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Entry
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- *605712 - SERINE PALMITOYLTRANSFERASE, LONG-CHAIN BASE SUBUNIT 1; SPTLC1
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*605712</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/605712">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000090054;t=ENST00000262554" 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=10558" 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=605712" 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=ENSG00000090054;t=ENST00000262554" 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_001281303,NM_001368272,NM_001368273,NM_006415,NM_178324,XM_024447378,XM_024447379,XM_047422638,XM_047422639" 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_006415" 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=605712" 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=05754&isoform_id=05754_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/SPTLC1" 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/2564247,5454084,6685579,13540158,13937948,30474871,46329880,62089100,119583208,119583209,119583210,158256524,194386784,444738579,526252798,1370513612,1370513614,1566185445,1566185477,2217375124,2217375126,2462622176,2462622178,2462622181,2462622183" 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/O15269" 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=10558" 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=ENSG00000090054;t=ENST00000262554" 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=SPTLC1" 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=SPTLC1" 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+10558" 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/SPTLC1" 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:10558" 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/10558" 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=chr9&hgg_gene=ENST00000262554.7&hgg_start=92031147&hgg_end=92115413&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://medlineplus.gov/genetics/gene/sptlc1" 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=605712[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=605712[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000090054" 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=SPTLC1" 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=SPTLC1" 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=SPTLC1" 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.molgen.ua.ac.be/CMTMutations/" 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=SPTLC1&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/PA36106" 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:11277" 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/FBgn0086532.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:1099431" 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/SPTLC1#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:1099431" 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/10558/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=10558" 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=WBGene00016020;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-050522-61" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
|
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:10558" 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=SPTLC1&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> 860813007<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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605712
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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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SERINE PALMITOYLTRANSFERASE, LONG-CHAIN BASE SUBUNIT 1; SPTLC1
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</span>
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</h3>
|
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
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SPT1<br />
|
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LCB1
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SPTLC1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SPTLC1</a></em></strong>
|
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/9/301?start=-3&limit=10&highlight=301">9q22.31</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr9:92031147-92115413&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'})">9:92,031,147-92,115,413</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
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</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>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=620285,162400" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/9/301?start=-3&limit=10&highlight=301">
|
|
9q22.31
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Amyotrophic lateral sclerosis 27, juvenile
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/620285"> 620285 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
|
</span>
|
|
</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Neuropathy, hereditary sensory and autonomic, type IA
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/162400"> 162400 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
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<p>Serine palmitoyltransferase (SPT; <a href="https://enzyme.expasy.org/EC/2.3.1.50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 2.3.1.50</a>) is the key enzyme in sphingolipid biosynthesis. It catalyzes the first and rate-limiting step: the pyridoxal-5-prime-phosphate-dependent condensation of L-serine and palmitoyl-CoA to 3-oxosphinganine (<a href="#28" class="mim-tip-reference" title="Weiss, B., Stoffel, W. <strong>Human and murine serine-palmitoyl-CoA transferase: cloning, expression and characterization of the key enzyme in sphingolipid synthesis.</strong> Europ. J. Biochem. 249: 239-247, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9363775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9363775</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1997.00239.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9363775">Weiss and Stoffel, 1997</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9363775" 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>SPT contains 2 main subunits: the common SPTLC1 subunit and either SPTLC2 (<a href="/entry/605713">605713</a>) or its isoform SPTLC2L (SPTLC3; <a href="/entry/611120">611120</a>), depending on the tissue in which biosynthesis occurs (<a href="#14" class="mim-tip-reference" title="Hornemann, T., Richard, S., Rutti, M. F., Wei, Y., von Eckardstein, A. <strong>Cloning and initial characterization of a new subunit for mammalian serine-palmitoyltransferase.</strong> J. Biol. Chem. 281: 37275-37281, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17023427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17023427</a>] [<a href="https://doi.org/10.1074/jbc.M608066200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17023427">Hornemann et al., 2006</a>). There are also 2 highly related isoforms of a third subunit, SSSPTA (<a href="/entry/613540">613540</a>) and SSSPTB (<a href="/entry/610412">610412</a>), that confer acyl-CoA preference of the SPT enzyme and are essential for maximal enzyme activity (<a href="#10" class="mim-tip-reference" title="Han, G., Gupta, S. D., Gable, K., Niranjanakumari, S., Moitra, P., Eichler, F., Brown, R. H., Jr., Harmon, J. M., Dunn, T. M. <strong>Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities.</strong> Proc. Nat. Acad. Sci. 106: 8186-8191, 2009. Note: Erratum: Proc. Nat. Acad. Sci. 106: 9931 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19416851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19416851</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19416851[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0811269106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19416851">Han et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19416851+17023427" 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="#28" class="mim-tip-reference" title="Weiss, B., Stoffel, W. <strong>Human and murine serine-palmitoyl-CoA transferase: cloning, expression and characterization of the key enzyme in sphingolipid synthesis.</strong> Europ. J. Biochem. 249: 239-247, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9363775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9363775</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1997.00239.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9363775">Weiss and Stoffel (1997)</a> cloned and characterized 2 complete human and murine cDNA sequences corresponding to the SPTLC1 and SPTLC2 (<a href="/entry/605713">605713</a>) genes, similar to yeast LCB1 and LCB2 genes, respectively. The SPTLC1 cDNA contains an open reading frame of 1,422 nucleotides and encodes a 473-amino acid protein (<a href="#4" class="mim-tip-reference" title="Bejaoui, K., Wu, C., Scheffler, M. D., Haan, G., Ashby, P., Wu, L., de Jong, P., Brown, R. H., Jr. <strong>SPTLC1 is mutated in hereditary sensory neuropathy, type 1.</strong> Nature Genet. 27: 261-262, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242106</a>] [<a href="https://doi.org/10.1038/85817" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242106">Bejaoui et al., 2001</a>). By Northern blot analysis, <a href="#7" class="mim-tip-reference" title="Dawkins, J. L., Hulme, D. J., Brahmbhatt, S. B., Auer-Grumbach, M., Nicholson, G. A. <strong>Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I.</strong> Nature Genet. 27: 309-312, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242114</a>] [<a href="https://doi.org/10.1038/85879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242114">Dawkins et al. (2001)</a> detected a single 3-kb SPTLC1 transcript in all 7 tissues tested, including spinal cord. A search of the UniGene database identified corresponding cDNA clones expressed in 29 different tissues, indicating that SPTLC1 is ubiquitously expressed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11242106+9363775+11242114" 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 quantitative real-time PCR analysis, <a href="#14" class="mim-tip-reference" title="Hornemann, T., Richard, S., Rutti, M. F., Wei, Y., von Eckardstein, A. <strong>Cloning and initial characterization of a new subunit for mammalian serine-palmitoyltransferase.</strong> J. Biol. Chem. 281: 37275-37281, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17023427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17023427</a>] [<a href="https://doi.org/10.1074/jbc.M608066200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17023427">Hornemann et al. (2006)</a> detected SPTLC1 expression in all 24 human tissues examined except for small intestine. Western blot analysis detected SPTLC1 at 55 kD. Overexpression of SPTLC1 in HEK293 cells showed no increase in SPT activity, suggesting that SPTLC2 and SPTLC3 (<a href="/entry/611120">611120</a>) are the limiting factors for SPT activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17023427" 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="#7" class="mim-tip-reference" title="Dawkins, J. L., Hulme, D. J., Brahmbhatt, S. B., Auer-Grumbach, M., Nicholson, G. A. <strong>Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I.</strong> Nature Genet. 27: 309-312, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242114</a>] [<a href="https://doi.org/10.1038/85879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242114">Dawkins et al. (2001)</a> determined that the SPTLC1 gene contains 15 exons and established the intron/exon boundaries. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11242114" 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="#7" class="mim-tip-reference" title="Dawkins, J. L., Hulme, D. J., Brahmbhatt, S. B., Auer-Grumbach, M., Nicholson, G. A. <strong>Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I.</strong> Nature Genet. 27: 309-312, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242114</a>] [<a href="https://doi.org/10.1038/85879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242114">Dawkins et al. (2001)</a> noted that the SPTLC1 gene maps to chromosome 9q22.1-q22.3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11242114" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Hereditary Sensory and Autonomic Neuropathy, Type IA</em></strong></p><p>
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<a href="#7" class="mim-tip-reference" title="Dawkins, J. L., Hulme, D. J., Brahmbhatt, S. B., Auer-Grumbach, M., Nicholson, G. A. <strong>Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I.</strong> Nature Genet. 27: 309-312, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242114</a>] [<a href="https://doi.org/10.1038/85879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242114">Dawkins et al. (2001)</a> identified mutations in the SPTLC1 gene in 11 families with hereditary sensory neuropathy type I (HSAN1A; <a href="/entry/162400">162400</a>). One family carried a C133Y mutation in exon 5 (<a href="#0001">605712.0001</a>); 8 families carried a C133W mutation in exon 5 (<a href="#0002">605712.0002</a>); and 2 families carried a V144D mutation in exon 6 (<a href="#0003">605712.0003</a>). All 6 families with definite or probable linkage to chromosome 9 were found to have mutations in SPTLC1. The families were of Australian/English, Australian/Scottish, English, Austrian/German, or Canadian extraction. <a href="#7" class="mim-tip-reference" title="Dawkins, J. L., Hulme, D. J., Brahmbhatt, S. B., Auer-Grumbach, M., Nicholson, G. A. <strong>Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I.</strong> Nature Genet. 27: 309-312, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242114</a>] [<a href="https://doi.org/10.1038/85879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242114">Dawkins et al. (2001)</a> noted that ceramide produced by catabolism of sphingomyelin mediates programmed cell death and that increased de novo ceramide synthesis due to an increase in SPT activity has been demonstrated to cause apoptosis in a number of tissues (<a href="#25" class="mim-tip-reference" title="Perry, D. K., Carton, J., Shah, A. K., Meredith, F., Uhlinger, D. J., Hannun, Y. A. <strong>Serine palmitoyltransferase regulates de novo ceramide generation during etoposide-induced apoptosis.</strong> J. Biol. Chem. 275: 9078-9084, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10722759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10722759</a>] [<a href="https://doi.org/10.1074/jbc.275.12.9078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10722759">Perry et al., 2000</a>), including differentiating neuronal cells (<a href="#11" class="mim-tip-reference" title="Herget, T., Esdar, C., Oehrlein, S. A., Heinrich, M., Schutze, S., Maelicke, A., van Echten-Deckert, G. <strong>Production of ceramides causes apoptosis during early neural differentiation in vitro.</strong> J. Biol. Chem. 275: 30344-30354, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10862608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10862608</a>] [<a href="https://doi.org/10.1074/jbc.M000714200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10862608">Herget et al., 2000</a>). <a href="#7" class="mim-tip-reference" title="Dawkins, J. L., Hulme, D. J., Brahmbhatt, S. B., Auer-Grumbach, M., Nicholson, G. A. <strong>Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I.</strong> Nature Genet. 27: 309-312, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242114</a>] [<a href="https://doi.org/10.1038/85879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242114">Dawkins et al. (2001)</a> determined that the mutations were associated with increased de novo glucosyl ceramide synthesis in lymphoblast cell lines in affected individuals. Increased de novo ceramide synthesis triggers apoptosis, and is associated with massive cell death during neural tube closure, raising the possibility that neural degeneration in HSN1 is due to ceramide-induced apoptotic cell death. <a href="#7" class="mim-tip-reference" title="Dawkins, J. L., Hulme, D. J., Brahmbhatt, S. B., Auer-Grumbach, M., Nicholson, G. A. <strong>Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I.</strong> Nature Genet. 27: 309-312, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242114</a>] [<a href="https://doi.org/10.1038/85879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242114">Dawkins et al. (2001)</a> labeled lipids with C14-serine and showed that lymphoblast lines from HSN1 patients synthesize higher levels of glucosyl ceramide than do comparable lines from healthy controls. Glucosyl ceramide synthesis in 5 HSN1 patients was 175% of the levels in 8 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11242114+10722759+10862608" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Bejaoui, K., Wu, C., Scheffler, M. D., Haan, G., Ashby, P., Wu, L., de Jong, P., Brown, R. H., Jr. <strong>SPTLC1 is mutated in hereditary sensory neuropathy, type 1.</strong> Nature Genet. 27: 261-262, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242106</a>] [<a href="https://doi.org/10.1038/85817" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242106">Bejaoui et al. (2001)</a> independently identified the C133Y and C133W mutations in 2 unrelated families with HSN1. <a href="#3" class="mim-tip-reference" title="Bejaoui, K., Uchida, Y., Yasuda, S., Ho, M., Nishijima, M., Brown, R. H., Jr., Holleran, W. M., Hanada, K. <strong>Hereditary sensory neuropathy type 1 mutations confer dominant negative effects on serine palmitoyltransferase, critical for sphingolipid synthesis.</strong> J. Clin. Invest. 110: 1301-1308, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12417569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12417569</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12417569[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI16450" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12417569">Bejaoui et al. (2002)</a> found that the C133Y and C133W mutations do not alter the steady state levels of the SPTLC1 or the SPTLC2 subunit. They did, however, result in reduced SPT activity and sphingolipid synthesis. The mutations did not complement the SPT deficiency found in a mutant CHO cell strain with defective SPT activity secondary to a lack of SPTLC1. Overproduction of either the C133Y or C133W subunit inhibited SPT activity in CHO cells despite the presence of wildtype SPTLC1. The mutant SPTLC1 proteins could also interact with the wildtype SPTLC2 subunit. The results indicated that both of these mutations have a dominant-negative effect on the SPT enzyme. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11242106+12417569" 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 in vitro functional expression assays in HEK293 cells, <a href="#13" class="mim-tip-reference" title="Hornemann, T., Penno, A., Richard, S., Nicholson, G., van Dijk, F. S., Rotthier, A., Timmerman, V., von Eckardstein, A. <strong>A systematic comparison of all mutations in hereditary sensory neuropathy type I (HSAN I) reveals that the G387A mutation is not disease associated.</strong> Neurogenetics 10: 135-143, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19132419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19132419</a>] [<a href="https://doi.org/10.1007/s10048-008-0168-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19132419">Hornemann et al. (2009)</a> found that none of the 4 SPTLC1 mutations, C133Y, C133W, V144D, or G387A (<a href="#0004">605712.0004</a>), interfered with formation of the SPT complex. The first 3 mutant proteins resulted in 40 to 50% decreased SPT activity, but the G387A protein showed no effect on SPT activity. Further studies showed that the G387A protein could rescue a SPTLC1-deficient cell line. <a href="#13" class="mim-tip-reference" title="Hornemann, T., Penno, A., Richard, S., Nicholson, G., van Dijk, F. S., Rotthier, A., Timmerman, V., von Eckardstein, A. <strong>A systematic comparison of all mutations in hereditary sensory neuropathy type I (HSAN I) reveals that the G387A mutation is not disease associated.</strong> Neurogenetics 10: 135-143, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19132419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19132419</a>] [<a href="https://doi.org/10.1007/s10048-008-0168-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19132419">Hornemann et al. (2009)</a> also identified homozygosity for the G387A variant in an unaffected mother of a heterozygous carrier with HSN1, and it was found in 1 of 190 controls. These findings indicated that G387A is not pathogenic. <a href="#13" class="mim-tip-reference" title="Hornemann, T., Penno, A., Richard, S., Nicholson, G., van Dijk, F. S., Rotthier, A., Timmerman, V., von Eckardstein, A. <strong>A systematic comparison of all mutations in hereditary sensory neuropathy type I (HSAN I) reveals that the G387A mutation is not disease associated.</strong> Neurogenetics 10: 135-143, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19132419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19132419</a>] [<a href="https://doi.org/10.1007/s10048-008-0168-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19132419">Hornemann et al. (2009)</a> postulated that the G387A variant, and perhaps the other 3 SPTLC1 variants previously associated with HSN1, may not be directly disease-causing, but rather have an indirect or bystander effect by increasing the risk for HSN1 in conjunction with another mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19132419" 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>SPT catalyzes the condensation of serine and palmitoyl-CoA, the initial step in the de novo synthesis of sphingolipids. <a href="#24" class="mim-tip-reference" title="Penno, A., Reilly, M. M., Houlden, H., Laura, M., Rentsch, K., Niederkofler, V., Stoeckli, E. T., Nicholson, G., Eichler, F., Brown, R. H., Jr., von Eckardstein, A., Hornemann, T. <strong>Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids.</strong> J. Biol. Chem. 285: 11178-11187, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20097765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20097765</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20097765[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/10.1074/jbc.M109.092973" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20097765">Penno et al. (2010)</a> showed that HSAN1A-related mutations in the SPTLC1 gene induce a shift in the substrate specificity of SPT, which leads to the formation of 2 atypical deoxysphingoid bases: 1-deoxysphinganine from condensation with alanine, and 1-deoxymethylsphinganine from condensation with glycine. Neither of these metabolites can be converted to complex sphingolipids or degraded, resulting in their intracellular accumulation. These atypical agents showed pronounced neurotoxic effects on neurite formation in cultured sensory neurons, and was associated with disturbed neurofilament structure. <a href="#24" class="mim-tip-reference" title="Penno, A., Reilly, M. M., Houlden, H., Laura, M., Rentsch, K., Niederkofler, V., Stoeckli, E. T., Nicholson, G., Eichler, F., Brown, R. H., Jr., von Eckardstein, A., Hornemann, T. <strong>Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids.</strong> J. Biol. Chem. 285: 11178-11187, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20097765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20097765</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20097765[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/10.1074/jbc.M109.092973" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20097765">Penno et al. (2010)</a> found increased levels of these atypical agents in lymphoblasts and plasma from HSAN1A patients with different SPTLC1 mutations. The findings indicated that HSAN1 results from gain-of-function mutations that cause the formation of atypical and neurotoxic sphingolipid metabolites, rather than from lack of de novo sphingolipid synthesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20097765" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with an unusually severe form of HSAN1A, <a href="#26" class="mim-tip-reference" title="Rotthier, A., Baets, J., De Vriendt, E., Jacobs, A., Auer-Grumbach, M., Levy, N., Bonello-Palot, N., Kilic, S. S., Weis, J., Nascimento, A., Swinkels, M., Kruyt, M. C., Jordanova, A., De Jonghe, P., Timmerman, V. <strong>Genes for hereditary sensory and autonomic neuropathies: a genotype-phenotype correlation.</strong> Brain 132: 2699-2711, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19651702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19651702</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19651702[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/10.1093/brain/awp198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19651702">Rotthier et al. (2009)</a> identified a de novo heterozygous mutation (S311F; <a href="#0005">605712.0005</a>) in the SPTLC1 gene. <a href="#2" class="mim-tip-reference" title="Auer-Grumbach, M., Bode, H., Pieber, T. R., Schabhuttl, M., Fischer, D., Seidl, R., Graf, E., Wieland, T., Schuh, R., Vacariu, G., Grill, F., Timmerman, V., Strom, T. M., Hornemann, T. <strong>Mutations at Ser331 in the HSN type I gene SPTLC1 are associated with a distinct syndromic phenotype.</strong> Europ. J. Med. Genet. 56: 266-269, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23454272/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23454272</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23454272[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.ejmg.2013.02.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23454272">Auer-Grumbach et al. (2013)</a> reported that a patient with a severe form of HSAN1, originally reported by <a href="#15" class="mim-tip-reference" title="Huehne, K., Zweier, C., Raab, K., Odent, S., Bonnaure-Mallet, M., Sixou, J. L., Landrieu, P., Goizet, C., Sarlangue, J., Baumann, M., Eggermann, T., Rauch, A., Ruppert, S., Stettner, G. M., Rautenstrauss, B. <strong>Novel missense, insertion and deletion mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) associated with congenital insensitivity to pain with anhidrosis.</strong> Neuromusc. Disord. 18: 159-166, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18077166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18077166</a>] [<a href="https://doi.org/10.1016/j.nmd.2007.10.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18077166">Huehne et al. (2008)</a>, was heterozygous for the same S311F mutation. In another patient with severe HSAN1, <a href="#2" class="mim-tip-reference" title="Auer-Grumbach, M., Bode, H., Pieber, T. R., Schabhuttl, M., Fischer, D., Seidl, R., Graf, E., Wieland, T., Schuh, R., Vacariu, G., Grill, F., Timmerman, V., Strom, T. M., Hornemann, T. <strong>Mutations at Ser331 in the HSN type I gene SPTLC1 are associated with a distinct syndromic phenotype.</strong> Europ. J. Med. Genet. 56: 266-269, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23454272/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23454272</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23454272[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.ejmg.2013.02.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23454272">Auer-Grumbach et al. (2013)</a> identified a different de novo heterozygous mutation at the same codon (S311Y; <a href="#0007">605712.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18077166+19651702+23454272" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Gantner, M. L., Eade, K., Wallace, M., Handzlik, M. K., Fallon, R., Trombley, J., Bonelli, R., Giles, S., Harkins-Perry, S., Heeren, T. F C., Sauer, L., Ideguchi, Y., and 20 others. <strong>Serine and lipid metabolism in macular disease and peripheral neuropathy.</strong> New Eng. J. Med. 381: 1422-1433, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31509666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31509666</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31509666[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/10.1056/NEJMoa1815111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31509666">Gantner et al. (2019)</a> identified 9 patients, including 8 patients from 2 unrelated families and an additional unrelated patient, with genetically confirmed HSAN1A who also had type 2 macular telangiectasia. All carried the same heterozygous C133Y mutation in the SPTLC1 gene (<a href="#0001">605712.0001</a>). Two additional unrelated patients (patient 2 and 3), who had HSAN1A due to a heterozygous missense C133W mutation in the SPTLC1 gene (<a href="#0002">605712.0002</a>), did not have macular telangiectasia. However, both patients were under the age of 50 and had been treated with serine supplementation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31509666" 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>Amyotrophic Lateral Sclerosis 27, Juvenile</em></strong></p><p>
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In 11 patients with juvenile amyotrophic lateral sclerosis-27 (ALS27; <a href="/entry/620285">620285</a>), <a href="#21" class="mim-tip-reference" title="Mohassel, P., Donkervoort, S., Lone, M. A., Nalls, M., Gable, K., Gupta, S. D., Foley, A. R., Hu, Y., Saute, J. A. M., Moreira, A. L., Kok, F., Introna, A., and 34 others. <strong>Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.</strong> Nature Med. 27: 1197-1204, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34059824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34059824</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34059824[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41591-021-01346-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34059824">Mohassel et al. (2021)</a> identified heterozygous mutations in exon 2 of the SPTLC1 gene (<a href="#0008">605712.0008</a>-<a href="#0011">605712.0011</a>). The mutation occurred de novo in 6 unrelated patients and was inherited from a mildly affected father in 1 family. Serum from affected patients had elevated free sphinganine and ceramide levels compared to controls, consistent with increased products of serine palmitoyltransferase activity. Heterozygous mutations (F40_S41del or deletion of exon 2) were introduced into the SPTLC1 gene in iPSCs, which were then differentiated into human motor neuron-like cells (iPSC-hMNs). The mutant iPSC-hMNs had increased sphingolipid levels, which was exacerbated by supplementation with serine. The increased SPT activity in the iPSC-hMNs was not mitigated with increased levels of ORMD3 or with ceramide treatment (both known inhibitors of SPT). <a href="#21" class="mim-tip-reference" title="Mohassel, P., Donkervoort, S., Lone, M. A., Nalls, M., Gable, K., Gupta, S. D., Foley, A. R., Hu, Y., Saute, J. A. M., Moreira, A. L., Kok, F., Introna, A., and 34 others. <strong>Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.</strong> Nature Med. 27: 1197-1204, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34059824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34059824</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34059824[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41591-021-01346-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34059824">Mohassel et al. (2021)</a> concluded that the mutations in exon 2 of the SPTLC1 gene identified in patients with juvenile ALS resulted in diminished SPT inhibition by ORDM3 and ceramide. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34059824" 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 whole-exome sequencing, <a href="#16" class="mim-tip-reference" title="Johnson, J. O., Chia, R., Miller, D. E., Li, R., Kumaran, R., Abramzon, Y., Alahmady, N., Renton, A. E., Topp, S. D., Gibbs, J. R., Cookson, M. R., Sabir, M. S., and 287 others. <strong>Association of variants in the SPTLC1 gene with juvenile amyotrophic lateral sclerosis.</strong> JAMA Neurol. 78: 1236-1248, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34459874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34459874</a>] [<a href="https://doi.org/10.1001/jamaneurol.2021.2598" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34459874">Johnson et al. (2021)</a> identified de novo heterozygous mutations in the SPTLC1 gene in 3 unrelated patients with ALS27 (S331F, <a href="#0007">605712.0007</a>; A20S, <a href="#0011">605712.0011</a>). The patient with the S331F mutation (patient 3) had prominent motor symptoms and modest sensory-autonomic symptoms, whereas the 2 patients with the A20S mutation had only motor symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34459874" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 12-year-old girl with ALS27, <a href="#18" class="mim-tip-reference" title="Liu, X., He, J., Yu, W., Fan, D. <strong>A de novo c.113 T>C: p.L38R mutation of SPTLC1: case report of a girl with sporadic juvenile amyotrophic lateral sclerosis.</strong> Amyotroph. Lateral Scler. Frontotemporal Degener. 23: 634-637, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36204986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36204986</a>] [<a href="https://doi.org/10.1080/21678421.2022.2096409" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36204986">Liu et al. (2022)</a> identified a de novo heterozygous missense mutation in the SPTLC1 gene (L38R; <a href="#0012">605712.0012</a>). The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies were not reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36204986" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Lone, M. A., Aaltonen, M. J., Zidell, A., Pedro, H. F., Morales Saute, J. A., Mathew, S., Mohassel, P., Bonnemann, C. G., Shoubridge, E. A., Hornemann, T. <strong>SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins.</strong> J. Clin. Invest. 132: e161908, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35900868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35900868</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35900868[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI161908" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35900868">Lone et al. (2022)</a> expressed SPTLC1 with the Y23F (<a href="#0008">605712.0008</a>), L39del (<a href="#0010">605712.0010</a>), S331F (<a href="#0005">605712.0005</a>), Ex2del (<a href="#0011">605712.0011</a>) or F40_S41del (<a href="#0009">605712.0009</a>) mutations in T-Rex293 cells. All of the mutant SPTLC1 proteins localized properly to the endoplasmic reticulum, except for the exon 2 deletion, which was mostly mislocalized to the cytoplasm. Immunoprecipitation assays showed that each mutant SPTLC1, except for the Y23F mutant, resulted in reduced interaction with ORMDLs (see <a href="/entry/610073">610073</a>) in the SPT complex. Each SPTLC1 mutation was then expressed in HEK293 cells and lipidomics analyses were performed. The mutant cells had a distinct ceramide profile and increased sphingolipid synthesis, which was not normalized/inhibited by C6 ceramide. In addition, the S331F and S331Y (<a href="#0007">605712.0007</a>) mutants produced increased deoxysphingolipids. <a href="#19" class="mim-tip-reference" title="Lone, M. A., Aaltonen, M. J., Zidell, A., Pedro, H. F., Morales Saute, J. A., Mathew, S., Mohassel, P., Bonnemann, C. G., Shoubridge, E. A., Hornemann, T. <strong>SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins.</strong> J. Clin. Invest. 132: e161908, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35900868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35900868</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35900868[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI161908" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35900868">Lone et al. (2022)</a> concluded that the mutations in SPLTC1 resulted in abnormal feedback inhibition and increased sphingolipid synthesis, and that mutations associated with motor symptoms had distinct lipid profiles from those that were associated with mixed sensory and motor symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35900868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using biochemical assays in transfected cells, <a href="#5" class="mim-tip-reference" title="Bode, H., Bourquin, F., Suriyanarayanan, S., Wei, Y., Alecu, I., Othman, A., Von Eckardstein, A., Hornemann, T. <strong>HSAN1 mutations in serine palmitoyltransferase reveal a close structure-function-phenotype relationship.</strong> Hum. Molec. Genet. 25: 853-865, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26681808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26681808</a>] [<a href="https://doi.org/10.1093/hmg/ddv611" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26681808">Bode et al. (2016)</a> assessed the enzymatic activity and biochemical consequences of 11 different missense variants in the SPTLC1 gene, including 7 that had previously been identified in HSAN1 patients. None of the variants resulted in a loss of activity, as had previously been suggested. Several variants, including V144D, A310G, A339V, and A352V, showed no change in canonical enzyme activity, did not show significant activity with alanine over serine, and did not form increased levels of neurotoxic 1-deoxySL compounds compared to wildtype. The authors suggested that these variants may not be pathogenic. Two mutations, C133Y and C133W, were associated with increased 1-deoxySL levels compared to wildtype, but had unaltered canonical activity and did not cause increased C20-sphingoid bases. These mutations were associated with a typical late-onset phenotype with primarily sensory and mild motor impairment. Two mutations, S331F and S331Y, were characterized by increased canonical enzyme activity as well as increased formation of C18-, 1-deoxy-, and C20-sphingoid bases, the latter of which was a unique and particular hallmark of these mutations. These mutations were associated with a severe phenotype characterized by early onset of symptoms, autonomic impairment, and juvenile cataracts. Further studies showed that the formation of toxic 1-deoxySL in animal models and patients with HSAN1 was reduced by increased availability of serine through oral supplementation. In contrast, increased availability of alanine resulted in augmented 1-deoxySL formation and aggravated neuropathic symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26681808" 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="#20" class="mim-tip-reference" title="McCampbell, A., Truong, D., Broom, D. C., Allchorne, A., Gable, K., Cutler, R. G., Mattson, M. P., Woolf, C. J., Frosch, M. P., Harmon, J. M., Dunn, T. M., Brown, R. H., Jr. <strong>Mutant SPTLC1 dominantly inhibits serine palmitoyltransferase activity in vivo and confers an age-dependent neuropathy.</strong> Hum. Molec. Genet. 14: 3507-3521, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16210380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16210380</a>] [<a href="https://doi.org/10.1093/hmg/ddi380" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16210380">McCampbell et al. (2005)</a> created transgenic mouse lines that ubiquitously overexpressed either wildtype or C133W-mutant SPTLC1. The C133W-mutant mice developed age-dependent weight loss and mild sensory and motor impairments. Aged C133W-mutant mice lost large myelinated axons in the ventral root of the spinal cord and demonstrated myelin thinning. There was also a loss of large myelinated axons in the dorsal roots, although the unmyelinated fibers were preserved. In the dorsal root ganglia, IB4 staining was diminished, whereas expression of the injury-induced transcription factor ATF3 (<a href="/entry/603148">603148</a>) was increased. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16210380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Kuo, A., Checa, A., Niaudet, C., Jung, B., Fu, Z., Wheelock, C. E., Singh, S. A., Aikawa, M., Smith, L. E., Proia, R. L., Hla, T. <strong>Murine endothelial serine palmitoyltransferase 1 (SPTLC1) is required for vascular development and systemic sphingolipid homeostasis.</strong> eLife 11: e78861, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36197001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36197001</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36197001[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/10.7554/eLife.78861" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36197001">Kuo et al. (2022)</a> found that mice with vascular endothelial cell (EC)-specific deletion of Sptlc1 had normal body weight, liver enzyme levels, kidney function, and blood chemistry. However, ablation of Sptlc1 in ECs reduced sphingolipid (SL) content in both EC and non-EC cell populations of lung, indicating that SPT supplied SL to both vascular and nonvascular cells in lung. Supply of SL by active SPT in endothelium was important for normal vascular development, as retinal vascular development was delayed in mice with EC-specific Sptlc1 knockout. Analysis of a mouse model of oxygen-induced retinopathy suggested that de novo synthesis of SL in ECs determined the pathologic phenotypes in retinal vasculature, likely due to reduced Vegf (<a href="/entry/192240">192240</a>) responsiveness. Vegf signaling was impaired in retina of Sptlc1-knockout mice, because de novo synthesis of SL was necessary for efficient Vegf signaling via modulation of lipid raft formation in wildtype mice, and loss of Sptlc1 impaired Vegf responsiveness. Deletion of Sptlc1 in ECs also led to rapid reduction of several SL metabolites in plasma, red blood cells, and peripheral organs, but not in retina, as endothelial SPT activity provided SL metabolites to those cells and organs through circulation postnatally. Further analysis indicated that EC SPT supply of liver sphingolipids through circulation impacted stress response of hepatocytes and liver injury in mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36197001" 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">rs119482081 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119482081;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=rs119482081" 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=rs119482081" 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=RCV000005067 OR RCV001027483 OR RCV001249800 OR RCV002512792 OR RCV004998075" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005067, RCV001027483, RCV001249800, RCV002512792, RCV004998075" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005067...</a>
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<p>In a family of Austrian/German origin with hereditary sensory neuropathy type I (HSAN1A; <a href="/entry/162400">162400</a>), <a href="#7" class="mim-tip-reference" title="Dawkins, J. L., Hulme, D. J., Brahmbhatt, S. B., Auer-Grumbach, M., Nicholson, G. A. <strong>Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I.</strong> Nature Genet. 27: 309-312, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242114</a>] [<a href="https://doi.org/10.1038/85879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242114">Dawkins et al. (2001)</a> identified a heterozygous c.398G-A transition in exon 5 of the SPTLC1 gene resulting in a cys133-to-tyr (C133Y) substitution. Cysteine-133 of SPTLC1 is invariant in human, mouse, Drosophila, and yeast. This mutation was also identified by <a href="#4" class="mim-tip-reference" title="Bejaoui, K., Wu, C., Scheffler, M. D., Haan, G., Ashby, P., Wu, L., de Jong, P., Brown, R. H., Jr. <strong>SPTLC1 is mutated in hereditary sensory neuropathy, type 1.</strong> Nature Genet. 27: 261-262, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242106</a>] [<a href="https://doi.org/10.1038/85817" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242106">Bejaoui et al. (2001)</a> in a family of German origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11242106+11242114" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Gantner, M. L., Eade, K., Wallace, M., Handzlik, M. K., Fallon, R., Trombley, J., Bonelli, R., Giles, S., Harkins-Perry, S., Heeren, T. F C., Sauer, L., Ideguchi, Y., and 20 others. <strong>Serine and lipid metabolism in macular disease and peripheral neuropathy.</strong> New Eng. J. Med. 381: 1422-1433, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31509666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31509666</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31509666[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/10.1056/NEJMoa1815111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31509666">Gantner et al. (2019)</a> identified 9 patients, including 8 patients from 2 unrelated families and an additional unrelated patient, with genetically confirmed HSAN1A who also had type 2 macular telangiectasia. All carried the same heterozygous C133Y mutation in the SPTLC1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31509666" 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">rs119482082 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119482082;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=rs119482082" 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=rs119482082" 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=RCV000005070 OR RCV001004021 OR RCV001174071 OR RCV001249798 OR RCV004597725" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005070, RCV001004021, RCV001174071, RCV001249798, RCV004597725" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005070...</a>
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<p>In 8 families of Australian/English, Australian/Scottish, English, or Canadian extraction with hereditary sensory neuropathy type IA (HSAN1A; <a href="/entry/162400">162400</a>), <a href="#7" class="mim-tip-reference" title="Dawkins, J. L., Hulme, D. J., Brahmbhatt, S. B., Auer-Grumbach, M., Nicholson, G. A. <strong>Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I.</strong> Nature Genet. 27: 309-312, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242114</a>] [<a href="https://doi.org/10.1038/85879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242114">Dawkins et al. (2001)</a> identified a heterozygous c.399T-G transversion in exon 5 of the SPTLC1 gene, resulting in a cysteine-to-tryptophan substitution at codon 133 (C133W). Cysteine-133 of SPTLC1 is invariant in human, mouse, Drosophila, and yeast. In a family of Canadian origin, <a href="#4" class="mim-tip-reference" title="Bejaoui, K., Wu, C., Scheffler, M. D., Haan, G., Ashby, P., Wu, L., de Jong, P., Brown, R. H., Jr. <strong>SPTLC1 is mutated in hereditary sensory neuropathy, type 1.</strong> Nature Genet. 27: 261-262, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242106</a>] [<a href="https://doi.org/10.1038/85817" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242106">Bejaoui et al. (2001)</a> independently identified this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11242106+11242114" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Nicholson, G. A., Dawkins, J. L., Blair, I. P., Auer-Grumbach, M., Brahmbhatt, S. B., Hulme, D. J. <strong>Hereditary sensory neuropathy type I: haplotype analysis shows founders in southern England and Europe.</strong> Am. J. Hum. Genet. 69: 655-659, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479835</a>] [<a href="https://doi.org/10.1086/323252" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479835">Nicholson et al. (2001)</a> performed haplotype analysis on 3 Australian families of English extraction and 3 English families (2 of which had been described elsewhere) with the cys133-to-trp mutation and demonstrated the same chromosome 9 haplotype as well as the same phenotype in all. They suggested that these families may have had a common founder who, on the basis of historical information, lived in southern England before 1800. The phenotype caused by the 399T-G SPTLC1 mutation is the same as that in the families reported by <a href="#6" class="mim-tip-reference" title="Campbell, A. M. G., Hoffman, H. L. <strong>Sensory radicular neuropathy associated with muscle wasting in two cases.</strong> Brain 87: 67-74, 1964.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14152213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14152213</a>] [<a href="https://doi.org/10.1093/brain/87.1.67" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14152213">Campbell and Hoffman (1964)</a> and possibly the original family reported by <a href="#12" class="mim-tip-reference" title="Hicks, E. P. <strong>Hereditary perforating ulcer of the foot.</strong> Lancet 199: 319-321, 1922. Note: Originally Volume I."None>Hicks (1922)</a>, all of which were English. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14152213+11479835" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In Chinese hamster ovary (CHO) cells and yeast, <a href="#8" class="mim-tip-reference" title="Gable, K., Gupta, S. D., Han, G., Niranjanakumari, S., Harmon, J. M., Dunn, T. M. <strong>A disease-causing mutation in the active site of serine palmitoyltransferase causes catalytic promiscuity.</strong> J. Biol. Chem. 285: 22846-22852, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20504773/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20504773</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20504773[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/10.1074/jbc.M110.122259" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20504773">Gable et al. (2010)</a> demonstrated that the C133W-mutant protein was expressed and formed a stable heterodimer with SPTLC2 (<a href="/entry/605713">605713</a>), but did not confer catalytic SPT activity even when cotransfected with wildtype SPTLC1, thus showing a dominant-negative effect. Coexpression of the mutant protein with the catalytic enhancers SSSPTB (<a href="/entry/610412">610412</a>) and SSSPTA (<a href="/entry/613540">613540</a>) provided sufficient SPT activity to support growth in yeast, although total enzyme activity was only 10 to 20% of wildtype. Yeast and CHO cells expressing the C133W mutant along with SPTLC2 and SSSPTA or SSSPTB showed preferential condensation of palmitoyl-CoA to alanine rather than serine. These results were not found with wildtype SPTLC1. Kinetic studies showed that the mutant protein had the same affinity to serine as the wildtype protein, but a lower Vmax for serine. These findings suggest that the C133W mutation perturbs the active site of the protein, facilitating the formation of alanine condensation products. However, small increases in extracellular serine levels were able to inhibit the reaction with alanine. The palmitoyl-CoA/alanine product, 1-deoxysphinganine (1-deoxySa), was shown to increase endoplasmic reticulum stress and the unfolded protein response, which may ultimately be toxic to neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20504773" 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> rs119482083 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119482083;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/rs119482083?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=rs119482083" 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=rs119482083" 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=RCV000005068 OR RCV000235837 OR RCV001174070 OR RCV001249799 OR RCV002326664 OR RCV004755711" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005068, RCV000235837, RCV001174070, RCV001249799, RCV002326664, RCV004755711" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005068...</a>
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<p>In 2 families of Australian/Scottish and Australian/English extraction with hereditary sensory neuropathy type I (HSAN1A; <a href="/entry/162400">162400</a>), <a href="#7" class="mim-tip-reference" title="Dawkins, J. L., Hulme, D. J., Brahmbhatt, S. B., Auer-Grumbach, M., Nicholson, G. A. <strong>Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I.</strong> Nature Genet. 27: 309-312, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242114</a>] [<a href="https://doi.org/10.1038/85879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242114">Dawkins et al. (2001)</a> identified a T-to-A transversion at nucleotide 431 in exon 6 of the SPTLC1 gene, resulting in a valine-to-aspartic acid substitution at codon 144 (V144D). Valine-144 of SPTLC1 is conserved in human, mouse, Drosophila, and yeast. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11242114" 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>Based on in vitro functional enzymatic studies, <a href="#5" class="mim-tip-reference" title="Bode, H., Bourquin, F., Suriyanarayanan, S., Wei, Y., Alecu, I., Othman, A., Von Eckardstein, A., Hornemann, T. <strong>HSAN1 mutations in serine palmitoyltransferase reveal a close structure-function-phenotype relationship.</strong> Hum. Molec. Genet. 25: 853-865, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26681808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26681808</a>] [<a href="https://doi.org/10.1093/hmg/ddv611" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26681808">Bode et al. (2016)</a> suggested that the V144D variant may not be pathogenic. The variant did not show significantly increased activity with alanine over serine and did not form significant amounts of neurotoxic 1-deoxySL compounds compared to the wildtype enzyme. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26681808" 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="#1" class="mim-tip-reference" title="Antony, A., Ng, N., Lauto, A., Coorssen, J. R., Myers, S. J. <strong>Calcium-mediated calpain activation and microtubule dissociation in cell model of hereditary sensory neuropathy type-1 expressing V144D SPTLC1 mutation.</strong> DNA Cell Biol. 41: 225-234, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34986032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34986032</a>] [<a href="https://doi.org/10.1089/dna.2021.0816" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34986032">Antony et al. (2022)</a> found that expression of the SPTLC1 V144D mutant increased cytoplasmic Ca(2+) but decreased mitochondrial Ca(2+) in SH-SY5Y cells, leading to activation of the Ca(2+)-dependent protease systems, calpain (see <a href="/entry/114220">114220</a>) and proteasome (see <a href="/entry/176843">176843</a>). Moreover, the calpain substrates MAP2 (<a href="/entry/157130">157130</a>) and tau (MAPT; <a href="/entry/157140">157140</a>) were significantly decreased in cells expressing V144D. Altered microtubule binding of motor proteins and decreased mitochondrial transport velocities were also observed in cells overexpressing V144D. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34986032" 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> rs119482084 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119482084;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/rs119482084?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=rs119482084" 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=rs119482084" 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=RCV000005069 OR RCV000789583 OR RCV001249812 OR RCV001310659 OR RCV002371761" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005069, RCV000789583, RCV001249812, RCV001310659, RCV002371761" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005069...</a>
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<p>This variant, formerly titled NEUROPATHY, HEREDITARY SENSORY, TYPE IA based on the report of <a href="#27" class="mim-tip-reference" title="Verhoeven, K., Coen, K., De Vriendt, E., Jacobs, A., Van Gerwen, V., Smouts, I., Pou-Serradell, A., Martin, J.-J., Timmerman, V., De Jonghe, P. <strong>SPTLC1 mutation in twin sisters with hereditary sensory neuropathy type I.</strong> Neurology 62: 1001-1002, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15037712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15037712</a>] [<a href="https://doi.org/10.1212/01.wnl.0000115388.10828.5c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15037712">Verhoeven et al. (2004)</a>, has been reclassified based on the reports of <a href="#13" class="mim-tip-reference" title="Hornemann, T., Penno, A., Richard, S., Nicholson, G., van Dijk, F. S., Rotthier, A., Timmerman, V., von Eckardstein, A. <strong>A systematic comparison of all mutations in hereditary sensory neuropathy type I (HSAN I) reveals that the G387A mutation is not disease associated.</strong> Neurogenetics 10: 135-143, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19132419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19132419</a>] [<a href="https://doi.org/10.1007/s10048-008-0168-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19132419">Hornemann et al. (2009)</a> and <a href="#5" class="mim-tip-reference" title="Bode, H., Bourquin, F., Suriyanarayanan, S., Wei, Y., Alecu, I., Othman, A., Von Eckardstein, A., Hornemann, T. <strong>HSAN1 mutations in serine palmitoyltransferase reveal a close structure-function-phenotype relationship.</strong> Hum. Molec. Genet. 25: 853-865, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26681808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26681808</a>] [<a href="https://doi.org/10.1093/hmg/ddv611" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26681808">Bode et al. (2016)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26681808+19132419+15037712" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In twin sisters with hereditary sensory neuropathy type I (HSAN1A; <a href="/entry/162400">162400</a>) from a Belgian family originally reported by <a href="#22" class="mim-tip-reference" title="Montanini, R. <strong>Acropatia ulcero-mutilante, amiotrofia frusta tipo Charcot-Marie e alessia in due gemelle univitelline.</strong> Riv. Neurol. 28: 593-609, 1958.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13646503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13646503</a>]" pmid="13646503">Montanini (1958)</a>, <a href="#27" class="mim-tip-reference" title="Verhoeven, K., Coen, K., De Vriendt, E., Jacobs, A., Van Gerwen, V., Smouts, I., Pou-Serradell, A., Martin, J.-J., Timmerman, V., De Jonghe, P. <strong>SPTLC1 mutation in twin sisters with hereditary sensory neuropathy type I.</strong> Neurology 62: 1001-1002, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15037712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15037712</a>] [<a href="https://doi.org/10.1212/01.wnl.0000115388.10828.5c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15037712">Verhoeven et al. (2004)</a> identified a c.1160G-C transversion in exon 13 of the SPTLC1 gene, resulting in a gly387-to-ala (G387A) substitution. The mutation was not identified in 300 control chromosomes. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=13646503+15037712" 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 in vitro functional studies, <a href="#13" class="mim-tip-reference" title="Hornemann, T., Penno, A., Richard, S., Nicholson, G., van Dijk, F. S., Rotthier, A., Timmerman, V., von Eckardstein, A. <strong>A systematic comparison of all mutations in hereditary sensory neuropathy type I (HSAN I) reveals that the G387A mutation is not disease associated.</strong> Neurogenetics 10: 135-143, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19132419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19132419</a>] [<a href="https://doi.org/10.1007/s10048-008-0168-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19132419">Hornemann et al. (2009)</a> demonstrated that overexpression of the G387A protein did not decrease SPT activity. In addition, expression of the G387A protein could rescue a SPTLC1-deficient cell line. Finally, homozygosity for G387A was identified in an unaffected mother of a heterozygous G387A mutation carrier with HSN1. The variant was also found in 1 of 190 unrelated controls. All of these findings indicated that it is likely not pathogenic. <a href="#13" class="mim-tip-reference" title="Hornemann, T., Penno, A., Richard, S., Nicholson, G., van Dijk, F. S., Rotthier, A., Timmerman, V., von Eckardstein, A. <strong>A systematic comparison of all mutations in hereditary sensory neuropathy type I (HSAN I) reveals that the G387A mutation is not disease associated.</strong> Neurogenetics 10: 135-143, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19132419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19132419</a>] [<a href="https://doi.org/10.1007/s10048-008-0168-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19132419">Hornemann et al. (2009)</a> postulated that the G387A variant, and perhaps the other 3 SPTLC1 variants previously associated with HSN1, may not be directly disease-causing, but rather have an indirect or bystander effect by increasing the risk for HSN1 in conjunction with another mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19132419" 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>Based on in vitro functional enzymatic studies, <a href="#5" class="mim-tip-reference" title="Bode, H., Bourquin, F., Suriyanarayanan, S., Wei, Y., Alecu, I., Othman, A., Von Eckardstein, A., Hornemann, T. <strong>HSAN1 mutations in serine palmitoyltransferase reveal a close structure-function-phenotype relationship.</strong> Hum. Molec. Genet. 25: 853-865, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26681808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26681808</a>] [<a href="https://doi.org/10.1093/hmg/ddv611" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26681808">Bode et al. (2016)</a> suggested that the G387A variant is likely not pathogenic. The variant did not show significantly increased activity with alanine over serine and did not form significant 1-deoxySL compounds compared to the wildtype enzyme. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26681808" 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">rs267607087 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607087;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=rs267607087" 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=rs267607087" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a French Gypsy with hereditary sensory and autonomic neuropathy type I (HSAN1A; <a href="/entry/162400">162400</a>), <a href="#26" class="mim-tip-reference" title="Rotthier, A., Baets, J., De Vriendt, E., Jacobs, A., Auer-Grumbach, M., Levy, N., Bonello-Palot, N., Kilic, S. S., Weis, J., Nascimento, A., Swinkels, M., Kruyt, M. C., Jordanova, A., De Jonghe, P., Timmerman, V. <strong>Genes for hereditary sensory and autonomic neuropathies: a genotype-phenotype correlation.</strong> Brain 132: 2699-2711, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19651702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19651702</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19651702[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/10.1093/brain/awp198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19651702">Rotthier et al. (2009)</a> identified a de novo heterozygous 992C-T transition in the SPTLC1 gene, resulting in a ser331-to-phe (S331F) substitution in a conserved residue. The patient had an unusually severe phenotype, with congenital onset, insensitivity to pain with eschar and foot ulceration, pes cavus/equinovarus, vocal cord paralysis, and gastroesophageal reflux. The patient also had severe growth and mental retardation, microcephaly, hypotonia, amyotrophy, and respiratory insufficiency. Nerve conduction studies showed absent sensory and motor responses in the upper and lower limbs. The mutation was absent from 600 control chromosomes. The phenotype expanded the clinical spectrum of HSAN1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19651702" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Auer-Grumbach, M., Bode, H., Pieber, T. R., Schabhuttl, M., Fischer, D., Seidl, R., Graf, E., Wieland, T., Schuh, R., Vacariu, G., Grill, F., Timmerman, V., Strom, T. M., Hornemann, T. <strong>Mutations at Ser331 in the HSN type I gene SPTLC1 are associated with a distinct syndromic phenotype.</strong> Europ. J. Med. Genet. 56: 266-269, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23454272/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23454272</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23454272[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.ejmg.2013.02.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23454272">Auer-Grumbach et al. (2013)</a> reported that a patient with a severe form of HSAN1, originally described by <a href="#15" class="mim-tip-reference" title="Huehne, K., Zweier, C., Raab, K., Odent, S., Bonnaure-Mallet, M., Sixou, J. L., Landrieu, P., Goizet, C., Sarlangue, J., Baumann, M., Eggermann, T., Rauch, A., Ruppert, S., Stettner, G. M., Rautenstrauss, B. <strong>Novel missense, insertion and deletion mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) associated with congenital insensitivity to pain with anhidrosis.</strong> Neuromusc. Disord. 18: 159-166, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18077166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18077166</a>] [<a href="https://doi.org/10.1016/j.nmd.2007.10.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18077166">Huehne et al. (2008)</a> (patient ER-CIPA-20374), was found to be heterozygous for the S331F mutation in the SPTLC1 gene. The authors noted that another patient with a severe form of HSAN1 was heterozygous for a different mutation at ser311 in the SPTLC1 gene (S311Y; <a href="#0007">605712.0007</a>). <a href="#2" class="mim-tip-reference" title="Auer-Grumbach, M., Bode, H., Pieber, T. R., Schabhuttl, M., Fischer, D., Seidl, R., Graf, E., Wieland, T., Schuh, R., Vacariu, G., Grill, F., Timmerman, V., Strom, T. M., Hornemann, T. <strong>Mutations at Ser331 in the HSN type I gene SPTLC1 are associated with a distinct syndromic phenotype.</strong> Europ. J. Med. Genet. 56: 266-269, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23454272/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23454272</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23454272[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.ejmg.2013.02.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23454272">Auer-Grumbach et al. (2013)</a> confirmed increased 1-deoxySL formation in HEK293 cells expressing the S331F or the S331Y mutant. Canonical serine activity was reduced by 60% in both mutants. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18077166+23454272" 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> rs267607088 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607088;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/rs267607088?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=rs267607088" 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=rs267607088" 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=RCV000005072 OR RCV001321436" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005072, RCV001321436" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005072...</a>
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<p>In an Austrian patient with HSN1 (HSAN1A; <a href="/entry/162400">162400</a>), <a href="#26" class="mim-tip-reference" title="Rotthier, A., Baets, J., De Vriendt, E., Jacobs, A., Auer-Grumbach, M., Levy, N., Bonello-Palot, N., Kilic, S. S., Weis, J., Nascimento, A., Swinkels, M., Kruyt, M. C., Jordanova, A., De Jonghe, P., Timmerman, V. <strong>Genes for hereditary sensory and autonomic neuropathies: a genotype-phenotype correlation.</strong> Brain 132: 2699-2711, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19651702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19651702</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19651702[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/10.1093/brain/awp198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19651702">Rotthier et al. (2009)</a> identified a heterozygous c.1055C-T transition in the SPTLC1 gene, resulting in an ala352-to-val (A352V) substitution. The patient had onset at age 16 years of severe sensory loss of the lower extremities with peroneal atrophy and decreased distal reflexes. There was mild pes cavus and lancinating pain in the lower extremities. DNA from family members was not available. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19651702" 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>Based on in vitro functional enzymatic studies, <a href="#5" class="mim-tip-reference" title="Bode, H., Bourquin, F., Suriyanarayanan, S., Wei, Y., Alecu, I., Othman, A., Von Eckardstein, A., Hornemann, T. <strong>HSAN1 mutations in serine palmitoyltransferase reveal a close structure-function-phenotype relationship.</strong> Hum. Molec. Genet. 25: 853-865, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26681808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26681808</a>] [<a href="https://doi.org/10.1093/hmg/ddv611" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26681808">Bode et al. (2016)</a> suggested that the A352V variant may not be pathogenic. The variant did not show significantly increased activity with alanine over serine and did not form significant 1-deoxySL compounds compared to the wildtype enzyme. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26681808" 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">rs267607087 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607087;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=rs267607087" 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=rs267607087" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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In a girl, born of nonconsanguineous parents, with hereditary sensory and autonomic neuropathy type I (HSAN1A; <a href="/entry/162400">162400</a>), <a href="#2" class="mim-tip-reference" title="Auer-Grumbach, M., Bode, H., Pieber, T. R., Schabhuttl, M., Fischer, D., Seidl, R., Graf, E., Wieland, T., Schuh, R., Vacariu, G., Grill, F., Timmerman, V., Strom, T. M., Hornemann, T. <strong>Mutations at Ser331 in the HSN type I gene SPTLC1 are associated with a distinct syndromic phenotype.</strong> Europ. J. Med. Genet. 56: 266-269, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23454272/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23454272</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23454272[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.ejmg.2013.02.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23454272">Auer-Grumbach et al. (2013)</a> identified a de novo heterozygous c.922G-T transversion in the SPTLC1 gene, resulting in a ser311-to-tyr (S311Y) substitution. The mutation segregated with the disorder in the family and was not found in 1,969 individuals in an in-house database. The girl had a severe form of the disorder, with onset at age 4 years of unsteady gait, hand tremor, progressive sensory disturbances, and a pes cavus foot deformity necessitating triple arthrodesis at age 5. Disease progression was rapid and led to severe scoliosis, respiratory problems, and wheelchair dependence at age 14. She had prominent growth retardation but normal intellectual development. The level of 1-deoxySL was significantly elevated in the patient's plasma. <a href="#2" class="mim-tip-reference" title="Auer-Grumbach, M., Bode, H., Pieber, T. R., Schabhuttl, M., Fischer, D., Seidl, R., Graf, E., Wieland, T., Schuh, R., Vacariu, G., Grill, F., Timmerman, V., Strom, T. M., Hornemann, T. <strong>Mutations at Ser331 in the HSN type I gene SPTLC1 are associated with a distinct syndromic phenotype.</strong> Europ. J. Med. Genet. 56: 266-269, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23454272/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23454272</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23454272[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.ejmg.2013.02.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23454272">Auer-Grumbach et al. (2013)</a> noted that a different mutation at ser331 in the SPTLC1 gene (S331F; <a href="#0005">605712.0005</a>) resulted in a severe form of the disorder in 2 patients with HSAN1. They confirmed increased 1-deoxySL formation in HEK293 cells expressing the S331Y or the S331F mutant. Canonical serine activity was reduced by 60% in both mutants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23454272" 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>Juvenile Amyotrophic Lateral Sclerosis 27</em></strong></p><p>
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In a patient (patient 3) with juvenile amyotrophic lateral sclerosis-27 (ALS27; <a href="/entry/620285">620285</a>), <a href="#16" class="mim-tip-reference" title="Johnson, J. O., Chia, R., Miller, D. E., Li, R., Kumaran, R., Abramzon, Y., Alahmady, N., Renton, A. E., Topp, S. D., Gibbs, J. R., Cookson, M. R., Sabir, M. S., and 287 others. <strong>Association of variants in the SPTLC1 gene with juvenile amyotrophic lateral sclerosis.</strong> JAMA Neurol. 78: 1236-1248, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34459874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34459874</a>] [<a href="https://doi.org/10.1001/jamaneurol.2021.2598" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34459874">Johnson et al. (2021)</a> identified heterozygosity for the S331Y mutation. The mutation was identified by whole-exome sequencing and shown to be de novo. The patient had prominent motor symptoms and modest sensory autonomic symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34459874" 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">rs1554716504 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554716504;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=rs1554716504" 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=rs1554716504" 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=RCV000522579 OR RCV001267702 OR RCV003152607" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000522579, RCV001267702, RCV003152607" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000522579...</a>
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<p>In 2 unrelated patients (patients 1 and 2) with juvenile amyotrophic lateral sclerosis-27 (ALS27; <a href="/entry/620285">620285</a>), <a href="#21" class="mim-tip-reference" title="Mohassel, P., Donkervoort, S., Lone, M. A., Nalls, M., Gable, K., Gupta, S. D., Foley, A. R., Hu, Y., Saute, J. A. M., Moreira, A. L., Kok, F., Introna, A., and 34 others. <strong>Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.</strong> Nature Med. 27: 1197-1204, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34059824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34059824</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34059824[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41591-021-01346-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34059824">Mohassel et al. (2021)</a> identified a de novo heterozygous c.68A-T transition (c.68A-T, NM_006415.4) in exon 2 of the SPTLC1 gene, resulting in a tyr23-to-phe (Y23F) substitution. The mutation, which was identified by whole-exome sequencing, was not present in the gnomAD database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34059824" 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">rs2118840030 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2118840030;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=rs2118840030" 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=rs2118840030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient (patient 3) with juvenile amyotrophic lateral sclerosis-27 (ALS27; <a href="/entry/620285">620285</a>), <a href="#21" class="mim-tip-reference" title="Mohassel, P., Donkervoort, S., Lone, M. A., Nalls, M., Gable, K., Gupta, S. D., Foley, A. R., Hu, Y., Saute, J. A. M., Moreira, A. L., Kok, F., Introna, A., and 34 others. <strong>Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.</strong> Nature Med. 27: 1197-1204, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34059824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34059824</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34059824[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41591-021-01346-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34059824">Mohassel et al. (2021)</a> identified a de novo heterozygous 6-bp deletion (c.118_123delTTCTCT, NM_006415.4) in exon 2 of the SPTLC1 gene, resulting in a Phe40_Ser41 deletion (F40_S41del). The mutation was identified by sequencing a hereditary neuropathy gene panel. The variant was not present in the gnomAD database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34059824" 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> rs1197928094 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1197928094;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/rs1197928094?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=rs1197928094" 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=rs1197928094" 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=RCV000988188 OR RCV001560232 OR RCV001858688 OR RCV002468610 OR RCV003152613" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000988188, RCV001560232, RCV001858688, RCV002468610, RCV003152613" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000988188...</a>
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<p>In 2 unrelated patients (patients 4 and 5) and a father and his 4 children from another unrelated family (family 7) with juvenile amyotrophic lateral sclerosis-27 (ALS27; <a href="/entry/620285">620285</a>), <a href="#21" class="mim-tip-reference" title="Mohassel, P., Donkervoort, S., Lone, M. A., Nalls, M., Gable, K., Gupta, S. D., Foley, A. R., Hu, Y., Saute, J. A. M., Moreira, A. L., Kok, F., Introna, A., and 34 others. <strong>Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.</strong> Nature Med. 27: 1197-1204, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34059824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34059824</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34059824[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41591-021-01346-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34059824">Mohassel et al. (2021)</a> identified heterozygosity for a 3-bp deletion (c.115_117delCTT, NM_006415.4) in exon 2 of the SPTLC1 gene, resulting in a deletion of Leu39 (L39del). The mutation was identified by whole-exome sequencing. In patients 4 and 5, the mutation occurred de novo. The variant was not present in the gnomAD database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34059824" 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">rs879254294 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879254294;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=rs879254294" 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=rs879254294" 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=RCV000236861 OR RCV003223342 OR RCV004594033" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000236861, RCV003223342, RCV004594033" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000236861...</a>
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<p>In a patient (patient 6) with juvenile amyotrophic lateral sclerosis-27 (ALS27), <a href="#21" class="mim-tip-reference" title="Mohassel, P., Donkervoort, S., Lone, M. A., Nalls, M., Gable, K., Gupta, S. D., Foley, A. R., Hu, Y., Saute, J. A. M., Moreira, A. L., Kok, F., Introna, A., and 34 others. <strong>Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.</strong> Nature Med. 27: 1197-1204, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34059824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34059824</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34059824[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41591-021-01346-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34059824">Mohassel et al. (2021)</a> identified a de novo heterozygous c.58G-T transversion adjacent to the splice acceptor site for exon 2 of the SPTLC1 gene. The mutation was predicted to result in an ala20-to-ser (A20S) substitution, but was found to result predominently in complete skipping of exon 2 and the entire first transmembrane domain of the protein. The mutation was identified by whole-exome sequencing and occurred de novo in the patient. The variant was not present in the gnomAD database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34059824" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated patients (patients 1 and 2) with ALS27, <a href="#16" class="mim-tip-reference" title="Johnson, J. O., Chia, R., Miller, D. E., Li, R., Kumaran, R., Abramzon, Y., Alahmady, N., Renton, A. E., Topp, S. D., Gibbs, J. R., Cookson, M. R., Sabir, M. S., and 287 others. <strong>Association of variants in the SPTLC1 gene with juvenile amyotrophic lateral sclerosis.</strong> JAMA Neurol. 78: 1236-1248, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34459874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34459874</a>] [<a href="https://doi.org/10.1001/jamaneurol.2021.2598" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34459874">Johnson et al. (2021)</a> identified 2 patients with a de novo heterozygous A20S mutation. The mutation was identified by whole-exome sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34459874" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 AMYOTROPHIC LATERAL SCLEROSIS 27, JUVENILE</strong>
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SPTLC1, LEU38ARG
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003152660" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003152660" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003152660</a>
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<p>In a 12-year-old Chinese girl with juvenile onset amyotrophic lateral sclerosis-27 (ALS27; <a href="/entry/620285">620285</a>), <a href="#18" class="mim-tip-reference" title="Liu, X., He, J., Yu, W., Fan, D. <strong>A de novo c.113 T>C: p.L38R mutation of SPTLC1: case report of a girl with sporadic juvenile amyotrophic lateral sclerosis.</strong> Amyotroph. Lateral Scler. Frontotemporal Degener. 23: 634-637, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36204986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36204986</a>] [<a href="https://doi.org/10.1080/21678421.2022.2096409" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36204986">Liu et al. (2022)</a> identified a de novo heterozygous c.113T-C transition in exon 2 of the SPTLC1 gene, resulting in a leu38-to-arg (L38R) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD, dbSNP, and 1000 Genomes Project databases or in 650 healthy Chinese controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36204986" 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 id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="Antony2022" class="mim-anchor"></a>
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Antony, A., Ng, N., Lauto, A., Coorssen, J. R., Myers, S. J.
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<strong>Calcium-mediated calpain activation and microtubule dissociation in cell model of hereditary sensory neuropathy type-1 expressing V144D SPTLC1 mutation.</strong>
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DNA Cell Biol. 41: 225-234, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34986032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34986032</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34986032" 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/10.1089/dna.2021.0816" target="_blank">Full Text</a>]
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Auer-Grumbach, M., Bode, H., Pieber, T. R., Schabhuttl, M., Fischer, D., Seidl, R., Graf, E., Wieland, T., Schuh, R., Vacariu, G., Grill, F., Timmerman, V., Strom, T. M., Hornemann, T.
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<strong>Mutations at Ser331 in the HSN type I gene SPTLC1 are associated with a distinct syndromic phenotype.</strong>
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Europ. J. Med. Genet. 56: 266-269, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23454272/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23454272</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23454272[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23454272" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ejmg.2013.02.002" target="_blank">Full Text</a>]
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<a id="Bejaoui2002" class="mim-anchor"></a>
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Bejaoui, K., Uchida, Y., Yasuda, S., Ho, M., Nishijima, M., Brown, R. H., Jr., Holleran, W. M., Hanada, K.
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<strong>Hereditary sensory neuropathy type 1 mutations confer dominant negative effects on serine palmitoyltransferase, critical for sphingolipid synthesis.</strong>
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J. Clin. Invest. 110: 1301-1308, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12417569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12417569</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12417569[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12417569" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI16450" target="_blank">Full Text</a>]
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<a id="Bejaoui2001" class="mim-anchor"></a>
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Bejaoui, K., Wu, C., Scheffler, M. D., Haan, G., Ashby, P., Wu, L., de Jong, P., Brown, R. H., Jr.
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<strong>SPTLC1 is mutated in hereditary sensory neuropathy, type 1.</strong>
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Nature Genet. 27: 261-262, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242106</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11242106" 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/10.1038/85817" target="_blank">Full Text</a>]
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<a id="Bode2016" class="mim-anchor"></a>
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Bode, H., Bourquin, F., Suriyanarayanan, S., Wei, Y., Alecu, I., Othman, A., Von Eckardstein, A., Hornemann, T.
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<strong>HSAN1 mutations in serine palmitoyltransferase reveal a close structure-function-phenotype relationship.</strong>
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Hum. Molec. Genet. 25: 853-865, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26681808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26681808</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26681808" 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/ddv611" target="_blank">Full Text</a>]
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<a id="Campbell1964" class="mim-anchor"></a>
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<div class="">
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Campbell, A. M. G., Hoffman, H. L.
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<strong>Sensory radicular neuropathy associated with muscle wasting in two cases.</strong>
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Brain 87: 67-74, 1964.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14152213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14152213</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14152213" 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/brain/87.1.67" target="_blank">Full Text</a>]
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<a id="Dawkins2001" class="mim-anchor"></a>
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Dawkins, J. L., Hulme, D. J., Brahmbhatt, S. B., Auer-Grumbach, M., Nicholson, G. A.
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<strong>Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I.</strong>
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Nature Genet. 27: 309-312, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242114</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11242114" 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/10.1038/85879" target="_blank">Full Text</a>]
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<a id="Gable2010" class="mim-anchor"></a>
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Gable, K., Gupta, S. D., Han, G., Niranjanakumari, S., Harmon, J. M., Dunn, T. M.
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<strong>A disease-causing mutation in the active site of serine palmitoyltransferase causes catalytic promiscuity.</strong>
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J. Biol. Chem. 285: 22846-22852, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20504773/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20504773</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20504773[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20504773" 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/10.1074/jbc.M110.122259" target="_blank">Full Text</a>]
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<a id="Gantner2019" class="mim-anchor"></a>
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Gantner, M. L., Eade, K., Wallace, M., Handzlik, M. K., Fallon, R., Trombley, J., Bonelli, R., Giles, S., Harkins-Perry, S., Heeren, T. F C., Sauer, L., Ideguchi, Y., and 20 others.
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<strong>Serine and lipid metabolism in macular disease and peripheral neuropathy.</strong>
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New Eng. J. Med. 381: 1422-1433, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31509666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31509666</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31509666[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31509666" 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/10.1056/NEJMoa1815111" target="_blank">Full Text</a>]
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<a id="Han2009" class="mim-anchor"></a>
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Han, G., Gupta, S. D., Gable, K., Niranjanakumari, S., Moitra, P., Eichler, F., Brown, R. H., Jr., Harmon, J. M., Dunn, T. M.
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<strong>Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities.</strong>
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Proc. Nat. Acad. Sci. 106: 8186-8191, 2009. Note: Erratum: Proc. Nat. Acad. Sci. 106: 9931 only, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19416851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19416851</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19416851[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19416851" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0811269106" target="_blank">Full Text</a>]
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Herget, T., Esdar, C., Oehrlein, S. A., Heinrich, M., Schutze, S., Maelicke, A., van Echten-Deckert, G.
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J. Biol. Chem. 275: 30344-30354, 2000.
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[<a href="https://doi.org/10.1074/jbc.M000714200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10048-008-0168-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M608066200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.nmd.2007.10.005" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/jamaneurol.2021.2598" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.7554/eLife.78861" target="_blank">Full Text</a>]
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<strong>A de novo c.113 T>C: p.L38R mutation of SPTLC1: case report of a girl with sporadic juvenile amyotrophic lateral sclerosis.</strong>
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[<a href="https://doi.org/10.1080/21678421.2022.2096409" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI161908" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16210380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16210380</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16210380" 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/ddi380" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/s41591-021-01346-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/323252" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M109.092973" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.275.12.9078" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/brain/awp198" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15037712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15037712</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15037712" 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/10.1212/01.wnl.0000115388.10828.5c" target="_blank">Full Text</a>]
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<a id="28" class="mim-anchor"></a>
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<a id="Weiss1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Weiss, B., Stoffel, W.
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<strong>Human and murine serine-palmitoyl-CoA transferase: cloning, expression and characterization of the key enzyme in sphingolipid synthesis.</strong>
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Europ. J. Biochem. 249: 239-247, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9363775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9363775</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9363775" 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/10.1111/j.1432-1033.1997.00239.x" target="_blank">Full Text</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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Hilary J. Vernon - updated : 03/14/2023
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Bao Lige - updated : 02/06/2023<br>Cassandra L. Kniffin - updated : 11/04/2019<br>Carol A. Bocchini - updated : 10/22/2019<br>Cassandra L. Kniffin - updated : 11/12/2010<br>Cassandra L. Kniffin - updated : 9/23/2010<br>George E. Tiller - updated : 9/3/2009<br>Cassandra L. Kniffin - updated : 5/14/2009<br>Jennifer L. Goldstein - updated : 6/19/2007<br>Denise L. M. Goh - updated : 4/10/2003<br>Carol A. Bocchini - reorganized : 10/5/2001<br>Victor A. McKusick - updated : 9/27/2001
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Creation Date:
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Ada Hamosh : 3/2/2001
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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carol : 04/21/2023
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carol : 03/16/2023<br>carol : 03/14/2023<br>mgross : 02/06/2023<br>carol : 07/20/2020<br>carol : 11/04/2019<br>ckniffin : 11/04/2019<br>carol : 10/25/2019<br>carol : 10/23/2019<br>carol : 10/22/2019<br>carol : 10/01/2013<br>terry : 12/19/2012<br>carol : 11/16/2010<br>ckniffin : 11/12/2010<br>wwang : 10/6/2010<br>ckniffin : 9/23/2010<br>terry : 1/20/2010<br>wwang : 9/17/2009<br>terry : 9/3/2009<br>wwang : 5/27/2009<br>ckniffin : 5/14/2009<br>terry : 3/27/2009<br>carol : 6/19/2007<br>wwang : 6/19/2007<br>tkritzer : 9/8/2004<br>ckniffin : 8/27/2004<br>carol : 5/21/2004<br>ckniffin : 5/18/2004<br>carol : 4/10/2003<br>carol : 7/30/2002<br>mcapotos : 10/5/2001<br>carol : 10/5/2001<br>carol : 10/5/2001<br>carol : 10/5/2001<br>mcapotos : 10/4/2001<br>terry : 9/27/2001<br>alopez : 3/5/2001<br>alopez : 3/2/2001<br>alopez : 3/2/2001
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<span class="mim-font">
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<strong>*</strong> 605712
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<h3>
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SERINE PALMITOYLTRANSFERASE, LONG-CHAIN BASE SUBUNIT 1; SPTLC1
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<em>Alternative titles; symbols</em>
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SPT1<br />
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LCB1
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SPTLC1</em></strong>
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<strong>SNOMEDCT:</strong> 860813007;
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Cytogenetic location: 9q22.31
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Genomic coordinates <span class="small">(GRCh38)</span> : 9:92,031,147-92,115,413 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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9q22.31
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<span class="mim-font">
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Amyotrophic lateral sclerosis 27, juvenile
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<span class="mim-font">
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620285
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Autosomal dominant
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<span class="mim-font">
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3
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Neuropathy, hereditary sensory and autonomic, type IA
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<span class="mim-font">
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162400
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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<strong>TEXT</strong>
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>Serine palmitoyltransferase (SPT; EC 2.3.1.50) is the key enzyme in sphingolipid biosynthesis. It catalyzes the first and rate-limiting step: the pyridoxal-5-prime-phosphate-dependent condensation of L-serine and palmitoyl-CoA to 3-oxosphinganine (Weiss and Stoffel, 1997). </p><p>SPT contains 2 main subunits: the common SPTLC1 subunit and either SPTLC2 (605713) or its isoform SPTLC2L (SPTLC3; 611120), depending on the tissue in which biosynthesis occurs (Hornemann et al., 2006). There are also 2 highly related isoforms of a third subunit, SSSPTA (613540) and SSSPTB (610412), that confer acyl-CoA preference of the SPT enzyme and are essential for maximal enzyme activity (Han et al., 2009). </p>
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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 class="mim-text-font">
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<p>Weiss and Stoffel (1997) cloned and characterized 2 complete human and murine cDNA sequences corresponding to the SPTLC1 and SPTLC2 (605713) genes, similar to yeast LCB1 and LCB2 genes, respectively. The SPTLC1 cDNA contains an open reading frame of 1,422 nucleotides and encodes a 473-amino acid protein (Bejaoui et al., 2001). By Northern blot analysis, Dawkins et al. (2001) detected a single 3-kb SPTLC1 transcript in all 7 tissues tested, including spinal cord. A search of the UniGene database identified corresponding cDNA clones expressed in 29 different tissues, indicating that SPTLC1 is ubiquitously expressed. </p><p>By quantitative real-time PCR analysis, Hornemann et al. (2006) detected SPTLC1 expression in all 24 human tissues examined except for small intestine. Western blot analysis detected SPTLC1 at 55 kD. Overexpression of SPTLC1 in HEK293 cells showed no increase in SPT activity, suggesting that SPTLC2 and SPTLC3 (611120) are the limiting factors for SPT activity. </p>
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<br />
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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 class="mim-text-font">
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<p>Dawkins et al. (2001) determined that the SPTLC1 gene contains 15 exons and established the intron/exon boundaries. </p>
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<div>
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<br />
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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>Dawkins et al. (2001) noted that the SPTLC1 gene maps to chromosome 9q22.1-q22.3. </p>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p><strong><em>Hereditary Sensory and Autonomic Neuropathy, Type IA</em></strong></p><p>
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Dawkins et al. (2001) identified mutations in the SPTLC1 gene in 11 families with hereditary sensory neuropathy type I (HSAN1A; 162400). One family carried a C133Y mutation in exon 5 (605712.0001); 8 families carried a C133W mutation in exon 5 (605712.0002); and 2 families carried a V144D mutation in exon 6 (605712.0003). All 6 families with definite or probable linkage to chromosome 9 were found to have mutations in SPTLC1. The families were of Australian/English, Australian/Scottish, English, Austrian/German, or Canadian extraction. Dawkins et al. (2001) noted that ceramide produced by catabolism of sphingomyelin mediates programmed cell death and that increased de novo ceramide synthesis due to an increase in SPT activity has been demonstrated to cause apoptosis in a number of tissues (Perry et al., 2000), including differentiating neuronal cells (Herget et al., 2000). Dawkins et al. (2001) determined that the mutations were associated with increased de novo glucosyl ceramide synthesis in lymphoblast cell lines in affected individuals. Increased de novo ceramide synthesis triggers apoptosis, and is associated with massive cell death during neural tube closure, raising the possibility that neural degeneration in HSN1 is due to ceramide-induced apoptotic cell death. Dawkins et al. (2001) labeled lipids with C14-serine and showed that lymphoblast lines from HSN1 patients synthesize higher levels of glucosyl ceramide than do comparable lines from healthy controls. Glucosyl ceramide synthesis in 5 HSN1 patients was 175% of the levels in 8 controls. </p><p>Bejaoui et al. (2001) independently identified the C133Y and C133W mutations in 2 unrelated families with HSN1. Bejaoui et al. (2002) found that the C133Y and C133W mutations do not alter the steady state levels of the SPTLC1 or the SPTLC2 subunit. They did, however, result in reduced SPT activity and sphingolipid synthesis. The mutations did not complement the SPT deficiency found in a mutant CHO cell strain with defective SPT activity secondary to a lack of SPTLC1. Overproduction of either the C133Y or C133W subunit inhibited SPT activity in CHO cells despite the presence of wildtype SPTLC1. The mutant SPTLC1 proteins could also interact with the wildtype SPTLC2 subunit. The results indicated that both of these mutations have a dominant-negative effect on the SPT enzyme. </p><p>By in vitro functional expression assays in HEK293 cells, Hornemann et al. (2009) found that none of the 4 SPTLC1 mutations, C133Y, C133W, V144D, or G387A (605712.0004), interfered with formation of the SPT complex. The first 3 mutant proteins resulted in 40 to 50% decreased SPT activity, but the G387A protein showed no effect on SPT activity. Further studies showed that the G387A protein could rescue a SPTLC1-deficient cell line. Hornemann et al. (2009) also identified homozygosity for the G387A variant in an unaffected mother of a heterozygous carrier with HSN1, and it was found in 1 of 190 controls. These findings indicated that G387A is not pathogenic. Hornemann et al. (2009) postulated that the G387A variant, and perhaps the other 3 SPTLC1 variants previously associated with HSN1, may not be directly disease-causing, but rather have an indirect or bystander effect by increasing the risk for HSN1 in conjunction with another mutation. </p><p>SPT catalyzes the condensation of serine and palmitoyl-CoA, the initial step in the de novo synthesis of sphingolipids. Penno et al. (2010) showed that HSAN1A-related mutations in the SPTLC1 gene induce a shift in the substrate specificity of SPT, which leads to the formation of 2 atypical deoxysphingoid bases: 1-deoxysphinganine from condensation with alanine, and 1-deoxymethylsphinganine from condensation with glycine. Neither of these metabolites can be converted to complex sphingolipids or degraded, resulting in their intracellular accumulation. These atypical agents showed pronounced neurotoxic effects on neurite formation in cultured sensory neurons, and was associated with disturbed neurofilament structure. Penno et al. (2010) found increased levels of these atypical agents in lymphoblasts and plasma from HSAN1A patients with different SPTLC1 mutations. The findings indicated that HSAN1 results from gain-of-function mutations that cause the formation of atypical and neurotoxic sphingolipid metabolites, rather than from lack of de novo sphingolipid synthesis. </p><p>In a patient with an unusually severe form of HSAN1A, Rotthier et al. (2009) identified a de novo heterozygous mutation (S311F; 605712.0005) in the SPTLC1 gene. Auer-Grumbach et al. (2013) reported that a patient with a severe form of HSAN1, originally reported by Huehne et al. (2008), was heterozygous for the same S311F mutation. In another patient with severe HSAN1, Auer-Grumbach et al. (2013) identified a different de novo heterozygous mutation at the same codon (S311Y; 605712.0007). </p><p>Gantner et al. (2019) identified 9 patients, including 8 patients from 2 unrelated families and an additional unrelated patient, with genetically confirmed HSAN1A who also had type 2 macular telangiectasia. All carried the same heterozygous C133Y mutation in the SPTLC1 gene (605712.0001). Two additional unrelated patients (patient 2 and 3), who had HSAN1A due to a heterozygous missense C133W mutation in the SPTLC1 gene (605712.0002), did not have macular telangiectasia. However, both patients were under the age of 50 and had been treated with serine supplementation. </p><p><strong><em>Amyotrophic Lateral Sclerosis 27, Juvenile</em></strong></p><p>
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In 11 patients with juvenile amyotrophic lateral sclerosis-27 (ALS27; 620285), Mohassel et al. (2021) identified heterozygous mutations in exon 2 of the SPTLC1 gene (605712.0008-605712.0011). The mutation occurred de novo in 6 unrelated patients and was inherited from a mildly affected father in 1 family. Serum from affected patients had elevated free sphinganine and ceramide levels compared to controls, consistent with increased products of serine palmitoyltransferase activity. Heterozygous mutations (F40_S41del or deletion of exon 2) were introduced into the SPTLC1 gene in iPSCs, which were then differentiated into human motor neuron-like cells (iPSC-hMNs). The mutant iPSC-hMNs had increased sphingolipid levels, which was exacerbated by supplementation with serine. The increased SPT activity in the iPSC-hMNs was not mitigated with increased levels of ORMD3 or with ceramide treatment (both known inhibitors of SPT). Mohassel et al. (2021) concluded that the mutations in exon 2 of the SPTLC1 gene identified in patients with juvenile ALS resulted in diminished SPT inhibition by ORDM3 and ceramide. </p><p>By whole-exome sequencing, Johnson et al. (2021) identified de novo heterozygous mutations in the SPTLC1 gene in 3 unrelated patients with ALS27 (S331F, 605712.0007; A20S, 605712.0011). The patient with the S331F mutation (patient 3) had prominent motor symptoms and modest sensory-autonomic symptoms, whereas the 2 patients with the A20S mutation had only motor symptoms. </p><p>In a 12-year-old girl with ALS27, Liu et al. (2022) identified a de novo heterozygous missense mutation in the SPTLC1 gene (L38R; 605712.0012). The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies were not reported. </p><p>Lone et al. (2022) expressed SPTLC1 with the Y23F (605712.0008), L39del (605712.0010), S331F (605712.0005), Ex2del (605712.0011) or F40_S41del (605712.0009) mutations in T-Rex293 cells. All of the mutant SPTLC1 proteins localized properly to the endoplasmic reticulum, except for the exon 2 deletion, which was mostly mislocalized to the cytoplasm. Immunoprecipitation assays showed that each mutant SPTLC1, except for the Y23F mutant, resulted in reduced interaction with ORMDLs (see 610073) in the SPT complex. Each SPTLC1 mutation was then expressed in HEK293 cells and lipidomics analyses were performed. The mutant cells had a distinct ceramide profile and increased sphingolipid synthesis, which was not normalized/inhibited by C6 ceramide. In addition, the S331F and S331Y (605712.0007) mutants produced increased deoxysphingolipids. Lone et al. (2022) concluded that the mutations in SPLTC1 resulted in abnormal feedback inhibition and increased sphingolipid synthesis, and that mutations associated with motor symptoms had distinct lipid profiles from those that were associated with mixed sensory and motor symptoms. </p>
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</span>
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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>Using biochemical assays in transfected cells, Bode et al. (2016) assessed the enzymatic activity and biochemical consequences of 11 different missense variants in the SPTLC1 gene, including 7 that had previously been identified in HSAN1 patients. None of the variants resulted in a loss of activity, as had previously been suggested. Several variants, including V144D, A310G, A339V, and A352V, showed no change in canonical enzyme activity, did not show significant activity with alanine over serine, and did not form increased levels of neurotoxic 1-deoxySL compounds compared to wildtype. The authors suggested that these variants may not be pathogenic. Two mutations, C133Y and C133W, were associated with increased 1-deoxySL levels compared to wildtype, but had unaltered canonical activity and did not cause increased C20-sphingoid bases. These mutations were associated with a typical late-onset phenotype with primarily sensory and mild motor impairment. Two mutations, S331F and S331Y, were characterized by increased canonical enzyme activity as well as increased formation of C18-, 1-deoxy-, and C20-sphingoid bases, the latter of which was a unique and particular hallmark of these mutations. These mutations were associated with a severe phenotype characterized by early onset of symptoms, autonomic impairment, and juvenile cataracts. Further studies showed that the formation of toxic 1-deoxySL in animal models and patients with HSAN1 was reduced by increased availability of serine through oral supplementation. In contrast, increased availability of alanine resulted in augmented 1-deoxySL formation and aggravated neuropathic symptoms. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>McCampbell et al. (2005) created transgenic mouse lines that ubiquitously overexpressed either wildtype or C133W-mutant SPTLC1. The C133W-mutant mice developed age-dependent weight loss and mild sensory and motor impairments. Aged C133W-mutant mice lost large myelinated axons in the ventral root of the spinal cord and demonstrated myelin thinning. There was also a loss of large myelinated axons in the dorsal roots, although the unmyelinated fibers were preserved. In the dorsal root ganglia, IB4 staining was diminished, whereas expression of the injury-induced transcription factor ATF3 (603148) was increased. </p><p>Kuo et al. (2022) found that mice with vascular endothelial cell (EC)-specific deletion of Sptlc1 had normal body weight, liver enzyme levels, kidney function, and blood chemistry. However, ablation of Sptlc1 in ECs reduced sphingolipid (SL) content in both EC and non-EC cell populations of lung, indicating that SPT supplied SL to both vascular and nonvascular cells in lung. Supply of SL by active SPT in endothelium was important for normal vascular development, as retinal vascular development was delayed in mice with EC-specific Sptlc1 knockout. Analysis of a mouse model of oxygen-induced retinopathy suggested that de novo synthesis of SL in ECs determined the pathologic phenotypes in retinal vasculature, likely due to reduced Vegf (192240) responsiveness. Vegf signaling was impaired in retina of Sptlc1-knockout mice, because de novo synthesis of SL was necessary for efficient Vegf signaling via modulation of lipid raft formation in wildtype mice, and loss of Sptlc1 impaired Vegf responsiveness. Deletion of Sptlc1 in ECs also led to rapid reduction of several SL metabolites in plasma, red blood cells, and peripheral organs, but not in retina, as endothelial SPT activity provided SL metabolites to those cells and organs through circulation postnatally. Further analysis indicated that EC SPT supply of liver sphingolipids through circulation impacted stress response of hepatocytes and liver injury in mice. </p>
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</span>
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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>ALLELIC VARIANTS</strong>
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</span>
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<strong>12 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 NEUROPATHY, HEREDITARY SENSORY, TYPE IA</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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SPTLC1, CYS133TYR
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<br />
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SNP: rs119482081,
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ClinVar: RCV000005067, RCV001027483, RCV001249800, RCV002512792, RCV004998075
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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 family of Austrian/German origin with hereditary sensory neuropathy type I (HSAN1A; 162400), Dawkins et al. (2001) identified a heterozygous c.398G-A transition in exon 5 of the SPTLC1 gene resulting in a cys133-to-tyr (C133Y) substitution. Cysteine-133 of SPTLC1 is invariant in human, mouse, Drosophila, and yeast. This mutation was also identified by Bejaoui et al. (2001) in a family of German origin. </p><p>Gantner et al. (2019) identified 9 patients, including 8 patients from 2 unrelated families and an additional unrelated patient, with genetically confirmed HSAN1A who also had type 2 macular telangiectasia. All carried the same heterozygous C133Y mutation in the SPTLC1 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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<h4>
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<span class="mim-font">
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<strong>.0002 NEUROPATHY, HEREDITARY SENSORY, TYPE IA</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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SPTLC1, CYS133TRP
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<br />
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SNP: rs119482082,
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ClinVar: RCV000005070, RCV001004021, RCV001174071, RCV001249798, RCV004597725
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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 8 families of Australian/English, Australian/Scottish, English, or Canadian extraction with hereditary sensory neuropathy type IA (HSAN1A; 162400), Dawkins et al. (2001) identified a heterozygous c.399T-G transversion in exon 5 of the SPTLC1 gene, resulting in a cysteine-to-tryptophan substitution at codon 133 (C133W). Cysteine-133 of SPTLC1 is invariant in human, mouse, Drosophila, and yeast. In a family of Canadian origin, Bejaoui et al. (2001) independently identified this mutation. </p><p>Nicholson et al. (2001) performed haplotype analysis on 3 Australian families of English extraction and 3 English families (2 of which had been described elsewhere) with the cys133-to-trp mutation and demonstrated the same chromosome 9 haplotype as well as the same phenotype in all. They suggested that these families may have had a common founder who, on the basis of historical information, lived in southern England before 1800. The phenotype caused by the 399T-G SPTLC1 mutation is the same as that in the families reported by Campbell and Hoffman (1964) and possibly the original family reported by Hicks (1922), all of which were English. </p><p>In Chinese hamster ovary (CHO) cells and yeast, Gable et al. (2010) demonstrated that the C133W-mutant protein was expressed and formed a stable heterodimer with SPTLC2 (605713), but did not confer catalytic SPT activity even when cotransfected with wildtype SPTLC1, thus showing a dominant-negative effect. Coexpression of the mutant protein with the catalytic enhancers SSSPTB (610412) and SSSPTA (613540) provided sufficient SPT activity to support growth in yeast, although total enzyme activity was only 10 to 20% of wildtype. Yeast and CHO cells expressing the C133W mutant along with SPTLC2 and SSSPTA or SSSPTB showed preferential condensation of palmitoyl-CoA to alanine rather than serine. These results were not found with wildtype SPTLC1. Kinetic studies showed that the mutant protein had the same affinity to serine as the wildtype protein, but a lower Vmax for serine. These findings suggest that the C133W mutation perturbs the active site of the protein, facilitating the formation of alanine condensation products. However, small increases in extracellular serine levels were able to inhibit the reaction with alanine. The palmitoyl-CoA/alanine product, 1-deoxysphinganine (1-deoxySa), was shown to increase endoplasmic reticulum stress and the unfolded protein response, which may ultimately be toxic to neurons. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 NEUROPATHY, HEREDITARY SENSORY, TYPE IA</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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SPTLC1, VAL144ASP
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<br />
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SNP: rs119482083,
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gnomAD: rs119482083,
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ClinVar: RCV000005068, RCV000235837, RCV001174070, RCV001249799, RCV002326664, RCV004755711
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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 2 families of Australian/Scottish and Australian/English extraction with hereditary sensory neuropathy type I (HSAN1A; 162400), Dawkins et al. (2001) identified a T-to-A transversion at nucleotide 431 in exon 6 of the SPTLC1 gene, resulting in a valine-to-aspartic acid substitution at codon 144 (V144D). Valine-144 of SPTLC1 is conserved in human, mouse, Drosophila, and yeast. </p><p>Based on in vitro functional enzymatic studies, Bode et al. (2016) suggested that the V144D variant may not be pathogenic. The variant did not show significantly increased activity with alanine over serine and did not form significant amounts of neurotoxic 1-deoxySL compounds compared to the wildtype enzyme. </p><p>Antony et al. (2022) found that expression of the SPTLC1 V144D mutant increased cytoplasmic Ca(2+) but decreased mitochondrial Ca(2+) in SH-SY5Y cells, leading to activation of the Ca(2+)-dependent protease systems, calpain (see 114220) and proteasome (see 176843). Moreover, the calpain substrates MAP2 (157130) and tau (MAPT; 157140) were significantly decreased in cells expressing V144D. Altered microtubule binding of motor proteins and decreased mitochondrial transport velocities were also observed in cells overexpressing V144D. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</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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SPTLC1, GLY387ALA
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<br />
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SNP: rs119482084,
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gnomAD: rs119482084,
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ClinVar: RCV000005069, RCV000789583, RCV001249812, RCV001310659, RCV002371761
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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>This variant, formerly titled NEUROPATHY, HEREDITARY SENSORY, TYPE IA based on the report of Verhoeven et al. (2004), has been reclassified based on the reports of Hornemann et al. (2009) and Bode et al. (2016). </p><p>In twin sisters with hereditary sensory neuropathy type I (HSAN1A; 162400) from a Belgian family originally reported by Montanini (1958), Verhoeven et al. (2004) identified a c.1160G-C transversion in exon 13 of the SPTLC1 gene, resulting in a gly387-to-ala (G387A) substitution. The mutation was not identified in 300 control chromosomes. Functional studies of the variant and studies of patient cells were not performed. </p><p>By in vitro functional studies, Hornemann et al. (2009) demonstrated that overexpression of the G387A protein did not decrease SPT activity. In addition, expression of the G387A protein could rescue a SPTLC1-deficient cell line. Finally, homozygosity for G387A was identified in an unaffected mother of a heterozygous G387A mutation carrier with HSN1. The variant was also found in 1 of 190 unrelated controls. All of these findings indicated that it is likely not pathogenic. Hornemann et al. (2009) postulated that the G387A variant, and perhaps the other 3 SPTLC1 variants previously associated with HSN1, may not be directly disease-causing, but rather have an indirect or bystander effect by increasing the risk for HSN1 in conjunction with another mutation. </p><p>Based on in vitro functional enzymatic studies, Bode et al. (2016) suggested that the G387A variant is likely not pathogenic. The variant did not show significantly increased activity with alanine over serine and did not form significant 1-deoxySL compounds compared to the wildtype enzyme. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IA, SEVERE</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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SPTLC1, SER331PHE
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<br />
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SNP: rs267607087,
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ClinVar: RCV000005071, RCV003223389
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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 French Gypsy with hereditary sensory and autonomic neuropathy type I (HSAN1A; 162400), Rotthier et al. (2009) identified a de novo heterozygous 992C-T transition in the SPTLC1 gene, resulting in a ser331-to-phe (S331F) substitution in a conserved residue. The patient had an unusually severe phenotype, with congenital onset, insensitivity to pain with eschar and foot ulceration, pes cavus/equinovarus, vocal cord paralysis, and gastroesophageal reflux. The patient also had severe growth and mental retardation, microcephaly, hypotonia, amyotrophy, and respiratory insufficiency. Nerve conduction studies showed absent sensory and motor responses in the upper and lower limbs. The mutation was absent from 600 control chromosomes. The phenotype expanded the clinical spectrum of HSAN1. </p><p>Auer-Grumbach et al. (2013) reported that a patient with a severe form of HSAN1, originally described by Huehne et al. (2008) (patient ER-CIPA-20374), was found to be heterozygous for the S331F mutation in the SPTLC1 gene. The authors noted that another patient with a severe form of HSAN1 was heterozygous for a different mutation at ser311 in the SPTLC1 gene (S311Y; 605712.0007). Auer-Grumbach et al. (2013) confirmed increased 1-deoxySL formation in HEK293 cells expressing the S331F or the S331Y mutant. Canonical serine activity was reduced by 60% in both mutants. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 NEUROPATHY, HEREDITARY SENSORY, TYPE IA</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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SPTLC1, ALA352VAL
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<br />
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SNP: rs267607088,
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gnomAD: rs267607088,
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ClinVar: RCV000005072, RCV001321436
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an Austrian patient with HSN1 (HSAN1A; 162400), Rotthier et al. (2009) identified a heterozygous c.1055C-T transition in the SPTLC1 gene, resulting in an ala352-to-val (A352V) substitution. The patient had onset at age 16 years of severe sensory loss of the lower extremities with peroneal atrophy and decreased distal reflexes. There was mild pes cavus and lancinating pain in the lower extremities. DNA from family members was not available. </p><p>Based on in vitro functional enzymatic studies, Bode et al. (2016) suggested that the A352V variant may not be pathogenic. The variant did not show significantly increased activity with alanine over serine and did not form significant 1-deoxySL compounds compared to the wildtype enzyme. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IA, SEVERE</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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AMYOTROPHIC LATERAL SCLEROSIS 27, JUVENILE, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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SPTLC1, SER331TYR
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<br />
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SNP: rs267607087,
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ClinVar: RCV000414705, RCV000790228, RCV000795948, RCV001249813, RCV003152600
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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 />
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<p><strong><em>Hereditary Sensory and Autonomic Neuropathy, Type IA</em></strong></p><p>
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In a girl, born of nonconsanguineous parents, with hereditary sensory and autonomic neuropathy type I (HSAN1A; 162400), Auer-Grumbach et al. (2013) identified a de novo heterozygous c.922G-T transversion in the SPTLC1 gene, resulting in a ser311-to-tyr (S311Y) substitution. The mutation segregated with the disorder in the family and was not found in 1,969 individuals in an in-house database. The girl had a severe form of the disorder, with onset at age 4 years of unsteady gait, hand tremor, progressive sensory disturbances, and a pes cavus foot deformity necessitating triple arthrodesis at age 5. Disease progression was rapid and led to severe scoliosis, respiratory problems, and wheelchair dependence at age 14. She had prominent growth retardation but normal intellectual development. The level of 1-deoxySL was significantly elevated in the patient's plasma. Auer-Grumbach et al. (2013) noted that a different mutation at ser331 in the SPTLC1 gene (S331F; 605712.0005) resulted in a severe form of the disorder in 2 patients with HSAN1. They confirmed increased 1-deoxySL formation in HEK293 cells expressing the S331Y or the S331F mutant. Canonical serine activity was reduced by 60% in both mutants. </p><p><strong><em>Juvenile Amyotrophic Lateral Sclerosis 27</em></strong></p><p>
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In a patient (patient 3) with juvenile amyotrophic lateral sclerosis-27 (ALS27; 620285), Johnson et al. (2021) identified heterozygosity for the S331Y mutation. The mutation was identified by whole-exome sequencing and shown to be de novo. The patient had prominent motor symptoms and modest sensory autonomic symptoms. </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>.0008 AMYOTROPHIC LATERAL SCLEROSIS 27, 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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SPTLC1, TYR23PHE
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<br />
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SNP: rs1554716504,
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ClinVar: RCV000522579, RCV001267702, RCV003152607
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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 2 unrelated patients (patients 1 and 2) with juvenile amyotrophic lateral sclerosis-27 (ALS27; 620285), Mohassel et al. (2021) identified a de novo heterozygous c.68A-T transition (c.68A-T, NM_006415.4) in exon 2 of the SPTLC1 gene, resulting in a tyr23-to-phe (Y23F) substitution. The mutation, which was identified by whole-exome sequencing, was not present in the gnomAD database. </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>.0009 AMYOTROPHIC LATERAL SCLEROSIS 27, 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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SPTLC1, 6-BP DEL, 118TTCTCT
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<br />
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SNP: rs2118840030,
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ClinVar: RCV001579316, RCV003152625
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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 (patient 3) with juvenile amyotrophic lateral sclerosis-27 (ALS27; 620285), Mohassel et al. (2021) identified a de novo heterozygous 6-bp deletion (c.118_123delTTCTCT, NM_006415.4) in exon 2 of the SPTLC1 gene, resulting in a Phe40_Ser41 deletion (F40_S41del). The mutation was identified by sequencing a hereditary neuropathy gene panel. The variant was not present in the gnomAD database. </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 AMYOTROPHIC LATERAL SCLEROSIS 27, 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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SPTLC1, 3-BP DEL, 115CTT
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<br />
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SNP: rs1197928094,
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|
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gnomAD: rs1197928094,
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ClinVar: RCV000988188, RCV001560232, RCV001858688, RCV002468610, RCV003152613
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 unrelated patients (patients 4 and 5) and a father and his 4 children from another unrelated family (family 7) with juvenile amyotrophic lateral sclerosis-27 (ALS27; 620285), Mohassel et al. (2021) identified heterozygosity for a 3-bp deletion (c.115_117delCTT, NM_006415.4) in exon 2 of the SPTLC1 gene, resulting in a deletion of Leu39 (L39del). The mutation was identified by whole-exome sequencing. In patients 4 and 5, the mutation occurred de novo. The variant was not present in the gnomAD database. </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">
|
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<strong>.0011 AMYOTROPHIC LATERAL SCLEROSIS 27, 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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SPTLC1, c.58G-T, EX2DEL
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<br />
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SNP: rs879254294,
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ClinVar: RCV000236861, RCV003223342, RCV004594033
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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 patient (patient 6) with juvenile amyotrophic lateral sclerosis-27 (ALS27), Mohassel et al. (2021) identified a de novo heterozygous c.58G-T transversion adjacent to the splice acceptor site for exon 2 of the SPTLC1 gene. The mutation was predicted to result in an ala20-to-ser (A20S) substitution, but was found to result predominently in complete skipping of exon 2 and the entire first transmembrane domain of the protein. The mutation was identified by whole-exome sequencing and occurred de novo in the patient. The variant was not present in the gnomAD database. </p><p>In 2 unrelated patients (patients 1 and 2) with ALS27, Johnson et al. (2021) identified 2 patients with a de novo heterozygous A20S mutation. The mutation was identified by whole-exome sequencing. </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>.0012 AMYOTROPHIC LATERAL SCLEROSIS 27, JUVENILE</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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SPTLC1, LEU38ARG
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<br />
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ClinVar: RCV003152660
|
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</span>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 12-year-old Chinese girl with juvenile onset amyotrophic lateral sclerosis-27 (ALS27; 620285), Liu et al. (2022) identified a de novo heterozygous c.113T-C transition in exon 2 of the SPTLC1 gene, resulting in a leu38-to-arg (L38R) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD, dbSNP, and 1000 Genomes Project databases or in 650 healthy Chinese controls. </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>REFERENCES</strong>
|
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</span>
|
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</h4>
|
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<div>
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<p />
|
|
</div>
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<div>
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<ol>
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<li>
|
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<p class="mim-text-font">
|
|
Antony, A., Ng, N., Lauto, A., Coorssen, J. R., Myers, S. J.
|
|
<strong>Calcium-mediated calpain activation and microtubule dissociation in cell model of hereditary sensory neuropathy type-1 expressing V144D SPTLC1 mutation.</strong>
|
|
DNA Cell Biol. 41: 225-234, 2022.
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[PubMed: 34986032]
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[Full Text: https://doi.org/10.1089/dna.2021.0816]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Auer-Grumbach, M., Bode, H., Pieber, T. R., Schabhuttl, M., Fischer, D., Seidl, R., Graf, E., Wieland, T., Schuh, R., Vacariu, G., Grill, F., Timmerman, V., Strom, T. M., Hornemann, T.
|
|
<strong>Mutations at Ser331 in the HSN type I gene SPTLC1 are associated with a distinct syndromic phenotype.</strong>
|
|
Europ. J. Med. Genet. 56: 266-269, 2013.
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[PubMed: 23454272]
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[Full Text: https://doi.org/10.1016/j.ejmg.2013.02.002]
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<li>
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<p class="mim-text-font">
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Bejaoui, K., Uchida, Y., Yasuda, S., Ho, M., Nishijima, M., Brown, R. H., Jr., Holleran, W. M., Hanada, K.
|
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<strong>Hereditary sensory neuropathy type 1 mutations confer dominant negative effects on serine palmitoyltransferase, critical for sphingolipid synthesis.</strong>
|
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J. Clin. Invest. 110: 1301-1308, 2002.
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[PubMed: 12417569]
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[Full Text: https://doi.org/10.1172/JCI16450]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Bejaoui, K., Wu, C., Scheffler, M. D., Haan, G., Ashby, P., Wu, L., de Jong, P., Brown, R. H., Jr.
|
|
<strong>SPTLC1 is mutated in hereditary sensory neuropathy, type 1.</strong>
|
|
Nature Genet. 27: 261-262, 2001.
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[PubMed: 11242106]
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[Full Text: https://doi.org/10.1038/85817]
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</p>
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<li>
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<p class="mim-text-font">
|
|
Bode, H., Bourquin, F., Suriyanarayanan, S., Wei, Y., Alecu, I., Othman, A., Von Eckardstein, A., Hornemann, T.
|
|
<strong>HSAN1 mutations in serine palmitoyltransferase reveal a close structure-function-phenotype relationship.</strong>
|
|
Hum. Molec. Genet. 25: 853-865, 2016.
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[PubMed: 26681808]
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[Full Text: https://doi.org/10.1093/hmg/ddv611]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Campbell, A. M. G., Hoffman, H. L.
|
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<strong>Sensory radicular neuropathy associated with muscle wasting in two cases.</strong>
|
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Brain 87: 67-74, 1964.
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[PubMed: 14152213]
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[Full Text: https://doi.org/10.1093/brain/87.1.67]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Dawkins, J. L., Hulme, D. J., Brahmbhatt, S. B., Auer-Grumbach, M., Nicholson, G. A.
|
|
<strong>Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I.</strong>
|
|
Nature Genet. 27: 309-312, 2001.
|
|
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|
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[PubMed: 11242114]
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[Full Text: https://doi.org/10.1038/85879]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Gable, K., Gupta, S. D., Han, G., Niranjanakumari, S., Harmon, J. M., Dunn, T. M.
|
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<strong>A disease-causing mutation in the active site of serine palmitoyltransferase causes catalytic promiscuity.</strong>
|
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J. Biol. Chem. 285: 22846-22852, 2010.
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[PubMed: 20504773]
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[Full Text: https://doi.org/10.1074/jbc.M110.122259]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Gantner, M. L., Eade, K., Wallace, M., Handzlik, M. K., Fallon, R., Trombley, J., Bonelli, R., Giles, S., Harkins-Perry, S., Heeren, T. F C., Sauer, L., Ideguchi, Y., and 20 others.
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<strong>Serine and lipid metabolism in macular disease and peripheral neuropathy.</strong>
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New Eng. J. Med. 381: 1422-1433, 2019.
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[PubMed: 31509666]
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[Full Text: https://doi.org/10.1056/NEJMoa1815111]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
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Han, G., Gupta, S. D., Gable, K., Niranjanakumari, S., Moitra, P., Eichler, F., Brown, R. H., Jr., Harmon, J. M., Dunn, T. M.
|
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<strong>Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities.</strong>
|
|
Proc. Nat. Acad. Sci. 106: 8186-8191, 2009. Note: Erratum: Proc. Nat. Acad. Sci. 106: 9931 only, 2009.
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[PubMed: 19416851]
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[Full Text: https://doi.org/10.1073/pnas.0811269106]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Herget, T., Esdar, C., Oehrlein, S. A., Heinrich, M., Schutze, S., Maelicke, A., van Echten-Deckert, G.
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<strong>Production of ceramides causes apoptosis during early neural differentiation in vitro.</strong>
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J. Biol. Chem. 275: 30344-30354, 2000.
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[PubMed: 10862608]
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[Full Text: https://doi.org/10.1074/jbc.M000714200]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Hicks, E. P.
|
|
<strong>Hereditary perforating ulcer of the foot.</strong>
|
|
Lancet 199: 319-321, 1922. Note: Originally Volume I.
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|
|
</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Hornemann, T., Penno, A., Richard, S., Nicholson, G., van Dijk, F. S., Rotthier, A., Timmerman, V., von Eckardstein, A.
|
|
<strong>A systematic comparison of all mutations in hereditary sensory neuropathy type I (HSAN I) reveals that the G387A mutation is not disease associated.</strong>
|
|
Neurogenetics 10: 135-143, 2009.
|
|
|
|
|
|
[PubMed: 19132419]
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|
|
[Full Text: https://doi.org/10.1007/s10048-008-0168-7]
|
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Hornemann, T., Richard, S., Rutti, M. F., Wei, Y., von Eckardstein, A.
|
|
<strong>Cloning and initial characterization of a new subunit for mammalian serine-palmitoyltransferase.</strong>
|
|
J. Biol. Chem. 281: 37275-37281, 2006.
|
|
|
|
|
|
[PubMed: 17023427]
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|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.M608066200]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Huehne, K., Zweier, C., Raab, K., Odent, S., Bonnaure-Mallet, M., Sixou, J. L., Landrieu, P., Goizet, C., Sarlangue, J., Baumann, M., Eggermann, T., Rauch, A., Ruppert, S., Stettner, G. M., Rautenstrauss, B.
|
|
<strong>Novel missense, insertion and deletion mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) associated with congenital insensitivity to pain with anhidrosis.</strong>
|
|
Neuromusc. Disord. 18: 159-166, 2008.
|
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|
|
|
|
[PubMed: 18077166]
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|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.nmd.2007.10.005]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Johnson, J. O., Chia, R., Miller, D. E., Li, R., Kumaran, R., Abramzon, Y., Alahmady, N., Renton, A. E., Topp, S. D., Gibbs, J. R., Cookson, M. R., Sabir, M. S., and 287 others.
|
|
<strong>Association of variants in the SPTLC1 gene with juvenile amyotrophic lateral sclerosis.</strong>
|
|
JAMA Neurol. 78: 1236-1248, 2021.
|
|
|
|
|
|
[PubMed: 34459874]
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|
|
[Full Text: https://doi.org/10.1001/jamaneurol.2021.2598]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Kuo, A., Checa, A., Niaudet, C., Jung, B., Fu, Z., Wheelock, C. E., Singh, S. A., Aikawa, M., Smith, L. E., Proia, R. L., Hla, T.
|
|
<strong>Murine endothelial serine palmitoyltransferase 1 (SPTLC1) is required for vascular development and systemic sphingolipid homeostasis.</strong>
|
|
eLife 11: e78861, 2022.
|
|
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|
|
|
[PubMed: 36197001]
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|
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[Full Text: https://doi.org/10.7554/eLife.78861]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Liu, X., He, J., Yu, W., Fan, D.
|
|
<strong>A de novo c.113 T>C: p.L38R mutation of SPTLC1: case report of a girl with sporadic juvenile amyotrophic lateral sclerosis.</strong>
|
|
Amyotroph. Lateral Scler. Frontotemporal Degener. 23: 634-637, 2022.
|
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|
|
|
[PubMed: 36204986]
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|
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[Full Text: https://doi.org/10.1080/21678421.2022.2096409]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Lone, M. A., Aaltonen, M. J., Zidell, A., Pedro, H. F., Morales Saute, J. A., Mathew, S., Mohassel, P., Bonnemann, C. G., Shoubridge, E. A., Hornemann, T.
|
|
<strong>SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins.</strong>
|
|
J. Clin. Invest. 132: e161908, 2022.
|
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|
|
|
[PubMed: 35900868]
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[Full Text: https://doi.org/10.1172/JCI161908]
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