that this mutation has been in the Cajun population since its founding and that it may be widely distributed within the population. In contrast, the intron 9 mutation was apparently introduced later and is probably limited to a few Louisiana families. <a href="#97" class="mim-tip-reference" title="Zlotogora, J. <strong>Is the presence of two different Tay-Sachs disease mutations in a Cajun population an unexpected observation? (Letter)</strong> Am. J. Hum. Genet. 52: 1014-1015, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8488832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8488832</a>]" pmid="8488832">Zlotogora (1993)</a> argued that 2 mutations would not be unexpected in the Cajun population. <a href="#87" class="mim-tip-reference" title="Thurmon, T. F. <strong>Tay-Sachs genes in Acadians. (Letter)</strong> Am. J. Hum. Genet. 53: 781-782, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8352284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8352284</a>]" pmid="8352284">Thurmon (1993)</a> gave a historical account of the 'Jews of Acadiana.' He indicated that the Jews were assimilated into the Acadian culture and suggested that this was the source of the Tay-Sachs genes. He also pointed out that about the same time Jewish merchants began to arrive in Acadiana, the French Revolution produced an influx of non-Acadian French immigrants. Many were of aristocratic lineage and held themselves aloof from the Acadians. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8488832+8352284+1307230" 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>This mutation is alternatively designated 1277TATC or 1278insTATC. See <a href="#0054">606869.0054</a>.</p><p>To investigate the genetic history of the 1278insTATC mutation, the most frequent cause of Tay-Sachs disease in Ashkenazi Jews, <a href="#22" class="mim-tip-reference" title="Frisch, A., Colombo, R., Michaelovsky, E., Karpati, M., Goldman, B., Peleg, L. <strong>Origin and spread of the 1278insTATC mutation causing Tay-Sachs disease in Ashkenazi Jews: genetic drift as a robust and parsimonious hypothesis.</strong> Hum. Genet. 114: 366-376, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14727180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14727180</a>] [<a href="https://doi.org/10.1007/s00439-003-1072-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14727180">Frisch et al. (2004)</a> identified a conserved haplotype in 1278insTATC chromosomes for 55 unrelated Ashkenazi Jewish individuals (15 homozygotes and 40 heterozygotes for the TSD mutation), suggesting the occurrence of a common founder. When 2 methods were used for analysis of linkage disequilibrium (LD) between flanking polymorphic markers and the disease locus and for study of the decay of LD over time, the estimated age of the insertion was found to be 40 +/- 12 generations (95% confidence interval, 30 to 50 generations), so that the most recent common ancestor of the mutation-bearing chromosomes would date to the 8th or 9th century. This corresponds with the demographic expansion of Ashkenazi Jews in central Europe, following the founding of the Ashkenazi settlement in the early Middle Ages. The results were also consistent with the geographic distribution of the mutation and with the coalescent times of mutations causing 2 other lysosomal storage diseases frequent in Ashkenazi Jews: Gaucher disease (<a href="/entry/230800">230800</a>) and mucolipidosis IV (<a href="/entry/252650">252650</a>). Evidence for the absence of a heterozygote advantage of the mutation was provided by comparison between the estimated age of 1278insTATC and the probability of the current Ashkenazi Jewish frequency of the mutant allele as a function of its age, calculated by use of a branching-process model. Therefore, the founder effect in a rapidly expanding population arising from a bottleneck provides a robust and parsimonious hypothesis explaining the spread of 1278insTATC-related TSD in Ashkenazi Jewish individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14727180" 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> rs147324677 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs147324677;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/rs147324677?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=rs147324677" 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=rs147324677" 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=RCV000004094 OR RCV000255737" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004094, RCV000255737" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004094...</a>
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<p><a href="#7" class="mim-tip-reference" title="Arpaia, E., Dumbrille-Ross, A., Maler, T., Neote, K., Tropak, M., Troxel, C., Stirling, J. L., Pitts, J. S., Bapat, B., Lamhonwah, A. M., Mahuran, D. J., Schuster, S. M., Clarke, J. T. R., Lowden, J. A., Gravel, R. A. <strong>Identification of an altered splice site in Ashkenazi Tay-Sachs disease.</strong> Nature 333: 85-86, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3362213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3362213</a>] [<a href="https://doi.org/10.1038/333085a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3362213">Arpaia et al. (1988)</a> identified a single-base mutation in a cloned fragment of the HEXA gene from an Ashkenazi Jewish patient with Tay-Sachs disease (<a href="/entry/272800">272800</a>). The change, a G-to-C substitution in the first nucleotide of intron 12, was expected to result in defective splicing of the mRNA. A test for the mutant allele based on amplification of DNA by the PCR and cleavage of a DdeI restriction site generated by the mutation showed that this case and 2 other cases of the Ashkenazi, infantile form of Tay-Sachs disease are heterozygous for 2 different mutations. The mutation was found in over 20% of the Tay-Sachs alleles that they examined in Ashkenazi Jewish patients and carriers but in none of 43 normal Jewish persons. <a href="#7" class="mim-tip-reference" title="Arpaia, E., Dumbrille-Ross, A., Maler, T., Neote, K., Tropak, M., Troxel, C., Stirling, J. L., Pitts, J. S., Bapat, B., Lamhonwah, A. M., Mahuran, D. J., Schuster, S. M., Clarke, J. T. R., Lowden, J. A., Gravel, R. A. <strong>Identification of an altered splice site in Ashkenazi Tay-Sachs disease.</strong> Nature 333: 85-86, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3362213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3362213</a>] [<a href="https://doi.org/10.1038/333085a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3362213">Arpaia et al. (1988)</a> suggested that the occurrence of multiple mutant alleles in Ashkenazim warrants further examination of the selective advantage hypothesis; the hypothesis of founder effect suggests the existence of a single mutant allele. In a case of classic infantile Tay-Sachs disease in an Ashkenazi Jewish patient, <a href="#64" class="mim-tip-reference" title="Ohno, K., Suzuki, K. <strong>A splicing defect due to an exon-intron junctional mutation results in abnormal beta-hexosaminidase alpha chain mRNAs in Ashkenazi Jewish patients with Tay-Sachs disease.</strong> Biochem. Biophys. Res. Commun. 153: 463-469, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2837213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2837213</a>] [<a href="https://doi.org/10.1016/s0006-291x(88)81247-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2837213">Ohno and Suzuki (1988)</a> found that there were 2 types of Hex-A mRNA: intact mRNA and mRNA with truncated intron 12 sequences. Sequence analysis showed a single G-to-C nucleotide transversion at the 5-prime donor site of intron 12, the same change as that in the patient of <a href="#7" class="mim-tip-reference" title="Arpaia, E., Dumbrille-Ross, A., Maler, T., Neote, K., Tropak, M., Troxel, C., Stirling, J. L., Pitts, J. S., Bapat, B., Lamhonwah, A. M., Mahuran, D. J., Schuster, S. M., Clarke, J. T. R., Lowden, J. A., Gravel, R. A. <strong>Identification of an altered splice site in Ashkenazi Tay-Sachs disease.</strong> Nature 333: 85-86, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3362213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3362213</a>] [<a href="https://doi.org/10.1038/333085a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3362213">Arpaia et al. (1988)</a>. Both patients were compound heterozygotes. <a href="#52" class="mim-tip-reference" title="Myerowitz, R. <strong>Splice junction mutation in some Ashkenazi Jews with Tay-Sachs disease: evidence against a single defect within this ethnic group.</strong> Proc. Nat. Acad. Sci. 85: 3955-3959, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3375249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3375249</a>] [<a href="https://doi.org/10.1073/pnas.85.11.3955" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3375249">Myerowitz (1988)</a> likewise found in each of 2 unrelated Ashkenazi patients that 1 alpha-chain allele harbored the splice junction mutation. Only 1 parent of each of these patients was positive for the defect. Thirty percent of obligate heterozygotes tested carried the splice junction mutation, whereas 20 Ashkenazi Jews designated noncarriers by enzymatic assay were negative for this alteration. In an Ashkenazi Jewish child with Tay-Sachs disease and a splicing defect at the 5-prime donor site of intron 12, present in heterozygous state, <a href="#65" class="mim-tip-reference" title="Ohno, K., Suzuki, K. <strong>Multiple abnormal beta-hexosaminidase alpha chain mRNAs in a compound-heterozygous Ashkenazi Jewish patient with Tay-Sachs disease.</strong> J. Biol. Chem. 263: 18563-18567, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2973464/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2973464</a>]" pmid="2973464">Ohno and Suzuki (1988)</a> found a variety of abnormal mRNAs. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3362213+3375249+2837213+2973464" 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>This mutation, the second most frequent among Ashkenazi Jews, accounted for approximately 13% of cases in this ethnic group. <a href="#79" class="mim-tip-reference" title="Strasberg, P., Warren, I., Skomorowski, M.-A., Feigenbaum, A. <strong>Homozygosity for the common Ashkenazi Jewish Tay-Sachs +1 IVS-12 splice-junction mutation: first report.</strong> Hum. Mutat. 10: 82-83, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9222766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9222766</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)10:1<82::AID-HUMU13>3.0.CO;2-W" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9222766">Strasberg et al. (1997)</a> reported the first incidence of homozygosity for the intron 12 mutation in a female infant with classic TSD. The child first presented at the age of 13.5 months with seizures associated with fever and pneumococcal bacteremia. Developmental delay had been recognized from early in life with no history of regression or exaggerated startle reflex. At 13 months, she showed central hypotonia and peripheral hypertonia with exaggerated deep tendon reflexes and bilateral ankle clonus. Funduscopy revealed bilateral cherry red spots of the macula. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9222766" 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>On the basis of study of 2 Ashkenazi patients and 2 French Canadian patients with a Hex-A cDNA probe, <a href="#48" class="mim-tip-reference" title="Myerowitz, R., Hogikyan, N. D. <strong>Different mutations in Ashkenazi Jewish and non-Jewish French Canadians with Tay-Sachs disease.</strong> Science 232: 1646-1648, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3754980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3754980</a>] [<a href="https://doi.org/10.1126/science.3754980" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3754980">Myerowitz and Hogikyan (1986)</a> concluded that each of these populations has a different mutation. In the Ashkenazi mutation the HEXA gene appeared to be intact, whereas in the French Canadian mutation the gene had a 5-prime deletion of 5 to 8 kilobases. The disorders are clinically identical and the heterozygote frequency in each is the same. It had previously been suspected that the Ashkenazi gene was introduced into the French Canadian population by someone, presumably male, of Ashkenazi extraction (the 'Jewish fur trader hypothesis'). <a href="#33" class="mim-tip-reference" title="Keats, B. J. B., Elston, R. C., Andermann, E. <strong>Pedigree discriminant analysis of two French Canadian Tay-Sachs families.</strong> Genet. Epidemiol. 4: 77-85, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2953646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2953646</a>] [<a href="https://doi.org/10.1002/gepi.1370040203" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2953646">Keats et al. (1987)</a> suspected that the mutation in French Canadians may be different from that in Ashkenazi Jews because the ratio HEXA/(HEXA + HEXB) was not a satisfactory statistic for carrier status in the French Canadian population whereas it is in Ashkenazi Jews. <a href="#49" class="mim-tip-reference" title="Myerowitz, R., Hogikyan, N. D. <strong>A deletion involving Alu sequences in the beta-hexosaminidase alpha-chain gene of French Canadians with Tay-Sachs disease.</strong> J. Biol. Chem. 262: 15396-15399, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2824459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2824459</a>]" pmid="2824459">Myerowitz and Hogikyan (1987)</a> showed that the deletion in the French Canadian form of Tay-Sachs disease (<a href="/entry/272800">272800</a>) is 7.6 kb long, includes part of intron 1 and all of exon 1, and extends 2,000 bp upstream past the putative promoter region of the alpha-chain gene. Sequence analysis of the deletion junction in the mutant gene and corresponding regions of the normal gene demonstrated the presence of similarly oriented Alu sequences at the 5-prime and 3-prime deletion boundaries. <a href="#49" class="mim-tip-reference" title="Myerowitz, R., Hogikyan, N. D. <strong>A deletion involving Alu sequences in the beta-hexosaminidase alpha-chain gene of French Canadians with Tay-Sachs disease.</strong> J. Biol. Chem. 262: 15396-15399, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2824459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2824459</a>]" pmid="2824459">Myerowitz and Hogikyan (1987)</a> interpreted this as indicating that the deletion had arisen during homologous recombination and unequal crossing-over between Alu sequences. <a href="#28" class="mim-tip-reference" title="Hechtman, P., Kaplan, F., Bayleran, J., Boulay, B., Andermann, E., de Braekeleer, M., Melancon, S., Lambert, M., Potier, M., Gagne, R., Kolodny, E., Clow, C., Capua, A., Prevost, C., Scriver, C. <strong>More than one mutant allele causes infantile Tay-Sachs disease in French-Canadians.</strong> Am. J. Hum. Genet. 47: 815-822, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2220821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2220821</a>]" pmid="2220821">Hechtman et al. (1990)</a> found the 7.6-kb deletion mutation at the 5-prime end of the HEXA gene in 18 of 22 independently segregating mutant chromosomes from patients of French Canadian origin. One chromosome carried the 4-nucleotide insertion in exon 11 (<a href="#0001">606869.0001</a>). None of the chromosomes carried the 5-prime splice site mutation in intron 12 found in Ashkenazi Jews (<a href="#0002">606869.0002</a>). One chromosome carried a 'novel,' but not yet characterized type of B1 mutation. The remaining 3 patients carried TSD alleles different from all of the above-mentioned ones. In French Canadians, the 5-prime deletion clustered in persons originating in southeastern Quebec (Gaspe) and adjacent counties of northern New Brunswick. <a href="#14" class="mim-tip-reference" title="De Braekeleer, M., Hechtman, P., Andermann, E., Kaplan, F. <strong>The French Canadian Tay-Sachs disease deletion mutation: identification of probable founders.</strong> Hum. Genet. 89: 83-87, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1577470/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1577470</a>] [<a href="https://doi.org/10.1007/BF00207048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1577470">De Braekeleer et al. (1992)</a> traced the ancestry of the persons carrying the 'French Canadian deletion' to an average depth of 12 generations, identifying 60 ancestors and 80 European founders common to all of them. The ancestral origins of the European founders showed a significantly greater number of individuals born in the French provinces of Normandy and Perche than expected based on information regarding the origins of the 8,500 immigrants who settled New France during the French regime. The failure to find the French Canadian deletion among TSD probands in France suggests that the mutation occurred on Canadian soil. If this is true, the search for the ancestral couple was narrowed to 7 possibilities. These included a man born in 1680 and his wife born in 1683, who had 11 offspring, at least 5 of whom must have been heterozygous for the deletion because they had carrier descendants through a total of 14 descendant lines. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2953646+2220821+3754980+2824459+1577470" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 TAY-SACHS DISEASE</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> rs121907952 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907952;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/rs121907952?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=rs121907952" 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=rs121907952" 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=RCV000004096 OR RCV002512734 OR RCV003480020" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004096, RCV002512734, RCV003480020" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004096...</a>
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<p>In a non-Jewish case of Tay-Sachs disease (<a href="/entry/272800">272800</a>), <a href="#74" class="mim-tip-reference" title="Proia, R. L., Neufeld, E. F. <strong>Synthesis of beta-hexosaminidase in cell-free translation and in intact fibroblasts: an insoluble precursor alpha chain in a rare form of Tay-Sachs disease.</strong> Proc. Nat. Acad. Sci. 79: 6360-6364, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6959123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6959123</a>] [<a href="https://doi.org/10.1073/pnas.79.20.6360" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6959123">Proia and Neufeld (1982)</a> found a normal amount of alpha chain of beta-hexosaminidase synthesized in a cell-free translation system using RNA from cultured fibroblasts of the patient. (RNA from fibroblasts of 4 other patients, 3 Jewish and 1 non-Jewish, did not direct the translation of immunoprecipitable alpha chain. In the same system, RNA from fibroblasts of 2 patients with Sandhoff disease did not direct translation of immunoprecipitable beta chain.) Intact fibroblasts from the atypical patient likewise synthesized the alpha chain as shown by labeling with (3H)leucine; however, strong detergent was required for extraction. The alpha chain could be labeled with (3H)mannose but not with (32P)phosphate; it was neither secreted nor accumulated in the proteolytically processed form, and it disappeared within a day of synthesis. The authors suggested that a plausible but not unique explanation is that the insoluble alpha chain is not transported from the endoplasmic reticulum (the site of glycosylation) to the Golgi apparatus (the site of phosphorylation) nor to the further destinations--lysosomes and the exterior of the cell. <a href="#56" class="mim-tip-reference" title="Nakano, T., Muscillo, M., Ohno, K., Hoffman, A. J., Suzuki, K. <strong>A point mutation in the coding sequence of the beta-hexosaminidase alpha gene results in defective processing of the enzyme protein in an unusual GM2-gangliosidosis variant.</strong> J. Neurochem. 51: 984-987, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2970528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2970528</a>] [<a href="https://doi.org/10.1111/j.1471-4159.1988.tb01836.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2970528">Nakano et al. (1988)</a> isolated cDNA clones from cultured fibroblasts of this patient, who was Italian. Sequence analysis showed a single nucleotide substitution, from G to A, at nucleotide 1444, which resulted in a change from glutamic acid to lysine at amino acid 482. The change from the strongly negative to strongly positive charge at amino acid 482 was thought to be responsible for the defective processing of the enzyme in this patient. <a href="#2" class="mim-tip-reference" title="Akalin, N., Shi, H.-P., Vavougios, G., Hechtman, P., Lo, W., Scriver, C. R., Mahuran, D., Kaplan, F. <strong>Novel Tay-Sachs disease mutations from China.</strong> Hum. Mutat. 1: 40-46, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301190</a>] [<a href="https://doi.org/10.1002/humu.1380010107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1301190">Akalin et al. (1992)</a> demonstrated the same mutation in a case of classic TSD in a Chinese patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2970528+6959123+1301190" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using structural modeling, <a href="#63" class="mim-tip-reference" title="Ohno, K., Saito, S., Sugawara, K., Sakuraba, H. <strong>Structural consequences of amino acid substitutions causing Tay-Sachs disease.</strong> Molec. Genet. Metab. 94: 462-468, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18490185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18490185</a>] [<a href="https://doi.org/10.1016/j.ymgme.2008.04.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18490185">Ohno et al. (2008)</a> found that the glu482 residue is buried within the folded enzyme and the E482K mutation affects atoms throughout the whole enzyme, which correlated with a more severe phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18490185" 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">rs797044433 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797044433;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=rs797044433" 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=rs797044433" 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=RCV000004098" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004098" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004098</a>
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<p>In an Italian patient with clinically classic Tay-Sachs disease (<a href="/entry/272800">272800</a>), <a href="#98" class="mim-tip-reference" title="Zokaeem, G., Bayleran, J., Kaplan, P., Hechtman, P., Neufeld, E. F. <strong>A shortened beta-hexosaminidase alpha-chain in an Italian patient with infantile Tay-Sachs disease.</strong> Am. J. Hum. Genet. 40: 537-547, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2954459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2954459</a>]" pmid="2954459">Zokaeem et al. (1987)</a> described a defect in the alpha chain that differed from all those previously described. Fibroblasts synthesized a precursor alpha chain that was smaller than its normal counterpart. Fibroblasts from the patient's parents, who were consanguineous, produced both normal and mutant alpha chains. The mutant alpha chain did not undergo the posttranslational modifications characteristic of its normal counterpart, i.e., synthesis of the mannosephosphate recognition marker, association with the beta-chain to give Hex-A, and proteolytic conversion to the mature form. Furthermore, the mutant alpha chain was not secreted. <a href="#40" class="mim-tip-reference" title="Lau, M. M. H., Neufeld, E. F. <strong>A frameshift mutation in a patient with Tay-Sachs disease causes premature termination and defective intracellular transport of the alpha-subunit of beta-hexosaminidase.</strong> J. Biol. Chem. 264: 21376-21380, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2531748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2531748</a>]" pmid="2531748">Lau and Neufeld (1989)</a> identified the mutation as a deletion of cytosine at position 1510 of the coding sequence. The frameshift mutation, which was found to be present on both alleles, caused premature termination 4 codons downstream, and the loss of a very hydrophilic stretch of 22 amino acids. Expression of alpha-subunit cDNA with the cytosine deletion in COS-1 cells reproduced the phenotype of the Italian patient referred to as WG1051, i.e., a truncated alpha subunit was retained. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2954459+2531748" 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> rs28941770 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28941770;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/rs28941770?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=rs28941770" 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=rs28941770" 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=RCV000004100 OR RCV000004101 OR RCV000396083 OR RCV000409508 OR RCV001255389 OR RCV002345228 OR RCV003964792" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004100, RCV000004101, RCV000396083, RCV000409508, RCV001255389, RCV002345228, RCV003964792" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004100...</a>
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<p><a href="#66" class="mim-tip-reference" title="Ohno, K., Suzuki, K. <strong>Mutation in GM2-gangliosidosis B1 variant.</strong> J. Neurochem. 50: 316-318, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2961848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2961848</a>] [<a href="https://doi.org/10.1111/j.1471-4159.1988.tb13266.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2961848">Ohno and Suzuki (1988)</a> defined the mutation in the B1 variant form of Tay-Sachs disease (<a href="/entry/272800">272800</a>) in a patient of Puerto Rican extraction residing in New York City. The variant was characterized by normal catalytic activity on certain artificial substrates but defective catalytic activity against natural substrates. The so-called DN allele shows a single-base transition at nucleotide 533 from the normal G-to-A within exon 5, resulting in a change from arginine to histidine at amino acid 178. The position of the mutation is about 90 amino acids from the N-terminus of the mature, processed enzyme. Computer analysis predicted substantial alteration in the secondary structure of the enzyme protein. Using two 21-mer oligonucleotide probes with the normal and mutant sequences, <a href="#84" class="mim-tip-reference" title="Tanaka, A., Ohno, K., Suzuki, K. <strong>GM2-gangliosidosis B1 variant: a wide geographic and ethnic distribution of the specific beta-hexosaminidase alpha chain mutation originally identified in a Puerto Rican patient.</strong> Biochem. Biophys. Res. Commun. 156: 1015-1019, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2973311/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2973311</a>] [<a href="https://doi.org/10.1016/s0006-291x(88)80945-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2973311">Tanaka et al. (1988)</a> found that 4 of 5 other patients of various ethnic origin (Spanish, Italian, Czechoslovakian, French, and English/Italian/Hungarian) showed the same defect. The only case that was completely negative for the DN mutation was the Czechoslovakian patient. These cell lines were tested for the splicing defect at the 5-prime donor site of intron 12 found among Ashkenazi Jewish patients, with negative results in all. Four of the patients, including the original Puerto Rican patient, gave positive signals for both the normal and the mutant probes. Thus these patients were clearly compound heterozygotes. The patient of Spanish origin (residing in Germany) was positive only for the mutant sequence. The parents of this patient came from the same village in Spain, although there was no clear record of consanguinity. The repeated occurrence of this rare mutation in unrelated populations indicates that the biochemical abnormality that defines B1 can be produced in only a limited number of ways. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2961848+2973311" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Goebel, H. H., Stolte, G., Kustermann-Kuhn, B., Harzer, K. <strong>B(1) variant of G(M2) gangliosidosis in a 12-year-old patient.</strong> Pediat. Res. 25: 89-93, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2521932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2521932</a>] [<a href="https://doi.org/10.1203/00006450-198901000-00019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2521932">Goebel et al. (1989)</a> described the B1 variant in a 12-year-old girl who suffered from a progressive nerve degenerative disorder marked by ataxia, extrapyramidal symptoms, and convulsions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2521932" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>According to the findings of <a href="#16" class="mim-tip-reference" title="dos Santos, M. R., Tanaka, A., sa Miranda, M. C., Ribeiro, M. G., Maia, M., Suzuki, K. <strong>G(M2)-gangliosidosis B1 variant: analysis of beta-hexosaminidase alpha gene mutations in 11 patients from a defined region in Portugal.</strong> Am. J. Hum. Genet. 49: 886-890, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1832817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1832817</a>]" pmid="1832817">dos Santos et al. (1991)</a>, the B1 variant occurs at an exceptionally high frequency in the northern part of Portugal. In most of the patients there, the disease manifests itself as a juvenile form. In 10 of 11 such patients, <a href="#16" class="mim-tip-reference" title="dos Santos, M. R., Tanaka, A., sa Miranda, M. C., Ribeiro, M. G., Maia, M., Suzuki, K. <strong>G(M2)-gangliosidosis B1 variant: analysis of beta-hexosaminidase alpha gene mutations in 11 patients from a defined region in Portugal.</strong> Am. J. Hum. Genet. 49: 886-890, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1832817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1832817</a>]" pmid="1832817">dos Santos et al. (1991)</a> found homozygosity for the DN allele; in the other patient, whose clinical profile more closely resembled the late infantile phenotype, compound heterozygosity for the DN allele and another, as yet unidentified abnormal allele was found. <a href="#95" class="mim-tip-reference" title="Whitley, C. B., Anderson, R. A., McIvor, R. S. <strong>Heterozygosity for the 'DN allele' (G533-to-A) of the beta-hexosaminidase alpha subunit gene identified by direct DNA sequencing in a family with the B1 variant of G(M2)-gangliosidosis.</strong> Neuropediatrics 23: 96-101, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1318511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1318511</a>] [<a href="https://doi.org/10.1055/s-2008-1071320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1318511">Whitley et al. (1992)</a> detected the arg178-to-his mutation by PCR amplification and direct DNA sequencing of exon 5 of the HEXA gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1832817+1318511" 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>.0007 TAY-SACHS DISEASE, B1 VARIANT</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> rs121907953 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907953;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/rs121907953?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=rs121907953" 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=rs121907953" 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=RCV000004102 OR RCV000416435" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004102, RCV000416435" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004102...</a>
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<p>See <a href="#83" class="mim-tip-reference" title="Tanaka, A., Ohno, K., Sandhoff, K., Maire, I., Kolodny, E. H., Brown, A., Suzuki, K. <strong>GM2-gangliosidosis B1 variant: analysis of beta-hexosaminidase alpha gene abnormalities in seven patients.</strong> Am. J. Hum. Genet. 46: 329-339, 1990. Note: Erratum: Am. J. Hum. Genet. 48: 176 only, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2137287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2137287</a>]" pmid="2137287">Tanaka et al. (1990)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2137287" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 GM2-GANGLIOSIDOSIS, ADULT</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> rs121907954 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907954;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/rs121907954?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=rs121907954" 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=rs121907954" 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=RCV000004104 OR RCV000168285 OR RCV000434025 OR RCV001810397 OR RCV002408450 OR RCV003924800" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004104, RCV000168285, RCV000434025, RCV001810397, RCV002408450, RCV003924800" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004104...</a>
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<p>In 8 Ashkenazi adult GM2-gangliosidosis (<a href="/entry/272800">272800</a>) patients from 5 different families, <a href="#59" class="mim-tip-reference" title="Navon, R., Proia, R. L. <strong>The mutations in Ashkenazi Jews with adult G(M2) gangliosidosis, the adult form of Tay-Sachs disease.</strong> Science 243: 1471-1474, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2522679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2522679</a>] [<a href="https://doi.org/10.1126/science.2522679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2522679">Navon and Proia (1989)</a> found a gly269-to-ser (G269S) substitution. This amino acid substitution was shown to depress drastically the catalytic activity of the alpha chain after expression in COS-1 cells. All the patients proved to be compound heterozygotes of the allele with the gly-to-ser change and 1 of the 2 Ashkenazi infantile Tay-Sachs alleles. <a href="#67" class="mim-tip-reference" title="Paw, B. H., Kaback, M. M., Neufeld, E. F. <strong>Molecular basis of adult-onset and chronic G(M2) gangliosidoses in patients of Ashkenazi Jewish origin: substitution of serine for glycine at position 269 of the alpha-subunit of beta-hexosaminidase.</strong> Proc. Nat. Acad. Sci. 86: 2413-2417, 1989. Note: Erratum: Proc. Nat. Acad. Sci. 86: 5625 only, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2522660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2522660</a>] [<a href="https://doi.org/10.1073/pnas.86.7.2413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2522660">Paw et al. (1989)</a> described the molecular basis of adult onset and chronic GM2 gangliosidoses in Ashkenazi Jewish patients known to have a defective association between the alpha and beta subunits of hexosaminidase. They identified a G-to-A substitution at the 3-prime end of exon 7, resulting in the substitution of serine for glycine at position 269 of the alpha subunit. One patient with the adult-onset disorder had inherited this gly-to-ser mutation at position 269 from his father and a null allele from his mother. The same combination of alleles was found in fetal fibroblasts from an association-defective phenotype and in cells from 5 patients with chronic Gm2-gangliosidoses. <a href="#58" class="mim-tip-reference" title="Navon, R., Kolodny, E. H., Mitsumoto, H., Thomas, G. H., Proia, R. L. <strong>Ashkenazi-Jewish and non-Jewish adult G(M2) gangliosidosis patients share a common genetic defect.</strong> Am. J. Hum. Genet. 46: 817-821, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2278539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2278539</a>]" pmid="2278539">Navon et al. (1990)</a> found the same gly269-to-ser mutation in 6 adult GM2-gangliosidosis patients from 4 different non-Jewish families. Three of these patients, 2 of whom were brothers, showed a hybridization pattern consistent with homozygosity for the mutation. The others were compound heterozygotes of the gly269-to-ser mutation together with an unidentified alpha-subunit mutation. <a href="#58" class="mim-tip-reference" title="Navon, R., Kolodny, E. H., Mitsumoto, H., Thomas, G. H., Proia, R. L. <strong>Ashkenazi-Jewish and non-Jewish adult G(M2) gangliosidosis patients share a common genetic defect.</strong> Am. J. Hum. Genet. 46: 817-821, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2278539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2278539</a>]" pmid="2278539">Navon et al. (1990)</a> suggested that the gly269-to-ser mutation in the Ashkenazi and non-Jewish patients might have had a common origin since the ancestry of the Ashkenazim could be traced to eastern Europe. <a href="#31" class="mim-tip-reference" title="Kappler, J., Gieselmann, V., Propping, P. <strong>Hexosaminidase--pseudodeficiency?. (Letter)</strong> Am. J. Hum. Genet. 47: 880-881, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2145759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2145759</a>]" pmid="2145759">Kappler et al. (1990)</a> suggested caution in concluding that homozygosity for the gly269-to-ser allele as reported by <a href="#58" class="mim-tip-reference" title="Navon, R., Kolodny, E. H., Mitsumoto, H., Thomas, G. H., Proia, R. L. <strong>Ashkenazi-Jewish and non-Jewish adult G(M2) gangliosidosis patients share a common genetic defect.</strong> Am. J. Hum. Genet. 46: 817-821, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2278539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2278539</a>]" pmid="2278539">Navon et al. (1990)</a> is responsible for adult GM2-gangliosidosis. They suggested that it might be a pseudodeficiency with coincidental association with neurologic disease. <a href="#73" class="mim-tip-reference" title="Proia, R. L., Kolodny, E. H., Navon, R. <strong>Reply to Kappler et al. (Letter)</strong> Am. J. Hum. Genet. 47: 881-882, 1990."None>Proia et al. (1990)</a> provided information suggesting that the mutation is indeed causative. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2522660+2145759+2522679+2278539" 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>Because hexosaminidase A is heterodimeric, analysis of alpha-chain mutations is not straightforward. <a href="#10" class="mim-tip-reference" title="Brown, C. A., Mahuran, D. J. <strong>Beta-hexosaminidase isozymes from cells cotransfected with alpha and beta cDNA constructs: analysis of the alpha-subunit missense mutation associated with the adult form of Tay-Sachs disease.</strong> Am. J. Hum. Genet. 53: 497-508, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8328462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8328462</a>]" pmid="8328462">Brown and Mahuran (1993)</a> used the techniques of in vitro mutagenesis and transient expression in COS cells to demonstrate that the G269S mutation does not directly affect alpha-dimerization but exerts an indirect effect on the dimer through destabilizing the folded alpha subunit at physiologic temperatures. Two other alpha mutations associated with more severe phenotypes, gly250-to-asp (<a href="#0013">606869.0013</a>) and glu482-to-lys (<a href="#0004">606869.0004</a>), appeared to inhibit the initial folding of the subunit. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8328462" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using structural modeling, <a href="#63" class="mim-tip-reference" title="Ohno, K., Saito, S., Sugawara, K., Sakuraba, H. <strong>Structural consequences of amino acid substitutions causing Tay-Sachs disease.</strong> Molec. Genet. Metab. 94: 462-468, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18490185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18490185</a>] [<a href="https://doi.org/10.1016/j.ymgme.2008.04.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18490185">Ohno et al. (2008)</a> demonstrated that the gly269 residue is located on the surface of the folded enzyme protein and the G269S mutation only influences a small number of atoms, which correlated with a less severe phenotype and residual enzyme activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18490185" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 GM2-GANGLIOSIDOSIS, JUVENILE</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> rs121907955 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907955;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/rs121907955?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=rs121907955" 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=rs121907955" 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=RCV000004099 OR RCV000409695 OR RCV001800288" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004099, RCV000409695, RCV001800288" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004099...</a>
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<p>In a patient with juvenile-onset GM2-gangliosidosis (<a href="/entry/272800">272800</a>), of Assyrian origin and with first-cousin parents, <a href="#68" class="mim-tip-reference" title="Paw, B. H., Moskowitz, S. M., Uhrhammer, N., Wright, N., Kaback, M. M., Neufeld, E. F. <strong>Juvenile G(M2) gangliosidosis caused by substitution of histidine for arginine at position 499 or 504 of the alpha-subunit of beta-hexosaminidase.</strong> J. Biol. Chem. 265: 9452-9457, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2140574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2140574</a>]" pmid="2140574">Paw et al. (1990)</a> identified a G-to-A transition at nucleotide 1511 resulting in substitution of histidine for arginine at position 504 in the HEXA molecule. Cultured fibroblasts from the patient synthesized an alpha subunit that could acquire mannose 6-phosphate and be secreted, but which failed to associate with the beta-subunit to form the enzymatically active heterodimer. The patient had progressive ataxia, spastic paraplegia, dysarthria, and cherry-red macula at the time she was first seen at age 10 years. The patient was homozygous for the arg504-to-his mutation, which occurred in a CpG dinucleotide. The same mutation was found in a patient with juvenile-onset GM2-gangliosidosis of Armenian extraction. The mutation again was present in homozygous state, consistent with the fact that his parents were first cousins. The same mutation was found by <a href="#9" class="mim-tip-reference" title="Boustany, R.-M. N., Tanaka, A., Nishimoto, J., Suzuki, K. <strong>Genetic cause of a juvenile form of Tay-Sachs disease in a Lebanese child.</strong> Ann. Neurol. 29: 104-107, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1996872/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1996872</a>] [<a href="https://doi.org/10.1002/ana.410290120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1996872">Boustany et al. (1991)</a> in heterozygous state in a Lebanese patient with the juvenile form of Tay-Sachs disease. The clinical features were progressive spasticity, ataxia, and cognitive decline. The patient came from a Maronite community. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1996872+2140574" 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 GM2-GANGLIOSIDOSIS, JUVENILE</strong>
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HEXA, ARG499HIS (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907956;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs121907956</a>)
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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> rs121907956 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907956;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/rs121907956?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=rs121907956" 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=rs121907956" 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=RCV000004105 OR RCV000210735 OR RCV000338961 OR RCV000520531" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004105, RCV000210735, RCV000338961, RCV000520531" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004105...</a>
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<p>In a patient of mixed Jewish and Scottish/Irish ancestry who had progressively severe neurologic deterioration beginning at age 3 to 5 years and progressing to death at age 26, <a href="#68" class="mim-tip-reference" title="Paw, B. H., Moskowitz, S. M., Uhrhammer, N., Wright, N., Kaback, M. M., Neufeld, E. F. <strong>Juvenile G(M2) gangliosidosis caused by substitution of histidine for arginine at position 499 or 504 of the alpha-subunit of beta-hexosaminidase.</strong> J. Biol. Chem. 265: 9452-9457, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2140574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2140574</a>]" pmid="2140574">Paw et al. (1990)</a> found a G-to-A transition at nucleotide 1496 resulting in substitution of histidine for arginine at position 499 (R499H) of the alpha subunit. The mutation was present in compound heterozygosity with a common infantile Tay-Sachs allele. This patient had a similarly affected brother. In another patient with juvenile GM2-gangliosidosis (<a href="/entry/272800">272800</a>), neither this nor the R504H mutation was found, indicating further heterogeneity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2140574" 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="#82" class="mim-tip-reference" title="Tanaka, A., Hoang, L. T. N., Nishi, Y., Maniwa, S., Oka, M., Yamano, T. <strong>Different attenuated phenotypes of GM2 gangliosidosis variant B in Japanese patients with HEXA mutations at codon 499, and five novel mutations responsible for infantile acute form.</strong> J. Hum. Genet. 48: 571-574, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14566483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14566483</a>] [<a href="https://doi.org/10.1007/s10038-003-0080-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14566483">Tanaka et al. (2003)</a> found the R499H missense mutation in 1 allele of a Japanese patient with the late infantile form of GM2-gangliosidosis and the R499C mutation (<a href="#0028">606869.0028</a>) on 1 allele of another Japanese patient with the juvenile form. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14566483" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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<strong>.0011 TAY-SACHS DISEASE</strong>
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HEXA, ARG170GLN
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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> rs121907957 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907957;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/rs121907957?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=rs121907957" 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=rs121907957" 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=RCV000004106 OR RCV000336253" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004106, RCV000336253" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004106...</a>
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<p>In compound heterozygous state in a Japanese infant, <a href="#57" class="mim-tip-reference" title="Nakano, T., Nanba, E., Tanaka, A., Ohno, K., Suzuki, Y., Suzuki, K. <strong>A new point mutation within exon 5 of beta-hexosaminidase alpha gene in a Japanese infant with Tay-Sachs disease.</strong> Ann. Neurol. 27: 465-473, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2141777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2141777</a>] [<a href="https://doi.org/10.1002/ana.410270503" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2141777">Nakano et al. (1990)</a> found substitution of glutamine for arginine-170, resulting from a G-to-A change at nucleotide 509. Expression of the mutant enzyme protein in the COS-1 cell system indicated that it is catalytically inactive and also unstable. The exact abnormality in the other allele could not be identified, but previously identified mutations of the HEXA gene were excluded. The arg170-to-gln mutation due to a G-to-A transition at a CpG site was also found as one of 3 main mutations in the Moroccan Jewish population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2141777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0012" class="mim-anchor"></a>
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<strong>.0012 TAY-SACHS DISEASE</strong>
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HEXA, TRP420CYS
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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> rs121907958 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907958;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/rs121907958?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=rs121907958" 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=rs121907958" 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=RCV000004107 OR RCV005054135" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004107, RCV005054135" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004107...</a>
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<p>In a Catholic family with parents of Irish and German descent, <a href="#85" class="mim-tip-reference" title="Tanaka, A., Punnett, H. H., Suzuki, K. <strong>A new point mutation in the beta-hexosaminidase alpha subunit gene responsible for infantile Tay-Sachs disease in a non-Jewish Caucasian patient (a Kpn mutant).</strong> Am. J. Hum. Genet. 47: 568-574, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2144098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2144098</a>]" pmid="2144098">Tanaka et al. (1990)</a> demonstrated that an infant with clinically typical infantile Tay-Sachs disease (<a href="/entry/272800">272800</a>) had a single nucleotide transversion in exon 11: 1260G-C; trp420-to-cys. Expression in the COS-1 cell system confirmed that the mutant gene did not produce functional enzyme protein. The mutation could be identified rapidly and reliably because it abolished one of the 2 KpnI sites in the coding sequence. The patient was a compound heterozygote; the nature of the abnormality in the other allele had not been identified. The 'Kpn mutation' was inherited from the maternal side of the family, which was of German descent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2144098" 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 TAY-SACHS DISEASE, JUVENILE</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> rs121907959 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907959;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/rs121907959?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=rs121907959" 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=rs121907959" 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=RCV000004108 OR RCV002226437" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004108, RCV002226437" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004108...</a>
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<p>In a Lebanese proband with juvenile-onset Tay-Sachs disease (<a href="/entry/272800">272800</a>), <a href="#93" class="mim-tip-reference" title="Trop, I., Kaplan, F., Hechtman, P. <strong>Juvenile-onset Tay-Sachs disease in a Lebanese proband is caused by gly(250)-to-asp substitution in the alpha subunit of hexosaminidase A. (Abstract)</strong> Am. J. Hum. Genet. 47 (suppl.): A168, 1990."None>Trop et al. (1990)</a> found, by direct sequencing of PCR products, a G-to-A transition at nucleotide 749 in exon 7. The mutation caused a glycine to aspartic acid change at amino acid 250. See <a href="#92" class="mim-tip-reference" title="Trop, I., Kaplan, F., Brown, C., Mahuran, D., Hechtman, P. <strong>A glycine250-to-asp substitution in the alpha-subunit of hexosaminidase A causes juvenile-onset Tay-Sachs disease in a Lebanese-Canadian family.</strong> Hum. Mutat. 1: 35-39, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301189</a>] [<a href="https://doi.org/10.1002/humu.1380010106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1301189">Trop et al. (1992)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1301189" 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 TAY-SACHS DISEASE</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">rs121907960 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907960;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=rs121907960" 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=rs121907960" 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=RCV000169148 OR RCV000622988 OR RCV001545560" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000169148, RCV000622988, RCV001545560" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000169148...</a>
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<p>In a Moroccan Jewish Tay-Sachs (<a href="/entry/272800">272800</a>) patient, <a href="#60" class="mim-tip-reference" title="Navon, R., Proia, R. L. <strong>Tay-Sachs disease in Moroccan Jews: deletion of a phenylalanine in the alpha-subunit of beta-hexosaminidase.</strong> Am. J. Hum. Genet. 48: 412-419, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1825014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1825014</a>]" pmid="1825014">Navon and Proia (1991)</a> found an in-frame deletion of 1 of the 2 adjacent phenylalanine codons present at positions 304 and 305 in the alpha subunit. The Moroccan patient was found also to carry a different, as yet unidentified, mutation. Among obligate carriers from 6 unrelated Moroccan Jewish families, 3 instances of the same deletion were found. See <a href="#18" class="mim-tip-reference" title="Drucker, L., Proia, R. L., Navon, R. <strong>Identification and rapid detection of three Tay-Sachs mutations in the Moroccan Jewish population.</strong> Am. J. Hum. Genet. 51: 371-377, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1322637/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1322637</a>]" pmid="1322637">Drucker et al. (1992)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1825014+1322637" 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 GM2-GANGLIOSIDOSIS, CHRONIC</strong>
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HEXA, ARG504CYS
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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> rs28942071 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28942071;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/rs28942071?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=rs28942071" 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=rs28942071" 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=RCV000004112 OR RCV000169084 OR RCV001000970 OR RCV001508769" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004112, RCV000169084, RCV001000970, RCV001508769" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004112...</a>
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<p>A female patient in a family of German origin had slow but progressive spinocerebellar degeneration from the age of 2.5 years (<a href="#76" class="mim-tip-reference" title="Raghavan, S. S., Krusell, A., Krusell, J., Lyerla, T. A., Kolodny, E. H. <strong>G(M2)-ganglioside metabolism in hexosaminidase A deficiency states: determination in situ using labeled G(M2) added to fibroblast cultures.</strong> Am. J. Hum. Genet. 37: 1071-1082, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2934978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2934978</a>]" pmid="2934978">Raghavan et al., 1985</a>). At the age of 26 years, she was in leg braces and had great difficulty rising from a sitting position. Her 25-year-old sister was only mildly affected; she had been clinically normal into her late teens but later developed signs of cerebellar dysfunction. <a href="#69" class="mim-tip-reference" title="Paw, B. H., Wood, L. C., Neufeld, E. F. <strong>A third mutation at the CpG dinucleotide of codon 504 and a silent mutation at codon 506 of the HEX A gene.</strong> Am. J. Hum. Genet. 48: 1139-1146, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1827944/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1827944</a>]" pmid="1827944">Paw et al. (1991)</a> found a substitution of cysteine for arginine at codon 504. The family was unique in another respect, namely, that the normal allele of the mother and of an arg504-to-cys heterozygous sib had a silent mutation, a G-to-A transition in the wobble position of the glutamic acid codon at position 506. A search for this mutation was prompted by the fact that 2 other mutations had been identified in this codon: a G-to-A transition resulting in an arg504-to-his substitution (<a href="#0009">606869.0009</a>) in a patient with juvenile GM2-gangliosidosis (<a href="/entry/272800">272800</a>) and a C deletion resulting in a premature termination of the alpha subunit (<a href="#0005">606869.0005</a>) in a patient with Tay-Sachs disease. Using chemical mismatch cleavage of PCR-amplified cDNA fragments, <a href="#5" class="mim-tip-reference" title="Akli, S., Chelly, J., Lacorte, J., Poenaru, L., Kahn, A. <strong>Seven novel Tay-Sachs mutations detected by chemical mismatch cleavage of PCR-amplified cDNA fragments.</strong> Genomics 11: 124-134, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1837283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1837283</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90109-r" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1837283">Akli et al. (1991)</a> demonstrated the same arg504-to-cys missense mutation in exon 13 in 2 patients. Change from CGC to TGC was responsible. One patient was a homozygote from Algeria; the other was a compound heterozygote from France (the other allele was an intron 2 splice mutation (<a href="#0026">606869.0026</a>).) Both patients had the classic infantile form of Tay-Sachs disease. It is unclear why the phenotype of the patients with this mutation was so different. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2934978+1837283+1827944" 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 TAY-SACHS DISEASE</strong>
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HEXA, IVS4, G-T, -1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs764343937 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs764343937;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/rs764343937?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=rs764343937" 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=rs764343937" 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=RCV000586741 OR RCV004719896" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000586741, RCV004719896" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000586741...</a>
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<p>In 2 unrelated American black infants with both biochemical and clinical features of classic infantile Tay-Sachs disease (<a href="/entry/272800">272800</a>), <a href="#45" class="mim-tip-reference" title="Mules, E. H., Dowling, C. E., Petersen, M. B., Kazazian, H. H., Jr., Thomas, G. H. <strong>A novel mutation in the invariant AG of the acceptor splice site of intron 4 of the beta-hexosaminidase alpha-subunit gene in two unrelated American black G(M2)-gangliosidosis (Tay-Sachs disease) patients.</strong> Am. J. Hum. Genet. 48: 1181-1185, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1827945/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1827945</a>]" pmid="1827945">Mules et al. (1991)</a> found a G-to-T transversion in the AG acceptor splice site preceding exon 5 of the HEXA gene. One patient was homozygous for the mutation; a second was a compound heterozygote. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1827945" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0017 TAY-SACHS DISEASE</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">rs121907961 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907961;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=rs121907961" 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=rs121907961" 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=RCV000004114" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004114" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004114</a>
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<p>Using chemical mismatch cleavage of PCR-amplified cDNA fragments, <a href="#5" class="mim-tip-reference" title="Akli, S., Chelly, J., Lacorte, J., Poenaru, L., Kahn, A. <strong>Seven novel Tay-Sachs mutations detected by chemical mismatch cleavage of PCR-amplified cDNA fragments.</strong> Genomics 11: 124-134, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1837283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1837283</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90109-r" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1837283">Akli et al. (1991)</a> demonstrated a missense mutation that altered the codon for serine-210 to phenylalanine in exon 6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1837283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0019 TAY-SACHS DISEASE</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> rs121907962 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907962;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/rs121907962?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=rs121907962" 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=rs121907962" 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=RCV000004110 OR RCV000255817" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004110, RCV000255817" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004110...</a>
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<p>Using chemical mismatch cleavage of PCR-amplified cDNA fragments, <a href="#5" class="mim-tip-reference" title="Akli, S., Chelly, J., Lacorte, J., Poenaru, L., Kahn, A. <strong>Seven novel Tay-Sachs mutations detected by chemical mismatch cleavage of PCR-amplified cDNA fragments.</strong> Genomics 11: 124-134, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1837283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1837283</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90109-r" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1837283">Akli et al. (1991)</a> detected a nonsense mutation in exon 3 that converted arginine-137 to stop. In a study of the nature of mutations in non-Jewish patients or carriers of some form of GM2-gangliosidosis (<a href="/entry/272800">272800</a>), <a href="#46" class="mim-tip-reference" title="Mules, E. H., Hayflick, S., Miller, C. S., Reynolds, L. W., Thomas, G. H. <strong>Six novel deleterious and three neutral mutations in the gene encoding the alpha-subunit of hexosaminidase A in non-Jewish individuals.</strong> Am. J. Hum. Genet. 50: 834-841, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1532289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1532289</a>]" pmid="1532289">Mules et al. (1992)</a> found a C-to-T transition at nucleotide 409 in exon 3 converting arginine-137 to a stop codon. The family was of possible Irish extraction. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1532289+1837283" 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>.0020 TAY-SACHS DISEASE</strong>
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HEXA, ARG393TER
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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> rs121907963 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907963;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/rs121907963?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=rs121907963" 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=rs121907963" 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=RCV000004111 OR RCV000522695" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004111, RCV000522695" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004111...</a>
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<p>Using chemical mismatch cleavage of PCR-amplified cDNA fragments, <a href="#5" class="mim-tip-reference" title="Akli, S., Chelly, J., Lacorte, J., Poenaru, L., Kahn, A. <strong>Seven novel Tay-Sachs mutations detected by chemical mismatch cleavage of PCR-amplified cDNA fragments.</strong> Genomics 11: 124-134, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1837283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1837283</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90109-r" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1837283">Akli et al. (1991)</a> detected a nonsense mutation in exon 11 that converted arginine-393 to stop. Both this and the arg137-to-ter mutation were associated with a marked decrease in the abundance of mRNA, probably because they resulted in mRNA instability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1837283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0021" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0021 TAY-SACHS DISEASE</strong>
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</h4>
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HEXA, 5-BP DEL, TCTCC, IVS9
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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> rs759219683 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs759219683;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/rs759219683?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=rs759219683" 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=rs759219683" 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=RCV000669592 OR RCV001584543" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000669592, RCV001584543" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000669592...</a>
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<p><a href="#89" class="mim-tip-reference" title="Triggs-Raine, B. L., Akerman, B. R., Clarke, J. T. R., Gravel, R. A. <strong>Sequence of DNA flanking the exons of the HEXA gene, and identification of mutations in Tay-Sachs disease.</strong> Am. J. Hum. Genet. 49: 1041-1054, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1833974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1833974</a>]" pmid="1833974">Triggs-Raine et al. (1991)</a> sequenced the portions of the introns flanking each of the 14 HEXA exons in order to specify oligonucleotide primers for the PCR-dependent amplification of each exon and splice junction sequence. Five novel mutations from Tay-Sachs disease (<a href="/entry/272800">272800</a>) patients were detected as well as 2 mutations that had previously been reported. The 5 novel mutations were a 5-bp deletion of TCTCC in IVS9; a 2-bp deletion of TG in exon 5; 78G-A, giving a stop codon in exon 1; 533G-T in exon 5, producing the third amino acid substitution detected at this site; and G to C at position 1 of IVS2, expected to produce abnormal splicing. The 2 previously reported mutations were 1496G-A in exon 13 (<a href="#0010">606869.0010</a>) and a 4-bp insertion in exon 11 (<a href="#0001">606869.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1833974" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0022" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0022 TAY-SACHS DISEASE</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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HEXA, 2-BP DEL, TG, EX5
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000004116" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004116" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004116</a>
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<p>See <a href="#0021">606869.0021</a> and <a href="#89" class="mim-tip-reference" title="Triggs-Raine, B. L., Akerman, B. R., Clarke, J. T. R., Gravel, R. A. <strong>Sequence of DNA flanking the exons of the HEXA gene, and identification of mutations in Tay-Sachs disease.</strong> Am. J. Hum. Genet. 49: 1041-1054, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1833974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1833974</a>]" pmid="1833974">Triggs-Raine et al. (1991)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1833974" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0023" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0023 TAY-SACHS DISEASE</strong>
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</h4>
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HEXA, TRP26TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121907964 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907964;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=rs121907964" 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=rs121907964" 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=RCV000004117" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004117" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004117</a>
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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><a href="#89" class="mim-tip-reference" title="Triggs-Raine, B. L., Akerman, B. R., Clarke, J. T. R., Gravel, R. A. <strong>Sequence of DNA flanking the exons of the HEXA gene, and identification of mutations in Tay-Sachs disease.</strong> Am. J. Hum. Genet. 49: 1041-1054, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1833974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1833974</a>]" pmid="1833974">Triggs-Raine et al. (1991)</a> found in exon 1 of the HEXA gene a 78G-A substitution which changed trp26 to a termination codon. <a href="#17" class="mim-tip-reference" title="Drucker, L., Navon, R. <strong>Tay-Sachs disease in an Israeli Arab family: trp26-to-stop in the alpha-subunit of hexosaminidase A.</strong> Hum. Mutat. 2: 415-417, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8257995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8257995</a>] [<a href="https://doi.org/10.1002/humu.1380020514" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8257995">Drucker and Navon (1993)</a> found the same mutation in an Arab TSD (<a href="/entry/272800">272800</a>) patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1833974+8257995" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0024" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0024 TAY-SACHS DISEASE</strong>
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</h4>
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HEXA, ARG178LEU
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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> rs28941770 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28941770;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/rs28941770?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=rs28941770" 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=rs28941770" 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=RCV000004118 OR RCV003476891" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004118, RCV003476891" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004118...</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p><a href="#89" class="mim-tip-reference" title="Triggs-Raine, B. L., Akerman, B. R., Clarke, J. T. R., Gravel, R. A. <strong>Sequence of DNA flanking the exons of the HEXA gene, and identification of mutations in Tay-Sachs disease.</strong> Am. J. Hum. Genet. 49: 1041-1054, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1833974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1833974</a>]" pmid="1833974">Triggs-Raine et al. (1991)</a> found in exon 5 a 533G-T substitution that changed arg178 to leu. This is the third amino acid substitution that has been detected at this site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1833974" 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>.0025 TAY-SACHS DISEASE</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">rs797044432 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797044432;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=rs797044432" 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=rs797044432" 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=RCV000004097" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004097" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004097</a>
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<p>In a case of Tay-Sachs disease (<a href="/entry/272800">272800</a>), <a href="#89" class="mim-tip-reference" title="Triggs-Raine, B. L., Akerman, B. R., Clarke, J. T. R., Gravel, R. A. <strong>Sequence of DNA flanking the exons of the HEXA gene, and identification of mutations in Tay-Sachs disease.</strong> Am. J. Hum. Genet. 49: 1041-1054, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1833974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1833974</a>]" pmid="1833974">Triggs-Raine et al. (1991)</a> found a G-to-C transition at the +1 position of IVS2. This change would be expected to produce abnormal splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1833974" 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>.0026 TAY-SACHS DISEASE</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">rs797044432 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797044432;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=rs797044432" 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=rs797044432" 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=RCV000672344" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000672344" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000672344</a>
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<p>Using chemical mismatch cleavage of PCR-amplified cDNA fragments, <a href="#5" class="mim-tip-reference" title="Akli, S., Chelly, J., Lacorte, J., Poenaru, L., Kahn, A. <strong>Seven novel Tay-Sachs mutations detected by chemical mismatch cleavage of PCR-amplified cDNA fragments.</strong> Genomics 11: 124-134, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1837283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1837283</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90109-r" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1837283">Akli et al. (1991)</a> detected a splice donor site mutation, a G-to-A change in the first nucleotide of IVS2, in a French patient with classic Tay-Sachs disease (<a href="/entry/272800">272800</a>). The other allele carried the arg504-to-cys mutation (<a href="#0015">606869.0015</a>). <a href="#46" class="mim-tip-reference" title="Mules, E. H., Hayflick, S., Miller, C. S., Reynolds, L. W., Thomas, G. H. <strong>Six novel deleterious and three neutral mutations in the gene encoding the alpha-subunit of hexosaminidase A in non-Jewish individuals.</strong> Am. J. Hum. Genet. 50: 834-841, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1532289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1532289</a>]" pmid="1532289">Mules et al. (1992)</a> found this mutation in compound heterozygous state in a non-Jewish, Pennsylvania Dutch kindred in which <a href="#34" class="mim-tip-reference" title="Kelly, T. E., Chase, G. A., Kaback, M. M., Kumor, K., McKusick, V. A. <strong>Tay-Sachs disease: high gene frequency in a non-Jewish population.</strong> Am. J. Hum. Genet. 27: 287-291, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/803011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">803011</a>]" pmid="803011">Kelly et al. (1975)</a> described a high frequency of TSD heterozygotes. The increased carrier frequency was noted following the birth of at least 2 (more by history) children with TSD. Subsequent screening of the extended family uncovered 98 of 333 persons tested who were apparent carriers of TSD. Evidence that the increased carrier frequency in this group might be due to more than one HEXA mutation was provided by the discovery of a healthy 37-year-old woman whose serum hexosaminidase A level was indistinguishable from that found in classic TSD patients. Further studies led <a href="#35" class="mim-tip-reference" title="Kelly, T. E., Reynolds, L. W., O'Brien, J. S. <strong>Segregation within a family to two mutant alleles for hexosaminidase A.</strong> Clin. Genet. 9: 540-543, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1269177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1269177</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1976.tb01609.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1269177">Kelly et al. (1976)</a> to conclude that she was a compound heterozygote for a TSD allele and a 'pseudodeficient' allele. <a href="#86" class="mim-tip-reference" title="Thomas, G. H., Raghavan, S., Kolodny, E. H., Frisch, A., Neufeld, E. F., O'Brien, J. S., Reynolds, L. W., Miller, C. S., Shapiro, J., Kazazian, H. H., Jr., Heller, R. H. <strong>Nonuniform deficiency of hexosaminidase A in tissues and fluids of two unrelated individuals.</strong> Pediat. Res. 16: 232-237, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7063277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7063277</a>] [<a href="https://doi.org/10.1203/00006450-198203000-00014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7063277">Thomas et al. (1982)</a> provided support for this interpretation; they demonstrated that while she lacked hexosaminidase A activity against the artificial substrate, her enzyme activity to cleave the natural substrate was similar to that of TSD heterozygotes. The pseudodeficiency allele carried an arg247-to-trp mutation (<a href="#0035">606869.0035</a>) as described by <a href="#91" class="mim-tip-reference" title="Triggs-Raine, B. L., Mules, E. H., Kaback, M. M., Lim-Steele, J. S. T., Dowling, C. E., Akerman, B. R., Natowicz, M. R., Grebner, E. E., Navon, R., Welch, J. P., Greenberg, C. R., Thomas, G. H., Gravel, R. A. <strong>A pseudodeficiency allele common in non-Jewish Tay-Sachs carriers: implications for carrier screening.</strong> Am. J. Hum. Genet. 51: 793-801, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1384323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1384323</a>]" pmid="1384323">Triggs-Raine et al. (1992)</a> in 2 members of the Pennsylvania Dutch community and in other unrelated persons. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1837283+1384323+7063277+1269177+1532289+803011" 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>.0027 TAY-SACHS DISEASE</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> rs121907965 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907965;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/rs121907965?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=rs121907965" 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=rs121907965" 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=RCV000004120" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004120" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004120</a>
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<p><a href="#46" class="mim-tip-reference" title="Mules, E. H., Hayflick, S., Miller, C. S., Reynolds, L. W., Thomas, G. H. <strong>Six novel deleterious and three neutral mutations in the gene encoding the alpha-subunit of hexosaminidase A in non-Jewish individuals.</strong> Am. J. Hum. Genet. 50: 834-841, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1532289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1532289</a>]" pmid="1532289">Mules et al. (1992)</a> found that only 3 of 34 'Tay-Sachs chromosomes' in 22 unrelated, non-Jewish patients or carriers of some form of GM2-gangliosidosis (<a href="/entry/272800">272800</a>) had either of the 2 mutations commonly found in the Jewish population. One of the 'new' mutations found, in an American black with classic TSD, was an initiator mutation, ATG to GTG, converting the initiating methionine to valine. Initiator codon mutations have been discovered as causes of beta-0-thalassemia (<a href="/entry/141900#0344">141900.0344</a>, <a href="/entry/141900#0345">141900.0345</a>), Albright hereditary osteodystrophy (<a href="/entry/139320#0001">139320.0001</a>), and ornithine aminotransferase deficiency (<a href="/entry/258870#0001">258870.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1532289" 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>.0028 GM2-GANGLIOSIDOSIS, ADULT-ONSET</strong>
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HEXA, ARG499CYS (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907966;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs121907966</a>)
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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> rs121907966 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907966;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/rs121907966?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=rs121907966" 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=rs121907966" 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=RCV000004121 OR RCV000169417 OR RCV002390089" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004121, RCV000169417, RCV002390089" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004121...</a>
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<p>Using PCR, single-strand conformation polymorphism (SSCP) analysis, and sequencing in a study of the nature of mutations in non-Jewish patients with GM2-gangliosidosis (<a href="/entry/272800">272800</a>), <a href="#46" class="mim-tip-reference" title="Mules, E. H., Hayflick, S., Miller, C. S., Reynolds, L. W., Thomas, G. H. <strong>Six novel deleterious and three neutral mutations in the gene encoding the alpha-subunit of hexosaminidase A in non-Jewish individuals.</strong> Am. J. Hum. Genet. 50: 834-841, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1532289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1532289</a>]" pmid="1532289">Mules et al. (1992)</a> found an arg499-to-cys substitution (R499C) resulting from a C-to-T transition at nucleotide 1495 in exon 13. The patient was of mixed European ancestry. <a href="#6" class="mim-tip-reference" title="Akli, S., Chomel, J.-C., Lacorte, J.-M., Bachner, L., Kahn, A., Poenaru, L. <strong>Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients.</strong> Hum. Molec. Genet. 2: 61-67, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8490625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8490625</a>] [<a href="https://doi.org/10.1093/hmg/2.1.61" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8490625">Akli et al. (1993)</a> also found this mutation in 2 non-Jewish patients, one French and the other Italian, who had the infantile form of Tay-Sachs disease. Both patients were compound heterozygotes, the other allele being the common exon 11 insertion (<a href="#0001">606869.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1532289+8490625" 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>Another Tay-Sachs mutation, arg499-to-his (R499H; <a href="#0010">606869.0010</a>), involves the same codon. <a href="#82" class="mim-tip-reference" title="Tanaka, A., Hoang, L. T. N., Nishi, Y., Maniwa, S., Oka, M., Yamano, T. <strong>Different attenuated phenotypes of GM2 gangliosidosis variant B in Japanese patients with HEXA mutations at codon 499, and five novel mutations responsible for infantile acute form.</strong> J. Hum. Genet. 48: 571-574, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14566483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14566483</a>] [<a href="https://doi.org/10.1007/s10038-003-0080-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14566483">Tanaka et al. (2003)</a> found the R499H missense mutation in 1 allele of a Japanese patient with the late infantile form of GM2-gangliosidosis and the R499C mutation on 1 allele of another Japanese patient with the juvenile form. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14566483" 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>.0029 GM2-GANGLIOSIDOSIS, B1 VARIANT</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">rs121907967 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907967;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=rs121907967" 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=rs121907967" 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=RCV000004122 OR RCV002281692" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004122, RCV002281692" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004122...</a>
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<p>In a study of 22 unrelated, non-Jewish patients or carriers of some form of GM2-gangliosidosis (<a href="/entry/272800">272800</a>), <a href="#46" class="mim-tip-reference" title="Mules, E. H., Hayflick, S., Miller, C. S., Reynolds, L. W., Thomas, G. H. <strong>Six novel deleterious and three neutral mutations in the gene encoding the alpha-subunit of hexosaminidase A in non-Jewish individuals.</strong> Am. J. Hum. Genet. 50: 834-841, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1532289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1532289</a>]" pmid="1532289">Mules et al. (1992)</a> found a patient with the B1 variant (late onset) who had a 'new' mutation: G to A at nucleotide 987 in exon 9, converting tryptophan-329 to a stop codon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1532289" 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>.0030 TAY-SACHS DISEASE</strong>
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HEXA, TRP485ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121907968 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907968;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=rs121907968" 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=rs121907968" 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=RCV000004123" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004123" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004123</a>
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<p>In a case of classic TSD (<a href="/entry/272800">272800</a>) in a Chinese patient, <a href="#2" class="mim-tip-reference" title="Akalin, N., Shi, H.-P., Vavougios, G., Hechtman, P., Lo, W., Scriver, C. R., Mahuran, D., Kaplan, F. <strong>Novel Tay-Sachs disease mutations from China.</strong> Hum. Mutat. 1: 40-46, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301190</a>] [<a href="https://doi.org/10.1002/humu.1380010107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1301190">Akalin et al. (1992)</a> identified a T-to-C transition at nucleotide 1453 in exon 13 leading to substitution of arginine for tryptophan-485. The change was identified by single strand conformation polymorphism analysis and direct sequencing. The proband was homozygous. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1301190" 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>.0031 TAY-SACHS DISEASE</strong>
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HEXA, 1-BP INS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1595801740 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1595801740;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=rs1595801740" 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=rs1595801740" 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=RCV000004124" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004124" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004124</a>
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<p>In a Chinese patient, <a href="#2" class="mim-tip-reference" title="Akalin, N., Shi, H.-P., Vavougios, G., Hechtman, P., Lo, W., Scriver, C. R., Mahuran, D., Kaplan, F. <strong>Novel Tay-Sachs disease mutations from China.</strong> Hum. Mutat. 1: 40-46, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301190</a>] [<a href="https://doi.org/10.1002/humu.1380010107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1301190">Akalin et al. (1992)</a> identified an insertion of an A after nucleotide 547. The change generated an early termination codon 6 bp downstream from the insertion site. The proband was homozygous. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1301190" 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>.0032 TAY-SACHS DISEASE</strong>
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HEXA, TYR180TER
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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> rs121907969 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907969;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/rs121907969?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=rs121907969" 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=rs121907969" 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=RCV000004125" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004125" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004125</a>
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<p>In Moroccan Jews, a subgroup of Sephardic Jews, a high frequency of Tay-Sachs disease (<a href="/entry/272800">272800</a>) has been found. One of the mutations is an in-frame deletion of 1 of 2 adjacent phenylalanine codons at position 304 or 305 (<a href="#0014">606869.0014</a>). <a href="#18" class="mim-tip-reference" title="Drucker, L., Proia, R. L., Navon, R. <strong>Identification and rapid detection of three Tay-Sachs mutations in the Moroccan Jewish population.</strong> Am. J. Hum. Genet. 51: 371-377, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1322637/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1322637</a>]" pmid="1322637">Drucker et al. (1992)</a> identified 2 additional mutations within exon 5 of the HEXA gene that account for the remaining TSD alleles in this population. One of the mutations was a G-to-A transition resulting in an arg170-to-gln substitution of the same type as described by others in a Japanese infant (see <a href="#0011">606869.0011</a>). The other was a novel C-to-G transversion resulting in replacement of tyrosine-180 by a stop codon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1322637" 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>.0033 TAY-SACHS DISEASE</strong>
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HEXA, IVS9, G-A, +1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs76173977 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs76173977;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/rs76173977?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=rs76173977" 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=rs76173977" 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=RCV000004126 OR RCV000079047 OR RCV002415396 OR RCV003952341" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004126, RCV000079047, RCV002415396, RCV003952341" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004126...</a>
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<p><a href="#5" class="mim-tip-reference" title="Akli, S., Chelly, J., Lacorte, J., Poenaru, L., Kahn, A. <strong>Seven novel Tay-Sachs mutations detected by chemical mismatch cleavage of PCR-amplified cDNA fragments.</strong> Genomics 11: 124-134, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1837283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1837283</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90109-r" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1837283">Akli et al. (1991)</a> described a G-to-A transition of the obligatory GT sequence of the intron 9 donor splice site of the HEXA gene in a case of classic Tay-Sachs disease (<a href="/entry/272800">272800</a>). In a case of infantile Tay-Sachs disease in a Louisiana Cajun family, <a href="#42" class="mim-tip-reference" title="McDowell, G. A., Mules, E. H., Fabacher, P., Shapira, E., Blitzer, M. G. <strong>The presence of two different infantile Tay-Sachs disease mutations in a Cajun population.</strong> Am. J. Hum. Genet. 51: 1071-1077, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1307230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1307230</a>]" pmid="1307230">McDowell et al. (1992)</a> found compound heterozygosity for the exon 11 insertion (<a href="#0001">606869.0001</a>) and for a G-to-A transition at position +1 of intron 9 changing the invariant GT of the donor splice site to AT. <a href="#3" class="mim-tip-reference" title="Akerman, B. R., Zielenski, J., Triggs-Raine, B. L., Prence, E. M., Natowicz, M. R., Lim-Steele, J. S. T., Kaback, M. M., Mules, E. H., Thomas, G. H., Clarke, J. T. R., Gravel, R. A. <strong>A mutation common in non-Jewish Tay-Sachs disease: frequency and RNA studies.</strong> Hum. Mutat. 1: 303-309, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301938</a>] [<a href="https://doi.org/10.1002/humu.1380010407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1301938">Akerman et al. (1992)</a> found a relatively high frequency of the IVS9 donor splice site mutation in non-Jewish Caucasians. The mutation was not identified among 12 black American TSD alleles or in any of 18 Ashkenazi Jewish, enzyme-defined carriers. This allele and the HEXA pseudodeficiency allele (<a href="#0035">606869.0035</a>) described by <a href="#91" class="mim-tip-reference" title="Triggs-Raine, B. L., Mules, E. H., Kaback, M. M., Lim-Steele, J. S. T., Dowling, C. E., Akerman, B. R., Natowicz, M. R., Grebner, E. E., Navon, R., Welch, J. P., Greenberg, C. R., Thomas, G. H., Gravel, R. A. <strong>A pseudodeficiency allele common in non-Jewish Tay-Sachs carriers: implications for carrier screening.</strong> Am. J. Hum. Genet. 51: 793-801, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1384323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1384323</a>]" pmid="1384323">Triggs-Raine et al. (1992)</a> account for almost 50% (29/64) of TSD or carrier alleles ascertained by enzyme screening in non-Jewish Caucasians. Of 24 unrelated mutant chromosomes from 20 non-Jewish subjects (15 TSD carriers, 4 TSD patients, and 1 TSD fetus) in the British Isles, 5 had mutations common in the Ashkenazi Jewish community (<a href="#0001">606869.0001</a> and <a href="#0002">606869.0002</a>) and 10 had the intron 9 splice site mutation (<a href="#38" class="mim-tip-reference" title="Landels, E. C., Green, P. M., Ellis, I. H., Fensom, A. H., Bobrow, M. <strong>Beta-hexosaminidase splice site mutation has a high frequency among non-Jewish Tay-Sachs disease carriers from the British Isles.</strong> J. Med. Genet. 29: 563-567, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1387685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1387685</a>] [<a href="https://doi.org/10.1136/jmg.29.8.563" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1387685">Landels et al., 1992</a>). This was an unexpected finding considering the diverse origin of the population of the British Isles. By cDNA-PCR amplification, <a href="#4" class="mim-tip-reference" title="Akli, S., Chelly, J., Kahn, A., Poenaru, L. <strong>A null allele frequent in non-Jewish Tay-Sachs patients.</strong> Hum. Genet. 90: 614-620, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8444467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8444467</a>] [<a href="https://doi.org/10.1007/BF00202478" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8444467">Akli et al. (1993)</a> found a 17-bp insertion due to the same mutation in 2 French patients with the infantile form of Tay-Sachs disease. One was a homozygote and one a compound heterozygote with a 4-bp insertion in exon 11 in the second allele. The G-to-A transition in the donor site resulted in activation of a cryptic donor site in the intron. <a href="#6" class="mim-tip-reference" title="Akli, S., Chomel, J.-C., Lacorte, J.-M., Bachner, L., Kahn, A., Poenaru, L. <strong>Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients.</strong> Hum. Molec. Genet. 2: 61-67, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8490625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8490625</a>] [<a href="https://doi.org/10.1093/hmg/2.1.61" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8490625">Akli et al. (1993)</a> found the mutation in 9 of 82 Tay-Sachs chromosomes. In the British Isles, the IVS9DS mutation was found more frequently in subjects of Irish, Scottish, and Welsh origin than in those of English origin (63% and 31%, respectively). In a blind study, <a href="#39" class="mim-tip-reference" title="Landels, E. C., Green, P. M., Ellis, I. H., Fensom, A. H., Kaback, M. M., Lim-Steele, J., Zeiger, K., Levy, N., Bobrow, M. <strong>Further investigation of the HEXA gene intron 9 donor splice site mutation frequently found in non-Jewish Tay-Sachs disease patients from the British Isles.</strong> J. Med. Genet. 30: 479-481, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8326491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8326491</a>] [<a href="https://doi.org/10.1136/jmg.30.6.479" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8326491">Landels et al. (1993)</a> tested 26 American TSD carriers and 28 noncarriers who had British ancestry for the IVS9DS mutation. Six of the carriers and none of the controls were positive for the mutation. All 6 had Irish ancestry compared with 9 of the 20 other IVS9DS-negative TSD carriers. These results confirmed the previously found high frequency of this specific mutation in non-Jewish TSD families of British Isles, particularly Irish, origin, and reinforced the need to screen such families for this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8444467+1837283+1384323+1387685+1301938+8490625+1307230+8326491" 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>.0034 TAY-SACHS DISEASE, B1 VARIANT</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">rs797044434 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797044434;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=rs797044434" 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=rs797044434" 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=RCV000004127" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004127" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004127</a>
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<p>In a carrier for the B1 variant (<a href="/entry/272800">272800</a>), <a href="#46" class="mim-tip-reference" title="Mules, E. H., Hayflick, S., Miller, C. S., Reynolds, L. W., Thomas, G. H. <strong>Six novel deleterious and three neutral mutations in the gene encoding the alpha-subunit of hexosaminidase A in non-Jewish individuals.</strong> Am. J. Hum. Genet. 50: 834-841, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1532289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1532289</a>]" pmid="1532289">Mules et al. (1992)</a> identified an in-frame deletion of 1 of 2 adjacent glycine codons (GGA) at position 320 or 321. The deletion was in exon 8. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1532289" 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> rs121907970 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907970;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/rs121907970?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=rs121907970" 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=rs121907970" 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=RCV000004128 OR RCV000242608 OR RCV000279029 OR RCV000549043" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004128, RCV000242608, RCV000279029, RCV000549043" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004128...</a>
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<p><a href="#91" class="mim-tip-reference" title="Triggs-Raine, B. L., Mules, E. H., Kaback, M. M., Lim-Steele, J. S. T., Dowling, C. E., Akerman, B. R., Natowicz, M. R., Grebner, E. E., Navon, R., Welch, J. P., Greenberg, C. R., Thomas, G. H., Gravel, R. A. <strong>A pseudodeficiency allele common in non-Jewish Tay-Sachs carriers: implications for carrier screening.</strong> Am. J. Hum. Genet. 51: 793-801, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1384323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1384323</a>]" pmid="1384323">Triggs-Raine et al. (1992)</a> identified a C-to-T transition at nucleotide 739, resulting in an arg247-to-trp substitution as the basis of pseudodeficiency of beta-hexosaminidase A (<a href="/entry/272800">272800</a>). This allele accounted for 32% (20/62) of non-Jewish enzyme-defined Tay-Sachs disease carriers but for none of 36 Jewish enzyme-defined carriers who did not have one of the 3 known mutations common to the Jewish group. In combination with a 'true' Tay-Sachs disease allele, the arg247-to-trp allele causes HEXA pseudodeficiency. Given both the large proportion of non-Jewish carriers with this allele and the fact that standard biochemical screening cannot differentiate between heterozygotes for the arg247-to-trp mutation and Tay-Sachs disease carriers, DNA testing for this mutation in at-risk couples is essential. Contrary to the findings of <a href="#91" class="mim-tip-reference" title="Triggs-Raine, B. L., Mules, E. H., Kaback, M. M., Lim-Steele, J. S. T., Dowling, C. E., Akerman, B. R., Natowicz, M. R., Grebner, E. E., Navon, R., Welch, J. P., Greenberg, C. R., Thomas, G. H., Gravel, R. A. <strong>A pseudodeficiency allele common in non-Jewish Tay-Sachs carriers: implications for carrier screening.</strong> Am. J. Hum. Genet. 51: 793-801, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1384323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1384323</a>]" pmid="1384323">Triggs-Raine et al. (1992)</a> of no cases of the C739-to-T pseudodeficiency allele among Jewish carriers, <a href="#88" class="mim-tip-reference" title="Tomczak, J., Boogen, C., Grebner, E. E. <strong>Distribution of a pseudodeficiency allele among Tay-Sachs carriers. (Letter)</strong> Am. J. Hum. Genet. 53: 537-539, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8328470/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8328470</a>]" pmid="8328470">Tomczak et al. (1993)</a> found that of 33 carriers who had none of the 3 common mutations, the pseudodeficiency mutation was present in 6 of 19 Jews and 8 of 14 non-Jews. <a href="#88" class="mim-tip-reference" title="Tomczak, J., Boogen, C., Grebner, E. E. <strong>Distribution of a pseudodeficiency allele among Tay-Sachs carriers. (Letter)</strong> Am. J. Hum. Genet. 53: 537-539, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8328470/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8328470</a>]" pmid="8328470">Tomczak et al. (1993)</a> suggested that DNA analysis should be part of a comprehensive screening program because 2 mutant alleles, the pseudodeficiency allele and the adult allele, are indistinguishable from the lethal infantile mutations by means of enzyme assay yet have very different phenotypic significance and together may account for as many as 12% of enzyme-defined carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8328470+1384323" 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>.0036 TAY-SACHS DISEASE, B1 VARIANT</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> rs1800429 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1800429;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/rs1800429?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=rs1800429" 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=rs1800429" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387906310 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906310;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/rs387906310?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=rs387906310" 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=rs387906310" 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=RCV000004129 OR RCV000664577 OR RCV002527443" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004129, RCV000664577, RCV002527443" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004129...</a>
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<p>In a patient with the B1 variant form of Tay-Sachs disease (<a href="/entry/272800">272800</a>) described by <a href="#25" class="mim-tip-reference" title="Gordon, B. A., Gordon, K. E., Hinton, G. G., Cadera, W., Feleki, V., Bayleran, J., Hechtman, P. <strong>Tay Sachs disease: B1 variant.</strong> Pediat. Neurol. 4: 54-57, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2976595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2976595</a>] [<a href="https://doi.org/10.1016/0887-8994(88)90026-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2976595">Gordon et al. (1988)</a>, <a href="#1" class="mim-tip-reference" title="Ainsworth, P. J., Coulter-Mackie, M. B. <strong>A double mutation in exon 6 of the beta-hexosaminidase alpha subunit in a patient with the B1 variant of Tay-Sachs disease.</strong> Am. J. Hum. Genet. 51: 802-809, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1415222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1415222</a>]" pmid="1415222">Ainsworth and Coulter-Mackie (1992)</a> found a double mutation in exon 6 of HEXA: a G-to-C transversion of nucleotide 574 causing a val192-to-leu substitution, and a G-to-A transition at nucleotide 598 resulting in a val200-to-met substitution. Transient expression studies of the 2 exon-6 mutations (singly or together) in COS-1 cells showed that the val192-to-leu change was sufficient to cause the loss of enzyme activity. Furthermore, the biochemical phenotype of this alteration in transfection studies was consistent with that expected for a B1 variant mutation. <a href="#13" class="mim-tip-reference" title="Coulter-Mackie, M. B. <strong>Molecular characterization of both alleles in an unusual Tay-Sachs disease B1 variant. (Letter)</strong> Am. J. Hum. Genet. 54: 1126-1127, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8198136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8198136</a>]" pmid="8198136">Coulter-Mackie (1994)</a> reported that the paternally derived allele carried the IVS9DS mutation described in <a href="#0033">606869.0033</a>. Subsequently, <a href="#30" class="mim-tip-reference" title="Hou, Y., Vavougios, G., Hinek, A., Wu, K. K., Hechtman, P., Kaplan, F., Mahuran, D. J. <strong>The val192-to-leu mutation in the alpha-subunit of beta-hexosaminidase A is not associated with the B1-variant form of Tay-Sachs disease.</strong> Am. J. Hum. Genet. 59: 52-58, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8659543/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8659543</a>]" pmid="8659543">Hou et al. (1996)</a> demonstrated that the val192-to-leu mutation in the alpha subunit of HEXA is not associated with the B1 variant form of Tay-Sachs disease. Most mutations in the alpha-subunit of HEXA that result in Tay-Sachs disease affect the initial folding of the pro-alpha chain in the endoplasmic reticulum, resulting in its retention and degradation. A much less common occurrence is a mutation that specifically affects an 'active site' residue necessary for substrate binding and/or catalysis. In this case, hexosaminidase A is present in the lysosome, but it lacks all alpha-specific activity. This is the biochemical phenotype of the B1 variant form of TSD. <a href="#30" class="mim-tip-reference" title="Hou, Y., Vavougios, G., Hinek, A., Wu, K. K., Hechtman, P., Kaplan, F., Mahuran, D. J. <strong>The val192-to-leu mutation in the alpha-subunit of beta-hexosaminidase A is not associated with the B1-variant form of Tay-Sachs disease.</strong> Am. J. Hum. Genet. 59: 52-58, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8659543/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8659543</a>]" pmid="8659543">Hou et al. (1996)</a> examined permanently cotransfected Chinese hamster ovary cells with an alpha-cDNA-construct including the val192-to-leu substitution and a mutant beta-cDNA, beta-arg211 to lys, encoding a beta subunit that is inactive but normal in all other respects. They found that the val192-to-leu substitution produced a pro-alpha chain that did not form alpha-beta dimers and was not transported to the lysosome. Furthermore, they reexamined the hexosaminidase activity and protein levels in the fibroblasts from the original patient. These data were also not consistent with the biochemical phenotype of the B1 variant of Tay-Sachs disease. Thus, they concluded that the val192-to-leu substitution does not specifically affect the alpha-active site. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8198136+2976595+1415222+8659543" 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> rs121907971 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907971;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/rs121907971?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=rs121907971" 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=rs121907971" 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=RCV000004130 OR RCV000801596 OR RCV001810829" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004130, RCV000801596, RCV001810829" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004130...</a>
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<p>In 2 unrelated non-Jewish compound heterozygous patients, <a href="#20" class="mim-tip-reference" title="Fernandes, M., Kaplan, F., Natowicz, M., Prence, E., Kolodny, E., Kaback, M., Hechtman, P. <strong>A new Tay-Sachs disease B1 allele in exon 7 in two compound heterozygotes each with a second novel mutation.</strong> Hum. Molec. Genet. 1: 759-761, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302612</a>] [<a href="https://doi.org/10.1093/hmg/1.9.759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1302612">Fernandes et al. (1992)</a> identified 3 novel TSD mutations. Both patients shared a G-to-C transversion of nucleotide 772 causing a substitution of histidine for aspartic acid-258. This mutant enzyme had been characterized previously as a B1, or alpha-subunit active site mutation. This was the first B1 mutation found in a codon other than 178 in exon 5 (<a href="#0006">606869.0006</a>). One of the patients also carried a C-to-T transition at nucleotide 508 causing an arg170-to-trp substitution (<a href="#0039">606869.0039</a>). The third mutation, found in the second patient, was a 2-base deletion occurring in exon 8 and involving the loss of either nucleotides 927-928 or nucleotides 929-930 in codon 310. The deletion created an in-frame termination codon 35 bases downstream (<a href="#0040">606869.0040</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1302612" 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> rs121907972 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907972;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/rs121907972?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=rs121907972" 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=rs121907972" 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=RCV000004131 OR RCV002345229 OR RCV004791196" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004131, RCV002345229, RCV004791196" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004131...</a>
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<p>See <a href="#0038">606869.0038</a>. <a href="#20" class="mim-tip-reference" title="Fernandes, M., Kaplan, F., Natowicz, M., Prence, E., Kolodny, E., Kaback, M., Hechtman, P. <strong>A new Tay-Sachs disease B1 allele in exon 7 in two compound heterozygotes each with a second novel mutation.</strong> Hum. Molec. Genet. 1: 759-761, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302612</a>] [<a href="https://doi.org/10.1093/hmg/1.9.759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1302612">Fernandes et al. (1992)</a> detected the arg170-to-trp mutation in 2 unrelated TSD (<a href="/entry/272800">272800</a>) patients. In both families, this allele was traced to French Canadian ancestors originating in the Estrie region of the province of Quebec. This mutation was the third TSD allele unique to the French Canadian population and the ancestral origins of the carrier parents were distant from the center of diffusion of the more common 7.6-kb deletion mutation (<a href="#0003">606869.0003</a>), which is in the eastern part the province. In a non-Jewish Italian child, <a href="#6" class="mim-tip-reference" title="Akli, S., Chomel, J.-C., Lacorte, J.-M., Bachner, L., Kahn, A., Poenaru, L. <strong>Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients.</strong> Hum. Molec. Genet. 2: 61-67, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8490625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8490625</a>] [<a href="https://doi.org/10.1093/hmg/2.1.61" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8490625">Akli et al. (1993)</a> used mismatch analysis to identify compound heterozygosity for the arg170-to-trp mutation of 1 HEXA allele and a gly454-to-ser mutation (<a href="#0048">606869.0048</a>) of the other allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8490625+1302612" 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> rs751248523 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs751248523;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/rs751248523?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=rs751248523" 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=rs751248523" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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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> rs121907973 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907973;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/rs121907973?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=rs121907973" 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=rs121907973" 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=RCV000004133 OR RCV000674617 OR RCV001508770 OR RCV001797585" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004133, RCV000674617, RCV001508770, RCV001797585" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004133...</a>
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<p><a href="#6" class="mim-tip-reference" title="Akli, S., Chomel, J.-C., Lacorte, J.-M., Bachner, L., Kahn, A., Poenaru, L. <strong>Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients.</strong> Hum. Molec. Genet. 2: 61-67, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8490625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8490625</a>] [<a href="https://doi.org/10.1093/hmg/2.1.61" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8490625">Akli et al. (1993)</a> used chemical mismatch cleavage (CMC), denaturing gradient gel electrophoresis (DGGE), and direct sequencing of amplified fragments displaying a cleaved product or an altered melting behavior to screen the HEXA gene for mutations in non-Jewish patients with Tay-Sachs disease (<a href="/entry/272800">272800</a>). In a Dutch patient with the adult form, they found by mismatch analysis an A-to-C transition converting codon 197 from lysine to threonine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8490625" 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>.0042 TAY-SACHS DISEASE, JUVENILE/ADULT</strong>
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HEXA, IVS6, +1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387906311 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906311;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/rs387906311?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=rs387906311" 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=rs387906311" 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=RCV000004134 OR RCV000412214 OR RCV000432194" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004134, RCV000412214, RCV000432194" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004134...</a>
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<p>In a non-Jewish patient with Tay-Sachs disease (<a href="/entry/272800">272800</a>) designated as juvenile/adult type, <a href="#6" class="mim-tip-reference" title="Akli, S., Chomel, J.-C., Lacorte, J.-M., Bachner, L., Kahn, A., Poenaru, L. <strong>Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients.</strong> Hum. Molec. Genet. 2: 61-67, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8490625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8490625</a>] [<a href="https://doi.org/10.1093/hmg/2.1.61" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8490625">Akli et al. (1993)</a> found a mutation affecting the dinucleotide GT of the intron 6 donor site and leading to skipping of exon 6 in the processed transcripts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8490625" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0043" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0043 TAY-SACHS DISEASE</strong>
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</h4>
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HEXA, PHE211SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121907974 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907974;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=rs121907974" 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=rs121907974" 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=RCV000004135" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004135" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004135</a>
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</span>
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</div>
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<span class="mim-text-font">
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<p>In a non-Jewish Italian child with infantile Tay-Sachs disease (<a href="/entry/272800">272800</a>), <a href="#6" class="mim-tip-reference" title="Akli, S., Chomel, J.-C., Lacorte, J.-M., Bachner, L., Kahn, A., Poenaru, L. <strong>Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients.</strong> Hum. Molec. Genet. 2: 61-67, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8490625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8490625</a>] [<a href="https://doi.org/10.1093/hmg/2.1.61" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8490625">Akli et al. (1993)</a> identified compound heterozygosity for the arg499-to-cys mutation and for another cys mutation (<a href="#0043">606869.0043</a>) and for another previously unknown mutation which converted codon 211 from phenylalanine to serine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8490625" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0044" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0044 TAY-SACHS DISEASE</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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<div style="float: left;">
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HEXA, LEU127ARG
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121907975 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907975;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=rs121907975" 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=rs121907975" 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=RCV000004136" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004136" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004136</a>
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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 non-Jewish Italian child with Tay-Sachs disease (<a href="/entry/272800">272800</a>), <a href="#6" class="mim-tip-reference" title="Akli, S., Chomel, J.-C., Lacorte, J.-M., Bachner, L., Kahn, A., Poenaru, L. <strong>Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients.</strong> Hum. Molec. Genet. 2: 61-67, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8490625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8490625</a>] [<a href="https://doi.org/10.1093/hmg/2.1.61" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8490625">Akli et al. (1993)</a> identified a T-to-G transversion changing codon 127 from leucine to arginine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8490625" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0045" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0045 TAY-SACHS DISEASE</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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<div style="float: left;">
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HEXA, HIS204ARG
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121907976 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907976;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=rs121907976" 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=rs121907976" 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=RCV000004137 OR RCV001778646 OR RCV002054413" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004137, RCV001778646, RCV002054413" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004137...</a>
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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 non-Jewish German child with Tay-Sachs disease (<a href="/entry/272800">272800</a>), <a href="#6" class="mim-tip-reference" title="Akli, S., Chomel, J.-C., Lacorte, J.-M., Bachner, L., Kahn, A., Poenaru, L. <strong>Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients.</strong> Hum. Molec. Genet. 2: 61-67, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8490625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8490625</a>] [<a href="https://doi.org/10.1093/hmg/2.1.61" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8490625">Akli et al. (1993)</a> identified compound heterozygosity for the exon 11 insertion (<a href="#0001">606869.0001</a>) and for a novel mutation which converted his-204 to arginine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8490625" 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>
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<div>
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<a id="0046" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0046 TAY-SACHS DISEASE</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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HEXA, 2-BP DEL, TT, CODON 142
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1057519458 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519458;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=rs1057519458" 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=rs1057519458" 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=RCV000004138" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004138" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004138</a>
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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 non-Jewish French child with Tay-Sachs disease (<a href="/entry/272800">272800</a>), <a href="#6" class="mim-tip-reference" title="Akli, S., Chomel, J.-C., Lacorte, J.-M., Bachner, L., Kahn, A., Poenaru, L. <strong>Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients.</strong> Hum. Molec. Genet. 2: 61-67, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8490625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8490625</a>] [<a href="https://doi.org/10.1093/hmg/2.1.61" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8490625">Akli et al. (1993)</a> identified a 2-bp deletion in codon 142 causing a frameshift. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8490625" 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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<div>
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<br />
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<div>
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<a id="0047" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0047 TAY-SACHS DISEASE</strong>
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</span>
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</h4>
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</div>
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HEXA, MET301ARG
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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> rs121907977 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907977;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/rs121907977?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=rs121907977" 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=rs121907977" 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=RCV000004139 OR RCV001250228" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004139, RCV001250228" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004139...</a>
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</span>
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<p>In a non-Jewish Yugoslav child with Tay-Sachs disease (<a href="/entry/272800">272800</a>), <a href="#6" class="mim-tip-reference" title="Akli, S., Chomel, J.-C., Lacorte, J.-M., Bachner, L., Kahn, A., Poenaru, L. <strong>Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients.</strong> Hum. Molec. Genet. 2: 61-67, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8490625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8490625</a>] [<a href="https://doi.org/10.1093/hmg/2.1.61" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8490625">Akli et al. (1993)</a> identified a novel mutation, a T-to-G transversion which changed codon 301 from methionine to arginine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8490625" 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>.0048 TAY-SACHS DISEASE</strong>
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HEXA, GLY454SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121907978 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907978;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=rs121907978" 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=rs121907978" 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=RCV000004140" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004140" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004140</a>
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<p>See <a href="#0039">606869.0039</a>.</p>
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<strong>.0049 TAY-SACHS DISEASE</strong>
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HEXA, LEU39ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121907979 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907979;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=rs121907979" 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=rs121907979" 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=RCV000004141" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004141" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004141</a>
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<p>In a non-Jewish Polish child with Tay-Sachs disease (<a href="/entry/272800">272800</a>), <a href="#6" class="mim-tip-reference" title="Akli, S., Chomel, J.-C., Lacorte, J.-M., Bachner, L., Kahn, A., Poenaru, L. <strong>Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients.</strong> Hum. Molec. Genet. 2: 61-67, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8490625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8490625</a>] [<a href="https://doi.org/10.1093/hmg/2.1.61" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8490625">Akli et al. (1993)</a> identified compound heterozygosity for the exon 11 insertion and a novel mutation, a T-to-G transversion which changed codon 39 from leucine to arginine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8490625" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0050" class="mim-anchor"></a>
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<strong>.0050 TAY-SACHS DISEASE</strong>
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HEXA, TRP392TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267606862 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606862;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=rs267606862" 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=rs267606862" 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=RCV000004142" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004142" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004142</a>
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<p>Approximately 20% of Ashkenazi carriers harbor a splice junction defect (<a href="#0002">606869.0002</a>), while about 78% have a 4-bp insertion (<a href="#0001">606869.0001</a>). However, the Ashkenazi patient used in the original description of the 4-bp insertion carried this lesion in only 1 allele and was negative for the splice junction mutation. <a href="#78" class="mim-tip-reference" title="Shore, S., Tomczak, J., Grebner, E. E., Myerowitz, R. <strong>An unusual genotype in an Ashkenazi Jewish patient with Tay-Sachs disease.</strong> Hum. Mutat. 1: 486-490, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301958/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301958</a>] [<a href="https://doi.org/10.1002/humu.1380010606" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1301958">Shore et al. (1992)</a> cloned the insertion negative allele and by sequence analysis of the exons found a point mutation in exon 11 that resulted in substitution of trp392 with a premature termination codon. They found that 9 Ashkenazi Jewish carriers who had tested negative for the major and minor mutations as well as for a lesion causing an adult form of Tay-Sachs disease (<a href="/entry/272800">272800</a>) did not carry the trp392-to-ter mutation, suggesting that the mutation may be recent and/or rare. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1301958" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0051" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0051 TAY-SACHS DISEASE</strong>
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</span>
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</h4>
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HEXA, IVS7, G-A, +1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121907980 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907980;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/rs121907980?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=rs121907980" 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=rs121907980" 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=RCV000409276 OR RCV003944800" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000409276, RCV003944800" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000409276...</a>
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<span class="mim-text-font">
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<p><a href="#27" class="mim-tip-reference" title="Hechtman, P., Boulay, B., De Braekeleer, M., Andermann, E., Melancon, S., Larochelle, J., Prevost, C., Kaplan, F. <strong>The intron 7 donor splice site transition: a second Tay-Sachs disease mutation in French Canada.</strong> Hum. Genet. 90: 402-406, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1483696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1483696</a>] [<a href="https://doi.org/10.1007/BF00220467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1483696">Hechtman et al. (1992)</a> found a second mutation as the cause of infantile Tay-Sachs disease (<a href="/entry/272800">272800</a>) in French Canadians in 3 families from the Saguenay-Lac-Saint-Jean region of Quebec: a G-to-A transition at the +1 position of intron 7 that abolished the donor splice site. The mutation occurred in a base adjacent to the site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1483696" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0052" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0052 GM2-GANGLIOSIDOSIS, LATE ONSET</strong>
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HEXA, c.805G-A
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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> rs121907954 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907954;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/rs121907954?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=rs121907954" 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=rs121907954" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121907980 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907980;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/rs121907980?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=rs121907980" 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=rs121907980" 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=RCV000004104 OR RCV000168285 OR RCV000434025 OR RCV001810397 OR RCV002408450 OR RCV003924800" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004104, RCV000168285, RCV000434025, RCV001810397, RCV002408450, RCV003924800" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004104...</a>
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<p><a href="#27" class="mim-tip-reference" title="Hechtman, P., Boulay, B., De Braekeleer, M., Andermann, E., Melancon, S., Larochelle, J., Prevost, C., Kaplan, F. <strong>The intron 7 donor splice site transition: a second Tay-Sachs disease mutation in French Canada.</strong> Hum. Genet. 90: 402-406, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1483696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1483696</a>] [<a href="https://doi.org/10.1007/BF00220467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1483696">Hechtman et al. (1992)</a> made reference to a HEXA mutation involving a c.805G-A transition and a clinical picture of adult-onset GM2-gangliosidosis (<a href="/entry/272800">272800</a>). The mutation is immediately adjacent to the IVS7DS +1 mutation (<a href="#0051">606869.0051</a>). Both mutations result in the loss of a cleavage site for the restriction endonuclease EcoRII; the 2 mutations can be unequivocally distinguished, however, using allele-specific oligonucleotide hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1483696" 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>.0053 GM2-GANGLIOSIDOSIS, LATE ONSET</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> rs28941771 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28941771;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/rs28941771?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=rs28941771" 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=rs28941771" 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=RCV000004145 OR RCV002512735" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004145, RCV002512735" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004145...</a>
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<p><a href="#15" class="mim-tip-reference" title="De Gasperi, R., Gama Sosa, M. A., Battistini, S., Yeretsian, J., Raghavan, S., Zelnik, N., Leshinsky, E., Kolodny, E. H. <strong>Late-onset G(M2)-gangliosidosis: Ashkenazi Jewish family with an exon 5 mutation (tyr180-to-his) in the Hex A alpha-chain gene.</strong> Neurology 47: 547-552, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8757036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8757036</a>] [<a href="https://doi.org/10.1212/wnl.47.2.547" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8757036">De Gasperi et al. (1996)</a> studied 2 sisters who developed mild learning disability at age 8, depression and ataxia in the early twenties, and who were diagnosed as having late-onset GM2-gangliosidosis (<a href="/entry/272800">272800</a>) on the basis of HEXA deficiency. Both sisters were compound heterozygotes for the common 4-bp insertion in exon 11 (<a href="#0001">606869.0001</a>) and a novel 538T-C transition causing a tyr180-to-his substitution in exon 5. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8757036" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0054" class="mim-anchor"></a>
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<strong>.0054 GM2-GANGLIOSIDOSIS, CHRONIC</strong>
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HEXA, IVS7, G-A, -7
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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> rs770932296 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs770932296;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/rs770932296?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=rs770932296" 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=rs770932296" 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=RCV000004146 OR RCV000191092 OR RCV001582679" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004146, RCV000191092, RCV001582679" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004146...</a>
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<p><a href="#19" class="mim-tip-reference" title="Fernandes, M. J. G., Hechtman, P., Boulay, B., Kaplan, F. <strong>A chronic GM(2) gangliosidosis variant with a HEXA splicing defect: quantitation of HEXA mRNAs in normal and mutant fibroblasts.</strong> Europ. J. Hum. Genet. 5: 129-136, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9272736/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9272736</a>]" pmid="9272736">Fernandes et al. (1997)</a> stated that more than 72 mutations had been identified in the HEXA gene, of which only 4 were thought to cause a chronic form of Tay Sachs disease (<a href="/entry/272800">272800</a>). In a Canadian patient of English ancestry with chronic TSD (no clinical details were provided), they identified a novel HEXA mutation, IVS7AS, -7, G-A. The second allele in this patient was the 4-bp insertion mutation in exon 11, 1277TATC (<a href="#0001">606869.0001</a>), which is the most frequent TSD allele in Ashkenazi Jews. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9272736" 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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<h4>
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<strong>.0055 GM2-GANGLIOSIDOSIS, SUBACUTE</strong>
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HEXA, TRP474CYS
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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> rs121907981 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907981;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/rs121907981?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=rs121907981" 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=rs121907981" 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=RCV000004147 OR RCV001244261" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004147, RCV001244261" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004147...</a>
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<p>In a non-Jewish proband who manifested a subacute variant of GM2-gangliosidosis (<a href="/entry/272800">272800</a>), <a href="#72" class="mim-tip-reference" title="Petroulakis, E., Cao, Z., Clarke, J. T. R., Mahuran, D. J., Lee, G., Triggs-Raine, B. <strong>W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.</strong> Hum. Mutat. 11: 432-442, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9603435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9603435</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)11:6<432::AID-HUMU3>3.0.CO;2-Z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9603435">Petroulakis et al. (1998)</a> identified a 1422G-C transversion in the first position of exon 13 of HEXA. The mutation was predicted to result in a trp474-to-cys (W474C) amino acid substitution. On the other allele, inherited from the mother, they identified the common infantile disease-causing 4-bp insertion in exon 11 (<a href="#0001">606869.0001</a>). Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently coexpressed with the beta-subunit to produce HEXA in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. The patient had presented at the age of 16 with an acute psychotic episode characterized by marked social and emotional withdrawal, paranoia, obsessional thinking, and compulsiveness associated with marked agitation. He had a history of increasing clumsiness, ataxia, and dysarthria dating back to age 10, although only becoming clinically obvious at age 14. He, and subsequently his younger brother, were diagnosed with a subacute encephalopathic form of GM2-gangliosidosis type I. At age 20, chronic psychosis with intermittent acute exacerbations remained the most disabling symptom, as it was in his affected brother, although both exhibited some ataxia and moderately severe dysarthria. The father was of German and Dutch descent and the mother of Portuguese and English descent. There was no family history of neurodegenerative disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9603435" 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 class="mim-font">
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<strong>.0056 TAY-SACHS DISEASE</strong>
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HEXA, LEU451VAL
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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> rs28940871 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940871;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/rs28940871?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=rs28940871" 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=rs28940871" 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=RCV000004148" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004148" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004148</a>
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<p>In the course of study of HEXA activity in Iraqi Jews to determine carriers of Tay-Sachs disease (<a href="/entry/272800">272800</a>), <a href="#32" class="mim-tip-reference" title="Karpati, M., Gazit, E., Goldman, B., Frisch, A., Colombo, R., Peleg, L. <strong>Specific mutations in the HEXA gene among Iraqi Jewish Tay-Sachs disease carriers: dating of founder ancestor.</strong> Neurogenetics 5: 35-40, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14648242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14648242</a>] [<a href="https://doi.org/10.1007/s10048-003-0166-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14648242">Karpati et al. (2004)</a> identified a 1351C-G transversion in exon 12 of the HEXA gene, resulting in a leu451-to-val (L451V) change. The mutation was found in 21 of 62 carriers (33.9%) and in none of 100 noncarrier Iraqi Jews. <a href="#32" class="mim-tip-reference" title="Karpati, M., Gazit, E., Goldman, B., Frisch, A., Colombo, R., Peleg, L. <strong>Specific mutations in the HEXA gene among Iraqi Jewish Tay-Sachs disease carriers: dating of founder ancestor.</strong> Neurogenetics 5: 35-40, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14648242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14648242</a>] [<a href="https://doi.org/10.1007/s10048-003-0166-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14648242">Karpati et al. (2004)</a> estimated that the 1351C-G transversion occurred sometime between 1519 BC and 635 AD, with 442 BC as the best estimate with wide confidence limits. The Iraqi Jewish community started around 586 BC when the Babylonian king Nebuchadnezzar deported 10,000 to 40,000 of the Jews from the kingdom of Judea to Babylon. This was probably the time of separation of the Iraqi Jews from the rest of the Jewish people. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14648242" 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>.0057 GM2-GANGLIOSIDOSIS, SUBACUTE</strong>
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HEXA, VAL324VAL
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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> rs28942072 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28942072;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/rs28942072?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=rs28942072" 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=rs28942072" 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=RCV000004149 OR RCV001781173 OR RCV003332074" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004149, RCV001781173, RCV003332074" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004149...</a>
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<p>In a child with severe subacute GM2-gangliosidosis (<a href="/entry/272800">272800</a>) who presented at age 22 months with classic cherry-red spots of the fundus but did not develop any neurologic deficit until almost age 4, <a href="#96" class="mim-tip-reference" title="Wicklow, B. A., Ivanovich, J. L., Plews, M. M., Salo, T. J., Noetzel, M. J., Lueder, G. T., Cartegni, L., Kaback, M. M., Sandhoff, K., Steiner, R. D., Triggs-Raine, B. L. <strong>Severe subacute GM2 gangliosidosis caused by an apparently silent HEXA mutation (V324V) that results in aberrant splicing and reduced HEXA mRNA.</strong> Am. J. Med. Genet. 127A: 158-166, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15108204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15108204</a>] [<a href="https://doi.org/10.1002/ajmg.a.20633" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15108204">Wicklow et al. (2004)</a> identified 3 mutations in the HEXA gene: 10T-C (S4P; <a href="#0014">606869.0014</a>) and 972T-A (V324V) on the maternal allele, and 1A-T (M1L; <a href="#0027">606869.0027</a>) on the paternal allele. Because the delay in onset of neurologic symptoms indicated the presence of residual HEXA, <a href="#96" class="mim-tip-reference" title="Wicklow, B. A., Ivanovich, J. L., Plews, M. M., Salo, T. J., Noetzel, M. J., Lueder, G. T., Cartegni, L., Kaback, M. M., Sandhoff, K., Steiner, R. D., Triggs-Raine, B. L. <strong>Severe subacute GM2 gangliosidosis caused by an apparently silent HEXA mutation (V324V) that results in aberrant splicing and reduced HEXA mRNA.</strong> Am. J. Med. Genet. 127A: 158-166, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15108204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15108204</a>] [<a href="https://doi.org/10.1002/ajmg.a.20633" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15108204">Wicklow et al. (2004)</a> analyzed the effects of the amino acid substitutions on HEXA expression in COS-7 cells. They found that no HEXA activity was associated with the M1L mutation, whereas the S4P mutation resulted in 59% of the activity expressed by wildtype DNA, a level associated with an adult-onset form of the disease. Further analysis revealed that the 972T-A mutation created a new exon 8 donor site, causing a 17-bp deletion and destabilization of the resulting abnormal transcript. <a href="#96" class="mim-tip-reference" title="Wicklow, B. A., Ivanovich, J. L., Plews, M. M., Salo, T. J., Noetzel, M. J., Lueder, G. T., Cartegni, L., Kaback, M. M., Sandhoff, K., Steiner, R. D., Triggs-Raine, B. L. <strong>Severe subacute GM2 gangliosidosis caused by an apparently silent HEXA mutation (V324V) that results in aberrant splicing and reduced HEXA mRNA.</strong> Am. J. Med. Genet. 127A: 158-166, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15108204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15108204</a>] [<a href="https://doi.org/10.1002/ajmg.a.20633" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15108204">Wicklow et al. (2004)</a> concluded that the remaining normal mRNA produced from the 972T-A allele must account for the delayed onset of symptoms in this child. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15108204" 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> rs387906949 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906949;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/rs387906949?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=rs387906949" 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=rs387906949" 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=RCV000023580" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023580" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023580</a>
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<p>In a family (M165) in which first-cousin parents had 5 healthy children and 3 with intellectual disability and seizures (<a href="/entry/272800">272800</a>), <a href="#54" class="mim-tip-reference" title="Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others. <strong>Deep sequencing reveals 50 novel genes for recessive cognitive disorders.</strong> Nature 478: 57-63, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21937992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21937992</a>] [<a href="https://doi.org/10.1038/nature10423" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21937992">Najmabadi et al. (2011)</a> identified a homozygous C-to-T transition at genomic coordinate chr15:70455195 (NCBI36), resulting in a cys58-to-tyr (C58Y) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21937992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Greenberg1982" class="mim-tip-reference" title="Greenberg, D. A., Kaback, M. M. <strong>Estimation of the frequency of hexosaminidase A variant alleles in the American Jewish population.</strong> Am. J. Hum. Genet. 34: 444-451, 1982.">Greenberg and Kaback (1982)</a>; <a href="#Hellkuhl1978" class="mim-tip-reference" title="Hellkuhl, B., Mayr, W. R., Grzeschik, K.-H. <strong>Localization of MPI, PK-M2, IDH-M, and the alpha subunit of hexosaminidase (HEX-A) to the q21-qter region of human chromosome 15.</strong> Cytogenet. Cell Genet. 22: 503-505, 1978.">Hellkuhl et al. (1978)</a>; <a href="#McDowell1989" class="mim-tip-reference" title="McDowell, G. A., Schultz, R. A., Schwartz, S., Blitzer, M. G. <strong>Presence of both Ashkenazi Tay-Sachs mutations in a non-Jewish inbred population. (Abstract)</strong> Am. J. Hum. Genet. 45 (suppl.): A9, 1989.">McDowell et al.
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(1989)</a>; <a href="#Myerowitz1984" class="mim-tip-reference" title="Myerowitz, R., Proia, R. L. <strong>cDNA clone for the alpha-chain of human beta-hexosaminidase: deficiency of alpha-chain mRNA in Ashkenazi Tay-Sachs fibroblasts.</strong> Proc. Nat. Acad. Sci. 81: 5394-5398, 1984.">Myerowitz and Proia (1984)</a>; <a href="#Petersen1983" class="mim-tip-reference" title="Petersen, G. M., Rotter, J. I., Cantor, R. M., Field, L. L., Greenwald, S., Lim, J. S. T., Roy, C., Schoenfeld, V., Lowden, J. A., Kaback, M. M. <strong>The Tay-Sachs disease gene in North American Jewish populations: geographic variations and origin.</strong> Am. J. Hum. Genet. 35: 1258-1269, 1983.">Petersen et al. (1983)</a>; <a href="#Suzuki1970" class="mim-tip-reference" title="Suzuki, Y., Suzuki, K. <strong>Partial deficiency of hexosaminidase component A in juvenile Gm(2)-gangliosidosis.</strong> Neurology 20: 848-851, 1970.">Suzuki
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Ainsworth, P. J., Coulter-Mackie, M. B.
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<strong>A double mutation in exon 6 of the beta-hexosaminidase alpha subunit in a patient with the B1 variant of Tay-Sachs disease.</strong>
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Am. J. Hum. Genet. 51: 802-809, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1415222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1415222</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1415222" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Akalin, N., Shi, H.-P., Vavougios, G., Hechtman, P., Lo, W., Scriver, C. R., Mahuran, D., Kaplan, F.
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<strong>Novel Tay-Sachs disease mutations from China.</strong>
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Hum. Mutat. 1: 40-46, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301190</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1301190" 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.1380010107" target="_blank">Full Text</a>]
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Akerman, B. R., Zielenski, J., Triggs-Raine, B. L., Prence, E. M., Natowicz, M. R., Lim-Steele, J. S. T., Kaback, M. M., Mules, E. H., Thomas, G. H., Clarke, J. T. R., Gravel, R. A.
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<strong>A mutation common in non-Jewish Tay-Sachs disease: frequency and RNA studies.</strong>
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Hum. Mutat. 1: 303-309, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301938</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1301938" 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.1380010407" target="_blank">Full Text</a>]
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Akli, S., Chelly, J., Kahn, A., Poenaru, L.
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<strong>A null allele frequent in non-Jewish Tay-Sachs patients.</strong>
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Hum. Genet. 90: 614-620, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8444467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8444467</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8444467" 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/BF00202478" target="_blank">Full Text</a>]
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Akli, S., Chelly, J., Lacorte, J., Poenaru, L., Kahn, A.
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<strong>Seven novel Tay-Sachs mutations detected by chemical mismatch cleavage of PCR-amplified cDNA fragments.</strong>
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Genomics 11: 124-134, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1837283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1837283</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1837283" 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)90109-r" target="_blank">Full Text</a>]
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Akli, S., Chomel, J.-C., Lacorte, J.-M., Bachner, L., Kahn, A., Poenaru, L.
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<strong>Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients.</strong>
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Hum. Molec. Genet. 2: 61-67, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8490625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8490625</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8490625" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/2.1.61" target="_blank">Full Text</a>]
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Arpaia, E., Dumbrille-Ross, A., Maler, T., Neote, K., Tropak, M., Troxel, C., Stirling, J. L., Pitts, J. S., Bapat, B., Lamhonwah, A. M., Mahuran, D. J., Schuster, S. M., Clarke, J. T. R., Lowden, J. A., Gravel, R. A.
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<strong>Identification of an altered splice site in Ashkenazi Tay-Sachs disease.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3362213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3362213</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3362213" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/333085a0" target="_blank">Full Text</a>]
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Beutler, E., Kuhl, W., Comings, D.
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<strong>Hexosaminidase isozyme in type O Gm2 gangliosidosis (Sandhoff-Jatzkewitz disease).</strong>
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Am. J. Hum. Genet. 27: 628-638, 1975.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/808963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">808963</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=808963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Boustany, R.-M. N., Tanaka, A., Nishimoto, J., Suzuki, K.
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<strong>Genetic cause of a juvenile form of Tay-Sachs disease in a Lebanese child.</strong>
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[<a href="https://doi.org/10.1002/ana.410290120" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.73.10.3637" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF01539065" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00207048" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.47.2.547" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/1.9.759" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00220467" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000131008" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10048-003-0166-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/gepi.1370040203" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.1976.tb01609.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.29.8.563" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.30.6.479" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.82.23.7830" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.81.17.5394" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2008.04.006" target="_blank">Full Text</a>]
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<strong>A splicing defect due to an exon-intron junctional mutation results in abnormal beta-hexosaminidase alpha chain mRNAs in Ashkenazi Jewish patients with Tay-Sachs disease.</strong>
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[<a href="https://doi.org/10.1016/s0006-291x(88)81247-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1471-4159.1988.tb13266.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.86.7.2413" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.271.29.17377" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)11:6<432::AID-HUMU3>3.0.CO;2-Z" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.79.20.6360" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0888-7543(91)90361-h" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.1380010606" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1620/tjem.160.203" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10038-003-0080-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0006-291x(88)80945-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1203/00006450-198203000-00014" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 1/6/2012
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 4/13/2009<br>Marla J. F. O'Neill - updated : 6/30/2004<br>Victor A. McKusick - updated : 4/8/2004<br>Victor A. McKusick - updated : 4/2/2004<br>Victor A. McKusick - updated : 12/23/2003<br>Ada Hamosh - updated : 3/5/2003
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<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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Cassandra L. Kniffin : 4/22/2002
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 03/15/2024
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 09/09/2021<br>carol : 07/28/2021<br>carol : 04/06/2018<br>joanna : 11/16/2017<br>carol : 07/05/2017<br>carol : 07/15/2016<br>alopez : 7/24/2015<br>carol : 5/12/2015<br>alopez : 4/20/2015<br>carol : 2/21/2014<br>carol : 8/5/2013<br>alopez : 11/29/2012<br>alopez : 11/27/2012<br>alopez : 11/27/2012<br>terry : 10/2/2012<br>carol : 5/30/2012<br>carol : 5/10/2012<br>carol : 1/9/2012<br>carol : 1/9/2012<br>terry : 1/6/2012<br>terry : 10/26/2011<br>carol : 11/4/2009<br>terry : 5/14/2009<br>wwang : 4/20/2009<br>ckniffin : 4/13/2009<br>carol : 10/1/2007<br>carol : 11/18/2005<br>terry : 4/21/2005<br>carol : 7/1/2004<br>terry : 6/30/2004<br>tkritzer : 4/14/2004<br>terry : 4/8/2004<br>tkritzer : 4/7/2004<br>terry : 4/2/2004<br>carol : 12/24/2003<br>terry : 12/23/2003<br>carol : 8/1/2003<br>cwells : 3/5/2003<br>carol : 5/7/2002<br>carol : 5/7/2002<br>ckniffin : 5/7/2002<br>ckniffin : 5/6/2002<br>ckniffin : 4/30/2002
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<h3>
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<span class="mim-font">
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<strong>*</strong> 606869
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</h3>
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<h3>
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<span class="mim-font">
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HEXOSAMINIDASE A; HEXA
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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BETA-HEXOSAMINIDASE A
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</span>
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</h4>
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<br />
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: HEXA</em></strong>
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</span>
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</p>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 111385000, 238024005, 9537004;
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<strong>ICD10CM:</strong> E75.02, E75.09;
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</span>
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</p>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 15q23
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Genomic coordinates <span class="small">(GRCh38)</span> : 15:72,340,924-72,376,014 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<tbody>
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<td rowspan="3">
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<span class="mim-font">
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15q23
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</td>
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<td>
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<span class="mim-font">
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[Hex A pseudodeficiency]
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<td>
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<span class="mim-font">
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272800
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</td>
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<tr>
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<span class="mim-font">
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GM2-gangliosidosis, several forms
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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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272800
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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Tay-Sachs disease
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</td>
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<td>
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<span class="mim-font">
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272800
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The HEXA gene encodes the alpha subunit of hexosaminidase A (EC 3.2.1.52), a lysosomal enzyme involved in the breakdown of gangliosides. There are 2 isoenzymes of hexosaminidase: Hex-A and Hex-B (HEXB; 606873). Beutler et al. (1975) concluded that Hex-A has the structure alpha-beta, while Hex-B has the structure beta-beta. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Myerowitz et al. (1985) cloned the alpha chain of Hex-A from an adult human liver library and found an open reading frame corresponding to 529 amino acids, with a molecular weight of approximately 60 kD. The first 17 to 22 amino acids satisfied the requirements of a signal sequence. They noted striking sequence homology with the amino acid sequence for the beta chain, and suggested that both chains evolved from a common ancestor. Korneluk et al. (1986) found 57% amino acid homology between Hex-A and Hex-B. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Proia and Soravia (1987) studied the structure of the HEXA gene by restriction endonuclease mapping, Southern blotting, and DNA sequencing. The alpha-chain gene is about 35 kb long and contains 14 exons. Differential transcription of processing of the most 3-prime exon of the gene resulted in 2 alpha-chain mRNAs with different 3-prime untranslated regions. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By study of somatic cell hybrids, Lalley et al. (1974) suggested that a locus determining hexosaminidase A is on chromosome 7. Subsequently, Van Heyningen et al. (1975) found that the MPI (154550) and PK3 (179050) loci are on chromosome 15, and Gilbert et al. (1975) concluded that MPI, PK3 and HEXA are syntenic. </p><p>Chern et al. (1976) studied heteropolymeric hexosaminidase A formed by human-mouse hybrid cells that contained an X;15 translocation chromosome but lacked human chromosome 5. Tests with specific antisera suggested that the hybrid molecule had human alpha units and mouse beta units. The findings are consistent with hexosaminidase A being composed of alpha and beta subunits coded by genes on chromosomes 15 and 5, respectively. </p><p>Chern et al. (1977) mapped the HEXA gene to chromosome 15q22-qter by somatic cell hybrid analysis. </p><p>Formiga et al. (1988) reported 2 cases of interstitial deletion of chromosome 15. Assay of hexosaminidase A in 1 case enabled them to confirm that the structural gene is located between 15q22 and 15q25 and is included in the deletion. By high resolution in situ hybridization, Takeda et al. (1990) narrowed the assignment to 15q23-q24. Using a cDNA clone for in situ hybridization, Nakai et al. (1991) assigned the HEXA gene to 15q23-q24. </p><p>Seldin et al. (1991) demonstrated that the HEXA homolog in the mouse is located on chromosome 9. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Pennybacker et al. (1996) identified domains in human hexosaminidase that confer distinctive substrate specificity to Hex-A (alpha-beta), Hex-B (beta-beta), and Hex-S (alpha-alpha) isozymes. The active site on the beta subunit primarily degrades neutral substrates, whereas the alpha-subunit site is active against sulfated substrates. Only Hex-A, together with the GM2 activator protein, can degrade GM2 ganglioside. Pennybacker et al. (1996) generated chimeric hexosaminidase subunits by interchanging analogous regions of the alpha and beta subunits. Chimeric constructs were expressed in HeLa cells and selected constructs were produced in the baculovirus expression system to determine their ability to degrade GM2 ganglioside in the presence of GM2 activator protein. Their results allowed them to define 2 noncontiguous sequences in the alpha subunit (amino acids 1-191 and 403-529) which, when substituted into analogous positions in the beta subunit, conferred activity against the sulfated substrate. Pennybacker et al. (1996) also found that amino acids 225-556 in the beta subunit are required for activator-dependent GM2 ganglioside degradation by HexA. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Crystal Structure</em></strong></p><p>
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Lemieux et al. (2006) reported that the 2.8-angstrom resolution x-ray crystallographic structure of Hex-A revealed an alpha/beta heterodimer, with each subunit having a functional active site. Only the alpha subunit active site can hydrolyze GM2 gangliosides due to a flexible loop structure that is removed posttranslationally from the beta subunit. The beta subunit lacks certain key residues and therefore cleaves only neutral substrates efficiently. The alpha subunit contains 2 domains. Domain I is an N-terminal domain with 2 parallel alpha-helices sandwiched between a 6-stranded antiparallel beta-sheet. Domain II is a C-terminal domain comprising a beta-alpha (8)-barrel structure with an active site pocket. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Beutler et al. (1975) concluded that Tay-Sachs disease (272800) is caused by mutation in the alpha subunit of hexosaminidase, causing a dysfunctional Hex-A enzyme, whereas Sandhoff disease (268800) is caused by mutation in the beta subunit (HEXB; 606873), causing dysfunctional Hex-A and Hex-B enzymes. </p><p>Myerowitz (1997) stated that 78 mutations in the HEXA gene had been described, including 65 single-base substitutions, 1 large and 10 small deletions, and 2 small insertions. Of the single-base substitutions, 45 caused missense mutations; 39 of these were disease-causing, 3 were benign but caused a change in phenotype, and 3 were neutral polymorphisms. Six nonsense mutations and 14 splice site lesions resulted from single-base substitutions; all but 1 of the splice site lesions caused a severe form of Tay-Sachs disease. Eight frameshift mutations arose from 6 deletion- and 2 insertion-type lesions. One of the insertions, consisting of 4 bp within exon 11 (606869.0001), is found in 80% of the carriers of Tay-Sachs disease from the Ashkenazi Jewish population. A very large deletion of 7.5 kb, including all of exon 1 and portions of DNA upstream and downstream from that exon (606869.0003), is the major mutation found in Tay-Sachs disease carriers from the French Canadian population. Most of the other mutations are confined to single pedigrees. </p><p>McGinniss et al. (2002) identified 8 novel mutations in the HEXA gene, as well as 31 previously described mutations in 49 subjects (47 enzymatically defined carriers and 2 disease afflicted) who were negative for the 4 common disease-associated and the 2 pseudodeficient mutations. Six novel mutations were found in non-Jewish carriers, and 2 were found in 2 patients with infantile Tay-Sachs disease. </p><p><strong><em>B1 Variant</em></strong></p><p>
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Tanaka et al. (1990) studied 7 patients with the enzymologic characteristics of the B1 variant of Tay-Sachs disease. The variant was characterized by normal catalytic activity on certain artificial substrates, but defective catalytic activity against natural substrates, including GM2 gangliosides. All of the patients, except 1 from Czechoslovakia, carried the same arg178-to-his mutation referred to as DN (see 606869.0006). The Czechoslovakian patient had a mutation in the same codon: a change of nucleotide 532 from C to T resulting in an arg178-to-cys change in the protein (see 606869.0007). Site-directed mutagenesis and expression studies in COS-1 cells demonstrated that either of the point mutations abolished catalytic activity of the alpha subunit. The HEXA gene has 1 intron that is exceptionally large. </p><p>By homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability, Najmabadi et al. (2011) identified a missense mutation in the HEXA gene (606869.0058) in a family (M165) in which the first-cousin parents had 5 healthy children and 3 children with moderate intellectual disability and seizures. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</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>Ohno et al. (2008) performed structural analysis of 33 missense mutations in the HEXA gene, including 24 associated with infantile onset and 9 associated with later onset. The authors used structural modeling of the mutant alpha subunits by calculating the number of atoms affected and determining the solvent-accessible surface area of the corresponding residue in the wildtype enzyme. Nineteen (79%) of the 24 mutations associated with the infantile form of the disease influenced 40 atoms or more (see, e.g., E482K; 606869.0004). Four (80%) of the other 5 infantile cases involving less than 39 atoms affected 1 or more atoms in a functionally important region, such as the active site pocket and/or dimer interface. In contrast, 7 (78%) of 9 late-onset cases influenced less than 39 atoms, and 5 (56%) did not influence any atoms in the functionally important region (see, e.g., G269S; 606869.0008). These results suggested that structural changes responsible for infantile TSD are generally large and/or located in the functionally important region, whereas those responsible for late-onset TSD are generally small. The findings showed that the structural changes significantly correlated with severity of the phenotype. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Nomenclature</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>O'Brien (1978) made suggestions for nomenclature of the various hexosaminidase A and B mutations. Three loci were postulated: alpha, responsible for the alpha subunit, mapped to chromosome 15; beta, responsible for the beta subunit, mapped to chromosome 5; and an activator locus (GM2A; 613109) or loci determining the structure of one or more proteins that stimulate Hex-A to cleave GM2 and GA2 gangliosides. Hex-A is assumed to have the structure alpha-2-beta-2. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>58 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 TAY-SACHS DISEASE</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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HEXA, 4-BP INS, 1278TATC
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<br />
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SNP: rs387906309,
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gnomAD: rs387906309,
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ClinVar: RCV000004093, RCV000224443, RCV000623223, RCV001250227, RCV001252517, RCV004755708
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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>Myerowitz and Costigan (1988) demonstrated that the most frequent DNA lesion in Tay-Sachs disease (272800) of Ashkenazi Jews is a homozygous 4-bp insertion in exon 11. This mutation introduces a premature termination signal in exon 11, resulting in a deficiency of mRNA. Using a dot-blot assay to screen patients and heterozygous carriers for the insertion mutation, Myerowitz and Costigan (1988) found the lesion in about 70% of carriers tested, thus identifying it as the most frequent defect underlying Tay-Sachs disease in the Ashkenazi Jewish population. Triggs-Raine and Gravel (1990) showed that this insertion mutation of only 4 bp can be detected by the formation of heteroduplexes. This mutation causes a frameshift and a termination codon 9 nucleotides downstream. By site-directed mutagenesis, Nishimoto et al. (1991) examined the basis of the paradox that the mutant gene with the 4-base insertion in exon 11 is transcribed normally but the mRNA is essentially undetectable. They found no evidence of interference with normal splicing of the transcript and the mutation did not destabilize properly spliced mRNA. Thus, the studies left open the question of the mechanism of the mutation. The possibility was mentioned that another still unidentified abnormality in the same allele may be responsible for the nearly complete absence of mRNA. </p><p>There appears to be an increased frequency of TSD in the Cajun population of southwest Louisiana which numbers less than one million persons. McDowell et al. (1992) reported that in the previous 3 decades, at least 8 infants from 6 apparently unrelated Cajun families had been identified. They found that the mutation in 11 of 12 of the TSD alleles in these 6 families was the exon 11 insertion present in approximately 70% of Ashkenazi Jewish TSD heterozygotes. The remaining allele was a single-base transition in the donor splice site of intron 9 (606869.0033). To trace the origins of these 2 mutations in the Cajun population, the TSD carrier status was determined enzymatically in 90 members of 4 of the 6 families, and extensive pedigrees were constructed for all carriers. A single ancestral couple from France was found to be common to most of the carriers of the exon 11 insertion. Pedigree data suggested that this mutation has been in the Cajun population since its founding and that it may be widely distributed within the population. In contrast, the intron 9 mutation was apparently introduced later and is probably limited to a few Louisiana families. Zlotogora (1993) argued that 2 mutations would not be unexpected in the Cajun population. Thurmon (1993) gave a historical account of the 'Jews of Acadiana.' He indicated that the Jews were assimilated into the Acadian culture and suggested that this was the source of the Tay-Sachs genes. He also pointed out that about the same time Jewish merchants began to arrive in Acadiana, the French Revolution produced an influx of non-Acadian French immigrants. Many were of aristocratic lineage and held themselves aloof from the Acadians. </p><p>This mutation is alternatively designated 1277TATC or 1278insTATC. See 606869.0054.</p><p>To investigate the genetic history of the 1278insTATC mutation, the most frequent cause of Tay-Sachs disease in Ashkenazi Jews, Frisch et al. (2004) identified a conserved haplotype in 1278insTATC chromosomes for 55 unrelated Ashkenazi Jewish individuals (15 homozygotes and 40 heterozygotes for the TSD mutation), suggesting the occurrence of a common founder. When 2 methods were used for analysis of linkage disequilibrium (LD) between flanking polymorphic markers and the disease locus and for study of the decay of LD over time, the estimated age of the insertion was found to be 40 +/- 12 generations (95% confidence interval, 30 to 50 generations), so that the most recent common ancestor of the mutation-bearing chromosomes would date to the 8th or 9th century. This corresponds with the demographic expansion of Ashkenazi Jews in central Europe, following the founding of the Ashkenazi settlement in the early Middle Ages. The results were also consistent with the geographic distribution of the mutation and with the coalescent times of mutations causing 2 other lysosomal storage diseases frequent in Ashkenazi Jews: Gaucher disease (230800) and mucolipidosis IV (252650). Evidence for the absence of a heterozygote advantage of the mutation was provided by comparison between the estimated age of 1278insTATC and the probability of the current Ashkenazi Jewish frequency of the mutant allele as a function of its age, calculated by use of a branching-process model. Therefore, the founder effect in a rapidly expanding population arising from a bottleneck provides a robust and parsimonious hypothesis explaining the spread of 1278insTATC-related TSD in Ashkenazi Jewish individuals. </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 TAY-SACHS DISEASE</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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HEXA, IVS12, G-C, +1
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<br />
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SNP: rs147324677,
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gnomAD: rs147324677,
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ClinVar: RCV000004094, RCV000255737
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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>Arpaia et al. (1988) identified a single-base mutation in a cloned fragment of the HEXA gene from an Ashkenazi Jewish patient with Tay-Sachs disease (272800). The change, a G-to-C substitution in the first nucleotide of intron 12, was expected to result in defective splicing of the mRNA. A test for the mutant allele based on amplification of DNA by the PCR and cleavage of a DdeI restriction site generated by the mutation showed that this case and 2 other cases of the Ashkenazi, infantile form of Tay-Sachs disease are heterozygous for 2 different mutations. The mutation was found in over 20% of the Tay-Sachs alleles that they examined in Ashkenazi Jewish patients and carriers but in none of 43 normal Jewish persons. Arpaia et al. (1988) suggested that the occurrence of multiple mutant alleles in Ashkenazim warrants further examination of the selective advantage hypothesis; the hypothesis of founder effect suggests the existence of a single mutant allele. In a case of classic infantile Tay-Sachs disease in an Ashkenazi Jewish patient, Ohno and Suzuki (1988) found that there were 2 types of Hex-A mRNA: intact mRNA and mRNA with truncated intron 12 sequences. Sequence analysis showed a single G-to-C nucleotide transversion at the 5-prime donor site of intron 12, the same change as that in the patient of Arpaia et al. (1988). Both patients were compound heterozygotes. Myerowitz (1988) likewise found in each of 2 unrelated Ashkenazi patients that 1 alpha-chain allele harbored the splice junction mutation. Only 1 parent of each of these patients was positive for the defect. Thirty percent of obligate heterozygotes tested carried the splice junction mutation, whereas 20 Ashkenazi Jews designated noncarriers by enzymatic assay were negative for this alteration. In an Ashkenazi Jewish child with Tay-Sachs disease and a splicing defect at the 5-prime donor site of intron 12, present in heterozygous state, Ohno and Suzuki (1988) found a variety of abnormal mRNAs. </p><p>This mutation, the second most frequent among Ashkenazi Jews, accounted for approximately 13% of cases in this ethnic group. Strasberg et al. (1997) reported the first incidence of homozygosity for the intron 12 mutation in a female infant with classic TSD. The child first presented at the age of 13.5 months with seizures associated with fever and pneumococcal bacteremia. Developmental delay had been recognized from early in life with no history of regression or exaggerated startle reflex. At 13 months, she showed central hypotonia and peripheral hypertonia with exaggerated deep tendon reflexes and bilateral ankle clonus. Funduscopy revealed bilateral cherry red spots of the macula. </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>.0003 TAY-SACHS DISEASE</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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HEXA, 7.6-KB DEL, EX1
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<br />
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ClinVar: RCV000004095
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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>On the basis of study of 2 Ashkenazi patients and 2 French Canadian patients with a Hex-A cDNA probe, Myerowitz and Hogikyan (1986) concluded that each of these populations has a different mutation. In the Ashkenazi mutation the HEXA gene appeared to be intact, whereas in the French Canadian mutation the gene had a 5-prime deletion of 5 to 8 kilobases. The disorders are clinically identical and the heterozygote frequency in each is the same. It had previously been suspected that the Ashkenazi gene was introduced into the French Canadian population by someone, presumably male, of Ashkenazi extraction (the 'Jewish fur trader hypothesis'). Keats et al. (1987) suspected that the mutation in French Canadians may be different from that in Ashkenazi Jews because the ratio HEXA/(HEXA + HEXB) was not a satisfactory statistic for carrier status in the French Canadian population whereas it is in Ashkenazi Jews. Myerowitz and Hogikyan (1987) showed that the deletion in the French Canadian form of Tay-Sachs disease (272800) is 7.6 kb long, includes part of intron 1 and all of exon 1, and extends 2,000 bp upstream past the putative promoter region of the alpha-chain gene. Sequence analysis of the deletion junction in the mutant gene and corresponding regions of the normal gene demonstrated the presence of similarly oriented Alu sequences at the 5-prime and 3-prime deletion boundaries. Myerowitz and Hogikyan (1987) interpreted this as indicating that the deletion had arisen during homologous recombination and unequal crossing-over between Alu sequences. Hechtman et al. (1990) found the 7.6-kb deletion mutation at the 5-prime end of the HEXA gene in 18 of 22 independently segregating mutant chromosomes from patients of French Canadian origin. One chromosome carried the 4-nucleotide insertion in exon 11 (606869.0001). None of the chromosomes carried the 5-prime splice site mutation in intron 12 found in Ashkenazi Jews (606869.0002). One chromosome carried a 'novel,' but not yet characterized type of B1 mutation. The remaining 3 patients carried TSD alleles different from all of the above-mentioned ones. In French Canadians, the 5-prime deletion clustered in persons originating in southeastern Quebec (Gaspe) and adjacent counties of northern New Brunswick. De Braekeleer et al. (1992) traced the ancestry of the persons carrying the 'French Canadian deletion' to an average depth of 12 generations, identifying 60 ancestors and 80 European founders common to all of them. The ancestral origins of the European founders showed a significantly greater number of individuals born in the French provinces of Normandy and Perche than expected based on information regarding the origins of the 8,500 immigrants who settled New France during the French regime. The failure to find the French Canadian deletion among TSD probands in France suggests that the mutation occurred on Canadian soil. If this is true, the search for the ancestral couple was narrowed to 7 possibilities. These included a man born in 1680 and his wife born in 1683, who had 11 offspring, at least 5 of whom must have been heterozygous for the deletion because they had carrier descendants through a total of 14 descendant lines. </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>.0004 TAY-SACHS DISEASE</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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|
|
HEXA, GLU482LYS
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<br />
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|
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SNP: rs121907952,
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gnomAD: rs121907952,
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ClinVar: RCV000004096, RCV002512734, RCV003480020
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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 non-Jewish case of Tay-Sachs disease (272800), Proia and Neufeld (1982) found a normal amount of alpha chain of beta-hexosaminidase synthesized in a cell-free translation system using RNA from cultured fibroblasts of the patient. (RNA from fibroblasts of 4 other patients, 3 Jewish and 1 non-Jewish, did not direct the translation of immunoprecipitable alpha chain. In the same system, RNA from fibroblasts of 2 patients with Sandhoff disease did not direct translation of immunoprecipitable beta chain.) Intact fibroblasts from the atypical patient likewise synthesized the alpha chain as shown by labeling with (3H)leucine; however, strong detergent was required for extraction. The alpha chain could be labeled with (3H)mannose but not with (32P)phosphate; it was neither secreted nor accumulated in the proteolytically processed form, and it disappeared within a day of synthesis. The authors suggested that a plausible but not unique explanation is that the insoluble alpha chain is not transported from the endoplasmic reticulum (the site of glycosylation) to the Golgi apparatus (the site of phosphorylation) nor to the further destinations--lysosomes and the exterior of the cell. Nakano et al. (1988) isolated cDNA clones from cultured fibroblasts of this patient, who was Italian. Sequence analysis showed a single nucleotide substitution, from G to A, at nucleotide 1444, which resulted in a change from glutamic acid to lysine at amino acid 482. The change from the strongly negative to strongly positive charge at amino acid 482 was thought to be responsible for the defective processing of the enzyme in this patient. Akalin et al. (1992) demonstrated the same mutation in a case of classic TSD in a Chinese patient. </p><p>Using structural modeling, Ohno et al. (2008) found that the glu482 residue is buried within the folded enzyme and the E482K mutation affects atoms throughout the whole enzyme, which correlated with a more severe 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>
|
|
<span class="mim-font">
|
|
<strong>.0005 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
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|
|
HEXA, 1-BP DEL, 1510C
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<br />
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|
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SNP: rs797044433,
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ClinVar: RCV000004098
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Italian patient with clinically classic Tay-Sachs disease (272800), Zokaeem et al. (1987) described a defect in the alpha chain that differed from all those previously described. Fibroblasts synthesized a precursor alpha chain that was smaller than its normal counterpart. Fibroblasts from the patient's parents, who were consanguineous, produced both normal and mutant alpha chains. The mutant alpha chain did not undergo the posttranslational modifications characteristic of its normal counterpart, i.e., synthesis of the mannosephosphate recognition marker, association with the beta-chain to give Hex-A, and proteolytic conversion to the mature form. Furthermore, the mutant alpha chain was not secreted. Lau and Neufeld (1989) identified the mutation as a deletion of cytosine at position 1510 of the coding sequence. The frameshift mutation, which was found to be present on both alleles, caused premature termination 4 codons downstream, and the loss of a very hydrophilic stretch of 22 amino acids. Expression of alpha-subunit cDNA with the cytosine deletion in COS-1 cells reproduced the phenotype of the Italian patient referred to as WG1051, i.e., a truncated alpha subunit was retained. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 TAY-SACHS DISEASE, B1 VARIANT</strong>
|
|
</span>
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</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
HEXA, DN ALLELE
|
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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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HEXA, ARG178HIS
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<br />
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|
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SNP: rs28941770,
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gnomAD: rs28941770,
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ClinVar: RCV000004100, RCV000004101, RCV000396083, RCV000409508, RCV001255389, RCV002345228, RCV003964792
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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>Ohno and Suzuki (1988) defined the mutation in the B1 variant form of Tay-Sachs disease (272800) in a patient of Puerto Rican extraction residing in New York City. The variant was characterized by normal catalytic activity on certain artificial substrates but defective catalytic activity against natural substrates. The so-called DN allele shows a single-base transition at nucleotide 533 from the normal G-to-A within exon 5, resulting in a change from arginine to histidine at amino acid 178. The position of the mutation is about 90 amino acids from the N-terminus of the mature, processed enzyme. Computer analysis predicted substantial alteration in the secondary structure of the enzyme protein. Using two 21-mer oligonucleotide probes with the normal and mutant sequences, Tanaka et al. (1988) found that 4 of 5 other patients of various ethnic origin (Spanish, Italian, Czechoslovakian, French, and English/Italian/Hungarian) showed the same defect. The only case that was completely negative for the DN mutation was the Czechoslovakian patient. These cell lines were tested for the splicing defect at the 5-prime donor site of intron 12 found among Ashkenazi Jewish patients, with negative results in all. Four of the patients, including the original Puerto Rican patient, gave positive signals for both the normal and the mutant probes. Thus these patients were clearly compound heterozygotes. The patient of Spanish origin (residing in Germany) was positive only for the mutant sequence. The parents of this patient came from the same village in Spain, although there was no clear record of consanguinity. The repeated occurrence of this rare mutation in unrelated populations indicates that the biochemical abnormality that defines B1 can be produced in only a limited number of ways. </p><p>Goebel et al. (1989) described the B1 variant in a 12-year-old girl who suffered from a progressive nerve degenerative disorder marked by ataxia, extrapyramidal symptoms, and convulsions. </p><p>According to the findings of dos Santos et al. (1991), the B1 variant occurs at an exceptionally high frequency in the northern part of Portugal. In most of the patients there, the disease manifests itself as a juvenile form. In 10 of 11 such patients, dos Santos et al. (1991) found homozygosity for the DN allele; in the other patient, whose clinical profile more closely resembled the late infantile phenotype, compound heterozygosity for the DN allele and another, as yet unidentified abnormal allele was found. Whitley et al. (1992) detected the arg178-to-his mutation by PCR amplification and direct DNA sequencing of exon 5 of the HEXA gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 TAY-SACHS DISEASE, B1 VARIANT</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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HEXA, CZECHOSLOVAKIAN ALLELE
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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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HEXA, ARG178CYS
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<br />
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SNP: rs121907953,
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gnomAD: rs121907953,
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ClinVar: RCV000004102, RCV000416435
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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>See Tanaka et al. (1990). </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>.0008 GM2-GANGLIOSIDOSIS, ADULT</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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HEXA, GLY269SER
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<br />
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SNP: rs121907954,
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|
|
gnomAD: rs121907954,
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|
|
ClinVar: RCV000004104, RCV000168285, RCV000434025, RCV001810397, RCV002408450, RCV003924800
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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 8 Ashkenazi adult GM2-gangliosidosis (272800) patients from 5 different families, Navon and Proia (1989) found a gly269-to-ser (G269S) substitution. This amino acid substitution was shown to depress drastically the catalytic activity of the alpha chain after expression in COS-1 cells. All the patients proved to be compound heterozygotes of the allele with the gly-to-ser change and 1 of the 2 Ashkenazi infantile Tay-Sachs alleles. Paw et al. (1989) described the molecular basis of adult onset and chronic GM2 gangliosidoses in Ashkenazi Jewish patients known to have a defective association between the alpha and beta subunits of hexosaminidase. They identified a G-to-A substitution at the 3-prime end of exon 7, resulting in the substitution of serine for glycine at position 269 of the alpha subunit. One patient with the adult-onset disorder had inherited this gly-to-ser mutation at position 269 from his father and a null allele from his mother. The same combination of alleles was found in fetal fibroblasts from an association-defective phenotype and in cells from 5 patients with chronic Gm2-gangliosidoses. Navon et al. (1990) found the same gly269-to-ser mutation in 6 adult GM2-gangliosidosis patients from 4 different non-Jewish families. Three of these patients, 2 of whom were brothers, showed a hybridization pattern consistent with homozygosity for the mutation. The others were compound heterozygotes of the gly269-to-ser mutation together with an unidentified alpha-subunit mutation. Navon et al. (1990) suggested that the gly269-to-ser mutation in the Ashkenazi and non-Jewish patients might have had a common origin since the ancestry of the Ashkenazim could be traced to eastern Europe. Kappler et al. (1990) suggested caution in concluding that homozygosity for the gly269-to-ser allele as reported by Navon et al. (1990) is responsible for adult GM2-gangliosidosis. They suggested that it might be a pseudodeficiency with coincidental association with neurologic disease. Proia et al. (1990) provided information suggesting that the mutation is indeed causative. </p><p>Because hexosaminidase A is heterodimeric, analysis of alpha-chain mutations is not straightforward. Brown and Mahuran (1993) used the techniques of in vitro mutagenesis and transient expression in COS cells to demonstrate that the G269S mutation does not directly affect alpha-dimerization but exerts an indirect effect on the dimer through destabilizing the folded alpha subunit at physiologic temperatures. Two other alpha mutations associated with more severe phenotypes, gly250-to-asp (606869.0013) and glu482-to-lys (606869.0004), appeared to inhibit the initial folding of the subunit. </p><p>Using structural modeling, Ohno et al. (2008) demonstrated that the gly269 residue is located on the surface of the folded enzyme protein and the G269S mutation only influences a small number of atoms, which correlated with a less severe phenotype and residual enzyme 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>.0009 GM2-GANGLIOSIDOSIS, JUVENILE</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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HEXA, ARG504HIS
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<br />
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SNP: rs121907955,
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gnomAD: rs121907955,
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|
ClinVar: RCV000004099, RCV000409695, RCV001800288
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</span>
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|
</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a patient with juvenile-onset GM2-gangliosidosis (272800), of Assyrian origin and with first-cousin parents, Paw et al. (1990) identified a G-to-A transition at nucleotide 1511 resulting in substitution of histidine for arginine at position 504 in the HEXA molecule. Cultured fibroblasts from the patient synthesized an alpha subunit that could acquire mannose 6-phosphate and be secreted, but which failed to associate with the beta-subunit to form the enzymatically active heterodimer. The patient had progressive ataxia, spastic paraplegia, dysarthria, and cherry-red macula at the time she was first seen at age 10 years. The patient was homozygous for the arg504-to-his mutation, which occurred in a CpG dinucleotide. The same mutation was found in a patient with juvenile-onset GM2-gangliosidosis of Armenian extraction. The mutation again was present in homozygous state, consistent with the fact that his parents were first cousins. The same mutation was found by Boustany et al. (1991) in heterozygous state in a Lebanese patient with the juvenile form of Tay-Sachs disease. The clinical features were progressive spasticity, ataxia, and cognitive decline. The patient came from a Maronite community. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0010 GM2-GANGLIOSIDOSIS, JUVENILE</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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HEXA, ARG499HIS ({dbSNP rs121907956})
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<br />
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SNP: rs121907956,
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gnomAD: rs121907956,
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ClinVar: RCV000004105, RCV000210735, RCV000338961, RCV000520531
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a patient of mixed Jewish and Scottish/Irish ancestry who had progressively severe neurologic deterioration beginning at age 3 to 5 years and progressing to death at age 26, Paw et al. (1990) found a G-to-A transition at nucleotide 1496 resulting in substitution of histidine for arginine at position 499 (R499H) of the alpha subunit. The mutation was present in compound heterozygosity with a common infantile Tay-Sachs allele. This patient had a similarly affected brother. In another patient with juvenile GM2-gangliosidosis (272800), neither this nor the R504H mutation was found, indicating further heterogeneity. </p><p>Tanaka et al. (2003) found the R499H missense mutation in 1 allele of a Japanese patient with the late infantile form of GM2-gangliosidosis and the R499C mutation (606869.0028) on 1 allele of another Japanese patient with the juvenile form. </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 TAY-SACHS DISEASE</strong>
|
|
</span>
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|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
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HEXA, ARG170GLN
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<br />
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SNP: rs121907957,
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gnomAD: rs121907957,
|
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|
|
|
|
ClinVar: RCV000004106, RCV000336253
|
|
|
|
|
|
</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>In compound heterozygous state in a Japanese infant, Nakano et al. (1990) found substitution of glutamine for arginine-170, resulting from a G-to-A change at nucleotide 509. Expression of the mutant enzyme protein in the COS-1 cell system indicated that it is catalytically inactive and also unstable. The exact abnormality in the other allele could not be identified, but previously identified mutations of the HEXA gene were excluded. The arg170-to-gln mutation due to a G-to-A transition at a CpG site was also found as one of 3 main mutations in the Moroccan Jewish population. </p>
|
|
</span>
|
|
</div>
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|
<div>
|
|
<br />
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</div>
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|
</div>
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|
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|
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<div>
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|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
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|
HEXA, TRP420CYS
|
|
|
|
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|
<br />
|
|
|
|
SNP: rs121907958,
|
|
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|
|
|
gnomAD: rs121907958,
|
|
|
|
|
|
ClinVar: RCV000004107, RCV005054135
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Catholic family with parents of Irish and German descent, Tanaka et al. (1990) demonstrated that an infant with clinically typical infantile Tay-Sachs disease (272800) had a single nucleotide transversion in exon 11: 1260G-C; trp420-to-cys. Expression in the COS-1 cell system confirmed that the mutant gene did not produce functional enzyme protein. The mutation could be identified rapidly and reliably because it abolished one of the 2 KpnI sites in the coding sequence. The patient was a compound heterozygote; the nature of the abnormality in the other allele had not been identified. The 'Kpn mutation' was inherited from the maternal side of the family, which was of German descent. </p>
|
|
</span>
|
|
</div>
|
|
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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>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 TAY-SACHS DISEASE, JUVENILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, GLY250ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121907959,
|
|
|
|
|
|
gnomAD: rs121907959,
|
|
|
|
|
|
ClinVar: RCV000004108, RCV002226437
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Lebanese proband with juvenile-onset Tay-Sachs disease (272800), Trop et al. (1990) found, by direct sequencing of PCR products, a G-to-A transition at nucleotide 749 in exon 7. The mutation caused a glycine to aspartic acid change at amino acid 250. See Trop et al. (1992). </p>
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
|
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, PHE304DEL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121907960,
|
|
|
|
|
|
|
|
ClinVar: RCV000169148, RCV000622988, RCV001545560
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Moroccan Jewish Tay-Sachs (272800) patient, Navon and Proia (1991) found an in-frame deletion of 1 of the 2 adjacent phenylalanine codons present at positions 304 and 305 in the alpha subunit. The Moroccan patient was found also to carry a different, as yet unidentified, mutation. Among obligate carriers from 6 unrelated Moroccan Jewish families, 3 instances of the same deletion were found. See Drucker et al. (1992). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 GM2-GANGLIOSIDOSIS, CHRONIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, ARG504CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28942071,
|
|
|
|
|
|
gnomAD: rs28942071,
|
|
|
|
|
|
ClinVar: RCV000004112, RCV000169084, RCV001000970, RCV001508769
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>A female patient in a family of German origin had slow but progressive spinocerebellar degeneration from the age of 2.5 years (Raghavan et al., 1985). At the age of 26 years, she was in leg braces and had great difficulty rising from a sitting position. Her 25-year-old sister was only mildly affected; she had been clinically normal into her late teens but later developed signs of cerebellar dysfunction. Paw et al. (1991) found a substitution of cysteine for arginine at codon 504. The family was unique in another respect, namely, that the normal allele of the mother and of an arg504-to-cys heterozygous sib had a silent mutation, a G-to-A transition in the wobble position of the glutamic acid codon at position 506. A search for this mutation was prompted by the fact that 2 other mutations had been identified in this codon: a G-to-A transition resulting in an arg504-to-his substitution (606869.0009) in a patient with juvenile GM2-gangliosidosis (272800) and a C deletion resulting in a premature termination of the alpha subunit (606869.0005) in a patient with Tay-Sachs disease. Using chemical mismatch cleavage of PCR-amplified cDNA fragments, Akli et al. (1991) demonstrated the same arg504-to-cys missense mutation in exon 13 in 2 patients. Change from CGC to TGC was responsible. One patient was a homozygote from Algeria; the other was a compound heterozygote from France (the other allele was an intron 2 splice mutation (606869.0026).) Both patients had the classic infantile form of Tay-Sachs disease. It is unclear why the phenotype of the patients with this mutation was so different. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, IVS4, G-T, -1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs764343937,
|
|
|
|
|
|
gnomAD: rs764343937,
|
|
|
|
|
|
ClinVar: RCV000586741, RCV004719896
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated American black infants with both biochemical and clinical features of classic infantile Tay-Sachs disease (272800), Mules et al. (1991) found a G-to-T transversion in the AG acceptor splice site preceding exon 5 of the HEXA gene. One patient was homozygous for the mutation; a second was a compound heterozygote. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, SER210PHE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121907961,
|
|
|
|
|
|
|
|
ClinVar: RCV000004114
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Using chemical mismatch cleavage of PCR-amplified cDNA fragments, Akli et al. (1991) demonstrated a missense mutation that altered the codon for serine-210 to phenylalanine in exon 6. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 REMOVED FROM DATABASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, ARG137TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121907962,
|
|
|
|
|
|
gnomAD: rs121907962,
|
|
|
|
|
|
ClinVar: RCV000004110, RCV000255817
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Using chemical mismatch cleavage of PCR-amplified cDNA fragments, Akli et al. (1991) detected a nonsense mutation in exon 3 that converted arginine-137 to stop. In a study of the nature of mutations in non-Jewish patients or carriers of some form of GM2-gangliosidosis (272800), Mules et al. (1992) found a C-to-T transition at nucleotide 409 in exon 3 converting arginine-137 to a stop codon. The family was of possible Irish extraction. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, ARG393TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121907963,
|
|
|
|
|
|
gnomAD: rs121907963,
|
|
|
|
|
|
ClinVar: RCV000004111, RCV000522695
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Using chemical mismatch cleavage of PCR-amplified cDNA fragments, Akli et al. (1991) detected a nonsense mutation in exon 11 that converted arginine-393 to stop. Both this and the arg137-to-ter mutation were associated with a marked decrease in the abundance of mRNA, probably because they resulted in mRNA instability. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 TAY-SACHS DISEASE</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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|
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|
HEXA, 5-BP DEL, TCTCC, IVS9
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|
<br />
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|
|
SNP: rs759219683,
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|
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|
|
|
gnomAD: rs759219683,
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|
|
|
|
ClinVar: RCV000669592, RCV001584543
|
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|
|
|
</span>
|
|
</div>
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|
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|
<div>
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<span class="mim-text-font">
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|
<p>Triggs-Raine et al. (1991) sequenced the portions of the introns flanking each of the 14 HEXA exons in order to specify oligonucleotide primers for the PCR-dependent amplification of each exon and splice junction sequence. Five novel mutations from Tay-Sachs disease (272800) patients were detected as well as 2 mutations that had previously been reported. The 5 novel mutations were a 5-bp deletion of TCTCC in IVS9; a 2-bp deletion of TG in exon 5; 78G-A, giving a stop codon in exon 1; 533G-T in exon 5, producing the third amino acid substitution detected at this site; and G to C at position 1 of IVS2, expected to produce abnormal splicing. The 2 previously reported mutations were 1496G-A in exon 13 (606869.0010) and a 4-bp insertion in exon 11 (606869.0001). </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>.0022 TAY-SACHS DISEASE</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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|
HEXA, 2-BP DEL, TG, EX5
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<br />
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ClinVar: RCV000004116
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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 606869.0021 and Triggs-Raine et al. (1991). </p>
|
|
</span>
|
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</div>
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<div>
|
|
<br />
|
|
</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>.0023 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
|
|
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|
<div>
|
|
<span class="mim-text-font">
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|
HEXA, TRP26TER
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|
<br />
|
|
|
|
SNP: rs121907964,
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|
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|
|
ClinVar: RCV000004117
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Triggs-Raine et al. (1991) found in exon 1 of the HEXA gene a 78G-A substitution which changed trp26 to a termination codon. Drucker and Navon (1993) found the same mutation in an Arab TSD (272800) patient. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, ARG178LEU
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs28941770,
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|
|
|
|
|
gnomAD: rs28941770,
|
|
|
|
|
|
ClinVar: RCV000004118, RCV003476891
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Triggs-Raine et al. (1991) found in exon 5 a 533G-T substitution that changed arg178 to leu. This is the third amino acid substitution that has been detected at this site. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0025 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, IVS2, G-C, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs797044432,
|
|
|
|
|
|
|
|
ClinVar: RCV000004097
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a case of Tay-Sachs disease (272800), Triggs-Raine et al. (1991) found a G-to-C transition at the +1 position of IVS2. This change would be expected to produce abnormal splicing. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0026 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, IVS2, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs797044432,
|
|
|
|
|
|
|
|
ClinVar: RCV000672344
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Using chemical mismatch cleavage of PCR-amplified cDNA fragments, Akli et al. (1991) detected a splice donor site mutation, a G-to-A change in the first nucleotide of IVS2, in a French patient with classic Tay-Sachs disease (272800). The other allele carried the arg504-to-cys mutation (606869.0015). Mules et al. (1992) found this mutation in compound heterozygous state in a non-Jewish, Pennsylvania Dutch kindred in which Kelly et al. (1975) described a high frequency of TSD heterozygotes. The increased carrier frequency was noted following the birth of at least 2 (more by history) children with TSD. Subsequent screening of the extended family uncovered 98 of 333 persons tested who were apparent carriers of TSD. Evidence that the increased carrier frequency in this group might be due to more than one HEXA mutation was provided by the discovery of a healthy 37-year-old woman whose serum hexosaminidase A level was indistinguishable from that found in classic TSD patients. Further studies led Kelly et al. (1976) to conclude that she was a compound heterozygote for a TSD allele and a 'pseudodeficient' allele. Thomas et al. (1982) provided support for this interpretation; they demonstrated that while she lacked hexosaminidase A activity against the artificial substrate, her enzyme activity to cleave the natural substrate was similar to that of TSD heterozygotes. The pseudodeficiency allele carried an arg247-to-trp mutation (606869.0035) as described by Triggs-Raine et al. (1992) in 2 members of the Pennsylvania Dutch community and in other unrelated persons. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0027 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, MET1VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121907965,
|
|
|
|
|
|
gnomAD: rs121907965,
|
|
|
|
|
|
ClinVar: RCV000004120
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Mules et al. (1992) found that only 3 of 34 'Tay-Sachs chromosomes' in 22 unrelated, non-Jewish patients or carriers of some form of GM2-gangliosidosis (272800) had either of the 2 mutations commonly found in the Jewish population. One of the 'new' mutations found, in an American black with classic TSD, was an initiator mutation, ATG to GTG, converting the initiating methionine to valine. Initiator codon mutations have been discovered as causes of beta-0-thalassemia (141900.0344, 141900.0345), Albright hereditary osteodystrophy (139320.0001), and ornithine aminotransferase deficiency (258870.0001). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0028 GM2-GANGLIOSIDOSIS, ADULT-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, ARG499CYS ({dbSNP rs121907966})
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121907966,
|
|
|
|
|
|
gnomAD: rs121907966,
|
|
|
|
|
|
ClinVar: RCV000004121, RCV000169417, RCV002390089
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Using PCR, single-strand conformation polymorphism (SSCP) analysis, and sequencing in a study of the nature of mutations in non-Jewish patients with GM2-gangliosidosis (272800), Mules et al. (1992) found an arg499-to-cys substitution (R499C) resulting from a C-to-T transition at nucleotide 1495 in exon 13. The patient was of mixed European ancestry. Akli et al. (1993) also found this mutation in 2 non-Jewish patients, one French and the other Italian, who had the infantile form of Tay-Sachs disease. Both patients were compound heterozygotes, the other allele being the common exon 11 insertion (606869.0001). </p><p>Another Tay-Sachs mutation, arg499-to-his (R499H; 606869.0010), involves the same codon. Tanaka et al. (2003) found the R499H missense mutation in 1 allele of a Japanese patient with the late infantile form of GM2-gangliosidosis and the R499C mutation on 1 allele of another Japanese patient with the juvenile form. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0029 GM2-GANGLIOSIDOSIS, B1 VARIANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, TRP329TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121907967,
|
|
|
|
|
|
|
|
ClinVar: RCV000004122, RCV002281692
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a study of 22 unrelated, non-Jewish patients or carriers of some form of GM2-gangliosidosis (272800), Mules et al. (1992) found a patient with the B1 variant (late onset) who had a 'new' mutation: G to A at nucleotide 987 in exon 9, converting tryptophan-329 to a stop codon. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0030 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, TRP485ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121907968,
|
|
|
|
|
|
|
|
ClinVar: RCV000004123
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a case of classic TSD (272800) in a Chinese patient, Akalin et al. (1992) identified a T-to-C transition at nucleotide 1453 in exon 13 leading to substitution of arginine for tryptophan-485. The change was identified by single strand conformation polymorphism analysis and direct sequencing. The proband was homozygous. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0031 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, 1-BP INS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1595801740,
|
|
|
|
|
|
|
|
ClinVar: RCV000004124
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Chinese patient, Akalin et al. (1992) identified an insertion of an A after nucleotide 547. The change generated an early termination codon 6 bp downstream from the insertion site. The proband was homozygous. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0032 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, TYR180TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121907969,
|
|
|
|
|
|
gnomAD: rs121907969,
|
|
|
|
|
|
ClinVar: RCV000004125
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Moroccan Jews, a subgroup of Sephardic Jews, a high frequency of Tay-Sachs disease (272800) has been found. One of the mutations is an in-frame deletion of 1 of 2 adjacent phenylalanine codons at position 304 or 305 (606869.0014). Drucker et al. (1992) identified 2 additional mutations within exon 5 of the HEXA gene that account for the remaining TSD alleles in this population. One of the mutations was a G-to-A transition resulting in an arg170-to-gln substitution of the same type as described by others in a Japanese infant (see 606869.0011). The other was a novel C-to-G transversion resulting in replacement of tyrosine-180 by a stop codon. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0033 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, IVS9, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs76173977,
|
|
|
|
|
|
gnomAD: rs76173977,
|
|
|
|
|
|
ClinVar: RCV000004126, RCV000079047, RCV002415396, RCV003952341
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Akli et al. (1991) described a G-to-A transition of the obligatory GT sequence of the intron 9 donor splice site of the HEXA gene in a case of classic Tay-Sachs disease (272800). In a case of infantile Tay-Sachs disease in a Louisiana Cajun family, McDowell et al. (1992) found compound heterozygosity for the exon 11 insertion (606869.0001) and for a G-to-A transition at position +1 of intron 9 changing the invariant GT of the donor splice site to AT. Akerman et al. (1992) found a relatively high frequency of the IVS9 donor splice site mutation in non-Jewish Caucasians. The mutation was not identified among 12 black American TSD alleles or in any of 18 Ashkenazi Jewish, enzyme-defined carriers. This allele and the HEXA pseudodeficiency allele (606869.0035) described by Triggs-Raine et al. (1992) account for almost 50% (29/64) of TSD or carrier alleles ascertained by enzyme screening in non-Jewish Caucasians. Of 24 unrelated mutant chromosomes from 20 non-Jewish subjects (15 TSD carriers, 4 TSD patients, and 1 TSD fetus) in the British Isles, 5 had mutations common in the Ashkenazi Jewish community (606869.0001 and 606869.0002) and 10 had the intron 9 splice site mutation (Landels et al., 1992). This was an unexpected finding considering the diverse origin of the population of the British Isles. By cDNA-PCR amplification, Akli et al. (1993) found a 17-bp insertion due to the same mutation in 2 French patients with the infantile form of Tay-Sachs disease. One was a homozygote and one a compound heterozygote with a 4-bp insertion in exon 11 in the second allele. The G-to-A transition in the donor site resulted in activation of a cryptic donor site in the intron. Akli et al. (1993) found the mutation in 9 of 82 Tay-Sachs chromosomes. In the British Isles, the IVS9DS mutation was found more frequently in subjects of Irish, Scottish, and Welsh origin than in those of English origin (63% and 31%, respectively). In a blind study, Landels et al. (1993) tested 26 American TSD carriers and 28 noncarriers who had British ancestry for the IVS9DS mutation. Six of the carriers and none of the controls were positive for the mutation. All 6 had Irish ancestry compared with 9 of the 20 other IVS9DS-negative TSD carriers. These results confirmed the previously found high frequency of this specific mutation in non-Jewish TSD families of British Isles, particularly Irish, origin, and reinforced the need to screen such families for this mutation. </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>.0034 TAY-SACHS DISEASE, B1 VARIANT</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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HEXA, GGA DEL, CODON 320 OR CODON 321
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<br />
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SNP: rs797044434,
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ClinVar: RCV000004127
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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 carrier for the B1 variant (272800), Mules et al. (1992) identified an in-frame deletion of 1 of 2 adjacent glycine codons (GGA) at position 320 or 321. The deletion was in exon 8. </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>.0035 BETA-HEXOSAMINIDASE A, PSEUDODEFICIENCY OF</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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HEXA, ARG247TRP
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<br />
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SNP: rs121907970,
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gnomAD: rs121907970,
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ClinVar: RCV000004128, RCV000242608, RCV000279029, RCV000549043
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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>Triggs-Raine et al. (1992) identified a C-to-T transition at nucleotide 739, resulting in an arg247-to-trp substitution as the basis of pseudodeficiency of beta-hexosaminidase A (272800). This allele accounted for 32% (20/62) of non-Jewish enzyme-defined Tay-Sachs disease carriers but for none of 36 Jewish enzyme-defined carriers who did not have one of the 3 known mutations common to the Jewish group. In combination with a 'true' Tay-Sachs disease allele, the arg247-to-trp allele causes HEXA pseudodeficiency. Given both the large proportion of non-Jewish carriers with this allele and the fact that standard biochemical screening cannot differentiate between heterozygotes for the arg247-to-trp mutation and Tay-Sachs disease carriers, DNA testing for this mutation in at-risk couples is essential. Contrary to the findings of Triggs-Raine et al. (1992) of no cases of the C739-to-T pseudodeficiency allele among Jewish carriers, Tomczak et al. (1993) found that of 33 carriers who had none of the 3 common mutations, the pseudodeficiency mutation was present in 6 of 19 Jews and 8 of 14 non-Jews. Tomczak et al. (1993) suggested that DNA analysis should be part of a comprehensive screening program because 2 mutant alleles, the pseudodeficiency allele and the adult allele, are indistinguishable from the lethal infantile mutations by means of enzyme assay yet have very different phenotypic significance and together may account for as many as 12% of enzyme-defined carriers. </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>.0036 TAY-SACHS DISEASE, B1 VARIANT</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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HEXA, VAL192LEU AND VAL200MET
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<br />
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SNP: rs1800429, rs387906310,
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gnomAD: rs1800429, rs387906310,
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ClinVar: RCV000004129, RCV000664577, RCV002527443
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with the B1 variant form of Tay-Sachs disease (272800) described by Gordon et al. (1988), Ainsworth and Coulter-Mackie (1992) found a double mutation in exon 6 of HEXA: a G-to-C transversion of nucleotide 574 causing a val192-to-leu substitution, and a G-to-A transition at nucleotide 598 resulting in a val200-to-met substitution. Transient expression studies of the 2 exon-6 mutations (singly or together) in COS-1 cells showed that the val192-to-leu change was sufficient to cause the loss of enzyme activity. Furthermore, the biochemical phenotype of this alteration in transfection studies was consistent with that expected for a B1 variant mutation. Coulter-Mackie (1994) reported that the paternally derived allele carried the IVS9DS mutation described in 606869.0033. Subsequently, Hou et al. (1996) demonstrated that the val192-to-leu mutation in the alpha subunit of HEXA is not associated with the B1 variant form of Tay-Sachs disease. Most mutations in the alpha-subunit of HEXA that result in Tay-Sachs disease affect the initial folding of the pro-alpha chain in the endoplasmic reticulum, resulting in its retention and degradation. A much less common occurrence is a mutation that specifically affects an 'active site' residue necessary for substrate binding and/or catalysis. In this case, hexosaminidase A is present in the lysosome, but it lacks all alpha-specific activity. This is the biochemical phenotype of the B1 variant form of TSD. Hou et al. (1996) examined permanently cotransfected Chinese hamster ovary cells with an alpha-cDNA-construct including the val192-to-leu substitution and a mutant beta-cDNA, beta-arg211 to lys, encoding a beta subunit that is inactive but normal in all other respects. They found that the val192-to-leu substitution produced a pro-alpha chain that did not form alpha-beta dimers and was not transported to the lysosome. Furthermore, they reexamined the hexosaminidase activity and protein levels in the fibroblasts from the original patient. These data were also not consistent with the biochemical phenotype of the B1 variant of Tay-Sachs disease. Thus, they concluded that the val192-to-leu substitution does not specifically affect the alpha-active site. </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>.0037 REMOVED FROM DATABASE</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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<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>.0038 TAY-SACHS DISEASE, B1 VARIANT</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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HEXA, ASP258HIS
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<br />
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SNP: rs121907971,
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gnomAD: rs121907971,
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ClinVar: RCV000004130, RCV000801596, RCV001810829
|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated non-Jewish compound heterozygous patients, Fernandes et al. (1992) identified 3 novel TSD mutations. Both patients shared a G-to-C transversion of nucleotide 772 causing a substitution of histidine for aspartic acid-258. This mutant enzyme had been characterized previously as a B1, or alpha-subunit active site mutation. This was the first B1 mutation found in a codon other than 178 in exon 5 (606869.0006). One of the patients also carried a C-to-T transition at nucleotide 508 causing an arg170-to-trp substitution (606869.0039). The third mutation, found in the second patient, was a 2-base deletion occurring in exon 8 and involving the loss of either nucleotides 927-928 or nucleotides 929-930 in codon 310. The deletion created an in-frame termination codon 35 bases downstream (606869.0040). </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0039 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, ARG170TRP
|
|
|
|
|
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<br />
|
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|
|
SNP: rs121907972,
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|
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|
|
|
gnomAD: rs121907972,
|
|
|
|
|
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ClinVar: RCV000004131, RCV002345229, RCV004791196
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>See 606869.0038. Fernandes et al. (1992) detected the arg170-to-trp mutation in 2 unrelated TSD (272800) patients. In both families, this allele was traced to French Canadian ancestors originating in the Estrie region of the province of Quebec. This mutation was the third TSD allele unique to the French Canadian population and the ancestral origins of the carrier parents were distant from the center of diffusion of the more common 7.6-kb deletion mutation (606869.0003), which is in the eastern part the province. In a non-Jewish Italian child, Akli et al. (1993) used mismatch analysis to identify compound heterozygosity for the arg170-to-trp mutation of 1 HEXA allele and a gly454-to-ser mutation (606869.0048) of the other allele. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
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|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0040 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, 2-BP DEL, CODON 310
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs751248523,
|
|
|
|
|
|
gnomAD: rs751248523,
|
|
|
|
|
|
ClinVar: RCV000681660, RCV001566339
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>See 606869.0038.</p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
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|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0041 GM2-GANGLIOSIDOSIS, LATE ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, LYS197THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121907973,
|
|
|
|
|
|
gnomAD: rs121907973,
|
|
|
|
|
|
ClinVar: RCV000004133, RCV000674617, RCV001508770, RCV001797585
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Akli et al. (1993) used chemical mismatch cleavage (CMC), denaturing gradient gel electrophoresis (DGGE), and direct sequencing of amplified fragments displaying a cleaved product or an altered melting behavior to screen the HEXA gene for mutations in non-Jewish patients with Tay-Sachs disease (272800). In a Dutch patient with the adult form, they found by mismatch analysis an A-to-C transition converting codon 197 from lysine to threonine. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0042 TAY-SACHS DISEASE, JUVENILE/ADULT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, IVS6, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906311,
|
|
|
|
|
|
gnomAD: rs387906311,
|
|
|
|
|
|
ClinVar: RCV000004134, RCV000412214, RCV000432194
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a non-Jewish patient with Tay-Sachs disease (272800) designated as juvenile/adult type, Akli et al. (1993) found a mutation affecting the dinucleotide GT of the intron 6 donor site and leading to skipping of exon 6 in the processed transcripts. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0043 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, PHE211SER
|
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|
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<br />
|
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|
|
SNP: rs121907974,
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|
|
|
|
|
|
|
ClinVar: RCV000004135
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a non-Jewish Italian child with infantile Tay-Sachs disease (272800), Akli et al. (1993) identified compound heterozygosity for the arg499-to-cys mutation and for another cys mutation (606869.0043) and for another previously unknown mutation which converted codon 211 from phenylalanine to serine. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0044 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, LEU127ARG
|
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|
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<br />
|
|
|
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SNP: rs121907975,
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|
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|
|
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|
|
ClinVar: RCV000004136
|
|
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|
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</span>
|
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</div>
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a non-Jewish Italian child with Tay-Sachs disease (272800), Akli et al. (1993) identified a T-to-G transversion changing codon 127 from leucine to arginine. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
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|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0045 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, HIS204ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121907976,
|
|
|
|
|
|
|
|
ClinVar: RCV000004137, RCV001778646, RCV002054413
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a non-Jewish German child with Tay-Sachs disease (272800), Akli et al. (1993) identified compound heterozygosity for the exon 11 insertion (606869.0001) and for a novel mutation which converted his-204 to arginine. </p>
|
|
</span>
|
|
</div>
|
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0046 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, 2-BP DEL, TT, CODON 142
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1057519458,
|
|
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|
|
|
|
|
ClinVar: RCV000004138
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a non-Jewish French child with Tay-Sachs disease (272800), Akli et al. (1993) identified a 2-bp deletion in codon 142 causing a frameshift. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
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<br />
|
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0047 TAY-SACHS DISEASE</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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|
HEXA, MET301ARG
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|
<br />
|
|
|
|
SNP: rs121907977,
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|
|
|
|
|
gnomAD: rs121907977,
|
|
|
|
|
|
ClinVar: RCV000004139, RCV001250228
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a non-Jewish Yugoslav child with Tay-Sachs disease (272800), Akli et al. (1993) identified a novel mutation, a T-to-G transversion which changed codon 301 from methionine to arginine. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
|
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</div>
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</div>
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|
<div>
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|
<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0048 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, GLY454SER
|
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|
|
<br />
|
|
|
|
SNP: rs121907978,
|
|
|
|
|
|
|
|
ClinVar: RCV000004140
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>See 606869.0039.</p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0049 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, LEU39ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121907979,
|
|
|
|
|
|
|
|
ClinVar: RCV000004141
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a non-Jewish Polish child with Tay-Sachs disease (272800), Akli et al. (1993) identified compound heterozygosity for the exon 11 insertion and a novel mutation, a T-to-G transversion which changed codon 39 from leucine to arginine. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0050 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, TRP392TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267606862,
|
|
|
|
|
|
|
|
ClinVar: RCV000004142
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Approximately 20% of Ashkenazi carriers harbor a splice junction defect (606869.0002), while about 78% have a 4-bp insertion (606869.0001). However, the Ashkenazi patient used in the original description of the 4-bp insertion carried this lesion in only 1 allele and was negative for the splice junction mutation. Shore et al. (1992) cloned the insertion negative allele and by sequence analysis of the exons found a point mutation in exon 11 that resulted in substitution of trp392 with a premature termination codon. They found that 9 Ashkenazi Jewish carriers who had tested negative for the major and minor mutations as well as for a lesion causing an adult form of Tay-Sachs disease (272800) did not carry the trp392-to-ter mutation, suggesting that the mutation may be recent and/or rare. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0051 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, IVS7, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121907980,
|
|
|
|
|
|
gnomAD: rs121907980,
|
|
|
|
|
|
ClinVar: RCV000409276, RCV003944800
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Hechtman et al. (1992) found a second mutation as the cause of infantile Tay-Sachs disease (272800) in French Canadians in 3 families from the Saguenay-Lac-Saint-Jean region of Quebec: a G-to-A transition at the +1 position of intron 7 that abolished the donor splice site. The mutation occurred in a base adjacent to the site. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0052 GM2-GANGLIOSIDOSIS, LATE ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, c.805G-A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121907954, rs121907980,
|
|
|
|
|
|
gnomAD: rs121907954, rs121907980,
|
|
|
|
|
|
ClinVar: RCV000004104, RCV000168285, RCV000434025, RCV001810397, RCV002408450, RCV003924800
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Hechtman et al. (1992) made reference to a HEXA mutation involving a c.805G-A transition and a clinical picture of adult-onset GM2-gangliosidosis (272800). The mutation is immediately adjacent to the IVS7DS +1 mutation (606869.0051). Both mutations result in the loss of a cleavage site for the restriction endonuclease EcoRII; the 2 mutations can be unequivocally distinguished, however, using allele-specific oligonucleotide hybridization. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0053 GM2-GANGLIOSIDOSIS, LATE ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, TYR180HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28941771,
|
|
|
|
|
|
gnomAD: rs28941771,
|
|
|
|
|
|
ClinVar: RCV000004145, RCV002512735
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>De Gasperi et al. (1996) studied 2 sisters who developed mild learning disability at age 8, depression and ataxia in the early twenties, and who were diagnosed as having late-onset GM2-gangliosidosis (272800) on the basis of HEXA deficiency. Both sisters were compound heterozygotes for the common 4-bp insertion in exon 11 (606869.0001) and a novel 538T-C transition causing a tyr180-to-his substitution in exon 5. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0054 GM2-GANGLIOSIDOSIS, CHRONIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, IVS7, G-A, -7
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs770932296,
|
|
|
|
|
|
gnomAD: rs770932296,
|
|
|
|
|
|
ClinVar: RCV000004146, RCV000191092, RCV001582679
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Fernandes et al. (1997) stated that more than 72 mutations had been identified in the HEXA gene, of which only 4 were thought to cause a chronic form of Tay Sachs disease (272800). In a Canadian patient of English ancestry with chronic TSD (no clinical details were provided), they identified a novel HEXA mutation, IVS7AS, -7, G-A. The second allele in this patient was the 4-bp insertion mutation in exon 11, 1277TATC (606869.0001), which is the most frequent TSD allele in Ashkenazi Jews. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0055 GM2-GANGLIOSIDOSIS, SUBACUTE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, TRP474CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121907981,
|
|
|
|
|
|
gnomAD: rs121907981,
|
|
|
|
|
|
ClinVar: RCV000004147, RCV001244261
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a non-Jewish proband who manifested a subacute variant of GM2-gangliosidosis (272800), Petroulakis et al. (1998) identified a 1422G-C transversion in the first position of exon 13 of HEXA. The mutation was predicted to result in a trp474-to-cys (W474C) amino acid substitution. On the other allele, inherited from the mother, they identified the common infantile disease-causing 4-bp insertion in exon 11 (606869.0001). Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently coexpressed with the beta-subunit to produce HEXA in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. The patient had presented at the age of 16 with an acute psychotic episode characterized by marked social and emotional withdrawal, paranoia, obsessional thinking, and compulsiveness associated with marked agitation. He had a history of increasing clumsiness, ataxia, and dysarthria dating back to age 10, although only becoming clinically obvious at age 14. He, and subsequently his younger brother, were diagnosed with a subacute encephalopathic form of GM2-gangliosidosis type I. At age 20, chronic psychosis with intermittent acute exacerbations remained the most disabling symptom, as it was in his affected brother, although both exhibited some ataxia and moderately severe dysarthria. The father was of German and Dutch descent and the mother of Portuguese and English descent. There was no family history of neurodegenerative disease. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0056 TAY-SACHS DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, LEU451VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28940871,
|
|
|
|
|
|
gnomAD: rs28940871,
|
|
|
|
|
|
ClinVar: RCV000004148
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In the course of study of HEXA activity in Iraqi Jews to determine carriers of Tay-Sachs disease (272800), Karpati et al. (2004) identified a 1351C-G transversion in exon 12 of the HEXA gene, resulting in a leu451-to-val (L451V) change. The mutation was found in 21 of 62 carriers (33.9%) and in none of 100 noncarrier Iraqi Jews. Karpati et al. (2004) estimated that the 1351C-G transversion occurred sometime between 1519 BC and 635 AD, with 442 BC as the best estimate with wide confidence limits. The Iraqi Jewish community started around 586 BC when the Babylonian king Nebuchadnezzar deported 10,000 to 40,000 of the Jews from the kingdom of Judea to Babylon. This was probably the time of separation of the Iraqi Jews from the rest of the Jewish people. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0057 GM2-GANGLIOSIDOSIS, SUBACUTE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, VAL324VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28942072,
|
|
|
|
|
|
gnomAD: rs28942072,
|
|
|
|
|
|
ClinVar: RCV000004149, RCV001781173, RCV003332074
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a child with severe subacute GM2-gangliosidosis (272800) who presented at age 22 months with classic cherry-red spots of the fundus but did not develop any neurologic deficit until almost age 4, Wicklow et al. (2004) identified 3 mutations in the HEXA gene: 10T-C (S4P; 606869.0014) and 972T-A (V324V) on the maternal allele, and 1A-T (M1L; 606869.0027) on the paternal allele. Because the delay in onset of neurologic symptoms indicated the presence of residual HEXA, Wicklow et al. (2004) analyzed the effects of the amino acid substitutions on HEXA expression in COS-7 cells. They found that no HEXA activity was associated with the M1L mutation, whereas the S4P mutation resulted in 59% of the activity expressed by wildtype DNA, a level associated with an adult-onset form of the disease. Further analysis revealed that the 972T-A mutation created a new exon 8 donor site, causing a 17-bp deletion and destabilization of the resulting abnormal transcript. Wicklow et al. (2004) concluded that the remaining normal mRNA produced from the 972T-A allele must account for the delayed onset of symptoms in this child. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0058 TAY SACHS DISEASE, MILD</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEXA, CYS58TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906949,
|
|
|
|
|
|
gnomAD: rs387906949,
|
|
|
|
|
|
ClinVar: RCV000023580
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family (M165) in which first-cousin parents had 5 healthy children and 3 with intellectual disability and seizures (272800), Najmabadi et al. (2011) identified a homozygous C-to-T transition at genomic coordinate chr15:70455195 (NCBI36), resulting in a cys58-to-tyr (C58Y) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Greenberg and Kaback (1982); Hellkuhl et al. (1978); McDowell et al.
|
|
(1989); Myerowitz and Proia (1984); Petersen et al. (1983); Suzuki
|
|
and Suzuki (1970)
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
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NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers,
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OMIM<sup>®</sup> and Online Mendelian Inheritance in Man<sup>®</sup> are registered trademarks of the Johns Hopkins University.
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