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Entry
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- *603729 - SPHINGOSINE-1-PHOSPHATE LYASE 1; SGPL1
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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">*603729</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/603729">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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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div 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=ENSG00000166224;t=ENST00000373202" 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=8879" 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=603729" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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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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<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=ENSG00000166224;t=ENST00000373202" 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_003901,XM_005270263,XM_011540316,XM_011540317,XM_011540318,XM_047425981,XM_047425982" 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_003901" 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=603729" 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=07224&isoform_id=07224_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/SGPL1" 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/5532487,10129683,31418633,31982936,37999486,119574799,125994709,189054408,530394579,767964182,767964184,767964186,929654464,2217279319,2217279324,2462521757,2462521760,2462521762,2462521764,2462521766,2462521768" 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/O95470" 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=8879" 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=ENSG00000166224;t=ENST00000373202" 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=SGPL1" 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=SGPL1" 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+8879" 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/SGPL1" 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:8879" 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/8879" 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=chr10&hgg_gene=ENST00000373202.8&hgg_start=70815948&hgg_end=70881184&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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=603729[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 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=603729[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/ENSG00000166224" 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=SGPL1" 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=SGPL1" 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=SGPL1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SGPL1&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/PA35725" 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:10817" 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/FBgn0010591.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:1261415" 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/SGPL1#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:1261415" 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/8879/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=8879" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00004981;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00004981 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00006418;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00006418 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00022427;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00022427 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-070410-24" 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:8879" 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=SGPL1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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603729
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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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SPHINGOSINE-1-PHOSPHATE LYASE 1; SGPL1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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SPL
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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=SGPL1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SGPL1</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>
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Cytogenetic location: <a href="/geneMap/10/277?start=-3&limit=10&highlight=277">10q22.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr10:70815948-70881184&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'})">10:70,815,948-70,881,184</a> </span>
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/10/277?start=-3&limit=10&highlight=277">
|
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10q22.1
|
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</a>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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RENI syndrome
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
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<a href="/entry/617575"> 617575 </a>
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/603729" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/603729" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
|
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
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<strong>TEXT</strong>
|
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</span>
|
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</span>
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</h4>
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<div>
|
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<p>The SGPL1 gene encodes sphingosine-1-phosphate lyase-1, an endoplasmic reticulum (ER) enzyme that is involved in sphingolipid catabolism. It catalyzes the final step of the sphingolipid breakdown pathway, initiating irreversible cleavage of the lipid-signaling molecule sphingosine-1-phosphate (S1P) (summary by <a href="#5" class="mim-tip-reference" title="Prasad, R., Hadjidemetriou, I., Maharaj, A. Meimaridou, E., Buonocore, F., Saleem, M., Hurcombe, J., Bierzynska, A., Barbagelata, E., Bergada, I., Cassinelli, H., Das, U., and 16 others. <strong>Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome.</strong> J. Clin. Invest. 127: 942-953, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28165343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28165343</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28165343[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/JCI90171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28165343">Prasad et al., 2017</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28165343" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Sphingosine-1-phosphate (SPP) participates in the proliferative signal transduction pathways of mammalian cells. SPP synthesis is catalyzed by sphingosine kinase (<a href="/entry/603730">603730</a>), and SPP degradation is catalyzed by SPP lyase (SPL). The first SPL gene cloned, BST1 ('bestowed of sphingosine tolerance'), was isolated from budding yeast (<a href="#7" class="mim-tip-reference" title="Saba, J. D., Nara, F., Bielawska, A., Garrett, S., Hannun, Y. A. <strong>The BST1 gene of Saccharomyces cerevisiae is the sphingosine-1-phosphate lyase.</strong> J. Biol. Chem. 272: 26087-26090, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9334171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9334171</a>] [<a href="https://doi.org/10.1074/jbc.272.42.26087" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9334171">Saba et al., 1997</a>). A yeast mutant strain containing a deletion of the entire BST1 coding region is sensitive to the growth-inhibitory effects of D-erythro-sphingosine, due to its inability to degrade SPP. <a href="#12" class="mim-tip-reference" title="Zhou, J., Saba, J. D. <strong>Identification of the first mammalian sphingosine phosphate lyase gene and its functional expression in yeast.</strong> Biochem. Biophys. Res. Commun. 242: 502-507, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9464245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9464245</a>] [<a href="https://doi.org/10.1006/bbrc.1997.7993" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9464245">Zhou and Saba (1998)</a> identified a mouse cDNA encoding a protein, which they named Spl, that has 59% sequence similarity to the BST1 gene product. They showed that this cDNA can functionally complement the yeast BST1 deletion, restoring a sphingosine-resistant phenotype. Northern blot analysis detected Spl expression in several mouse tissues, with the highest level found in the liver. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9334171+9464245" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Prasad, R., Hadjidemetriou, I., Maharaj, A. Meimaridou, E., Buonocore, F., Saleem, M., Hurcombe, J., Bierzynska, A., Barbagelata, E., Bergada, I., Cassinelli, H., Das, U., and 16 others. <strong>Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome.</strong> J. Clin. Invest. 127: 942-953, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28165343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28165343</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28165343[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/JCI90171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28165343">Prasad et al. (2017)</a> found ubiquitous expression of SGPL1 in human tissues, with moderate levels of expression in the adrenal cortex and kidneys and high levels of expression in the testes and thyroid. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28165343" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In mouse kidney, <a href="#3" class="mim-tip-reference" title="Lovric, S., Goncalves, S., Gee, H. Y., Oskouian, B., Srinivas, H., Choi, W.-I., Shril, S., Ashraf, S., Tan, W., Rao, J., Airik, M., Schapiro, D., and 53 others. <strong>Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency.</strong> J. Clin. Invest. 127: 912-928, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28165339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28165339</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28165339[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/JCI89626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28165339">Lovric et al. (2017)</a> found expression of Sgpl1 in podocytes, as well as in other renal glomerular cell types, including mesangial and endothelial cells. Sgpl1 colocalized with ER markers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28165339" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 interspecific backcross mapping, <a href="#12" class="mim-tip-reference" title="Zhou, J., Saba, J. D. <strong>Identification of the first mammalian sphingosine phosphate lyase gene and its functional expression in yeast.</strong> Biochem. Biophys. Res. Commun. 242: 502-507, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9464245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9464245</a>] [<a href="https://doi.org/10.1006/bbrc.1997.7993" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9464245">Zhou and Saba (1998)</a> localized the mouse Spl gene to chromosome 10, between the Eif4ebp2 (<a href="/entry/602224">602224</a>) and Egr2 (<a href="/entry/129010">129010</a>) genes. By homology of synteny, they mapped the human homolog of Spl, SGPL1, to 10q21. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9464245" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Lymphocyte egress from the thymus and from peripheral lymphoid organs depends on sphingosine 1-phosphate (S1P) receptor-1 (<a href="/entry/601974">601974</a>) and is thought to occur in response to circulatory S1P. To further define gene egress requirements, <a href="#9" class="mim-tip-reference" title="Schwab, S. R., Pereira, J. P., Matloubian, M., Xu, Y., Huang, Y., Cyster, J. G. <strong>Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients.</strong> Science 309: 1735-1739, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16151014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16151014</a>] [<a href="https://doi.org/10.1126/science.1113640" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16151014">Schwab et al. (2005)</a> addressed why treatment with the food colorant 2-acetyl-4-tetrahydroxybutylimidazole (THI) induces lymphopenia. <a href="#9" class="mim-tip-reference" title="Schwab, S. R., Pereira, J. P., Matloubian, M., Xu, Y., Huang, Y., Cyster, J. G. <strong>Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients.</strong> Science 309: 1735-1739, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16151014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16151014</a>] [<a href="https://doi.org/10.1126/science.1113640" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16151014">Schwab et al. (2005)</a> found that S1P abundance in lymphoid tissues of mice is normally low but increases more than 100-fold after TH1 treatment and that this treatment inhibits the S1P-degrading enzyme sphingosine 1-phosphate lyase (SGPL1). <a href="#9" class="mim-tip-reference" title="Schwab, S. R., Pereira, J. P., Matloubian, M., Xu, Y., Huang, Y., Cyster, J. G. <strong>Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients.</strong> Science 309: 1735-1739, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16151014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16151014</a>] [<a href="https://doi.org/10.1126/science.1113640" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16151014">Schwab et al. (2005)</a> concluded that lymphocyte egress is mediated by S1P gradients that are established by S1P lyase activity and that the lyase may represent a novel immunosuppressant drug target. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16151014" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 8 patients from 5 unrelated families with RENI syndrome (RENI; <a href="/entry/617575">617575</a>), <a href="#5" class="mim-tip-reference" title="Prasad, R., Hadjidemetriou, I., Maharaj, A. Meimaridou, E., Buonocore, F., Saleem, M., Hurcombe, J., Bierzynska, A., Barbagelata, E., Bergada, I., Cassinelli, H., Das, U., and 16 others. <strong>Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome.</strong> J. Clin. Invest. 127: 942-953, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28165343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28165343</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28165343[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/JCI90171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28165343">Prasad et al. (2017)</a> identified homozygous loss-of-function mutations in the SGPL1 gene (see, e.g., <a href="#0001">603729.0001</a>-<a href="#0004">603729.0004</a>). All but 1 of the families were consanguineous. The mutations were found by whole-exome or Sanger sequencing and segregated with the disorder in the families. Cellular expression assays of 2 of the mutations (R222Q, <a href="#0001">603729.0001</a> and F545del, <a href="#0002">603729.0002</a>) showed that they resulted in decreased stability of the protein and almost complete absence of enzyme activity, consistent with a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28165343" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 patients from 7 unrelated, mostly consanguineous families of various ethnic origins with RENI syndrome, <a href="#3" class="mim-tip-reference" title="Lovric, S., Goncalves, S., Gee, H. Y., Oskouian, B., Srinivas, H., Choi, W.-I., Shril, S., Ashraf, S., Tan, W., Rao, J., Airik, M., Schapiro, D., and 53 others. <strong>Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency.</strong> J. Clin. Invest. 127: 912-928, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28165339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28165339</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28165339[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/JCI89626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28165339">Lovric et al. (2017)</a> identified homozygous or compound heterozygous mutations in the SGPL1 gene (see, e.g., <a href="#0001">603729.0001</a>; <a href="#0004">603729.0004</a>-<a href="#0006">603729.0006</a>). The mutation in the first family was found by a combination of homozygosity mapping and whole-exome sequencing; subsequent mutations were found by whole-exome sequencing or Sanger sequencing. All mutations segregated with the disorder in the families. The mutation spectrum included frameshift, splice site, and missense mutations, and all were associated with reduced or absent SGPL1 protein and/or enzyme activity as measured in patient fibroblasts or transfected cells. Detailed functional studies of 2 of the missense mutations (R222Q and S346I, <a href="#0006">603729.0006</a>) showed a loss-of-function effect, with reduced protein levels, enzyme activity, impaired degradation of long-chain sphingoid bases, and altered subcellular localization. Disease-associated variants were unable to rescue growth defects in yeast or abnormalities in Drosophila deficient in Sgpl1. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, and patient fibroblasts showed reduced cell migration compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28165339" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 male patients, both born of consanguineous parents, with RENI syndrome, <a href="#2" class="mim-tip-reference" title="Janecke, A. R., Xu, R., Steichen-Gersdorf, E., Waldegger, S., Entenmann, A., Giner, T., Krainer, I., Huber, L. A., Hess, M. W., Frishberg, Y., Barash, H., Tzur, S., Schreyer-Shafir, N., Sukenik-Halevy, R., Zehavi, T., Raas-Rothschild, A., Mao, C., Muller, T. <strong>Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications.</strong> Hum. Mutat. 38: 365-372, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28181337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28181337</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28181337[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.23192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28181337">Janecke et al. (2017)</a> identified homozygous truncating mutations in the SGPL1 gene (<a href="#0007">603729.0007</a> and <a href="#0008">603729.0008</a>). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The levels of SGPL1 substrates, S1P, and sphingosine were markedly increased in blood and fibroblasts from one of the patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28181337" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Settas, N., Persky, R., Faucz, F. R., Sheanon, N., Voutetakis, A., Lodish, M., Metherell, L. A., Stratakis, C. A. <strong>SGPL1 deficiency: a rare cause of primary adrenal insufficiency.</strong> J. Clin. Endocr. Metab. 104: 1484-1490, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30517686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30517686</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30517686[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1210/jc.2018-02238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30517686">Settas et al. (2019)</a> screened 21 patients with clinical features of primary adrenal insufficiency for variants in the SGPL1 gene and identified 2 patients with homozygosity and 2 with heterozygosity. The 2 patients with homozygosity were a 5.5-year-old proband, born of consanguineous parents, with RENI syndrome and his 15-year-old first cousin with the previously identified R222Q mutation (<a href="#0001">603729.0001</a>). The 2 patients with heterozygosity had a missense variant (c.61G-T; V21L) that had an allele frequency of 0.09 in ExAC; the authors posited that this variant was unrelated to their adrenal insufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30517686" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 15-year-old girl, born to consanguineous Turkish parents, with RENI syndrome, <a href="#4" class="mim-tip-reference" title="Maharaj, A., Guran, T., Buonocore, F., Achermann, J. C., Metherell, L., Prasad, R., Cetinkaya, S. <strong>Insights from long-term follow-up of a girl with adrenal insufficiency and sphingosine-1-phosphate lyase deficiency.</strong> J. Endocr. Soc. 6: bvac020, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35308304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35308304</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35308304[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1210/jendso/bvac020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35308304">Maharaj et al. (2022)</a> identified a homozygous missense mutation in the SGPL1 gene (c.1049A-G, chr10:72631733A-G, D350G). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. Examination of SGPL1 protein levels in the patient by immunoblotting showed decreased expression of the D350G variant. CRISPR-engineered human adrenocortical cells with SGPL1 knockout showed minimal cortisol output. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35308304" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 set of Chinese identical twin girls with RENI syndrome, <a href="#11" class="mim-tip-reference" title="Yang, S., He, Y., Zhou, J., Yuan, H., Qiu, L. <strong>Steroid-resistant nephrotic syndrome associated with certain SGPL1 variants in a family: case report and literature review.</strong> Front. Pediat. 11: 1079758, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36873630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36873630</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36873630[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/10.3389/fped.2023.1079758" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36873630">Yang et al. (2023)</a> identified compound heterozygous intronic mutations in the SGPL1 gene (<a href="#0003">603729.0003</a> and <a href="#0009">603729.0009</a>). The mutations were found by exome sequencing and segregated with the disorder in the family. <a href="#11" class="mim-tip-reference" title="Yang, S., He, Y., Zhou, J., Yuan, H., Qiu, L. <strong>Steroid-resistant nephrotic syndrome associated with certain SGPL1 variants in a family: case report and literature review.</strong> Front. Pediat. 11: 1079758, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36873630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36873630</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36873630[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/10.3389/fped.2023.1079758" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36873630">Yang et al. (2023)</a> conducted a review of 31 patients in the literature with SGPL1 variants causing nephrotic syndrome, including their 2 patients. Twenty-five patients (80.6%) had homozygous mutations (15 missense, 8 frameshift, and 2 truncation) and 6 patients (19.4%) had compound heterozygous mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36873630" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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<a href="#1" class="mim-tip-reference" title="Atkinson, D., Nikodinovic Glumac, J., Asselbergh, B., Ermanoska, B., Blocquel, D., Steiner, R., Estrada-Cuzcano, A., Peeters, K., Ooms, T., De Vriendt, E., Yang, X. L., Hornemann, T., Milic Rasic, V., Jordanova, A. <strong>Sphingosine 1-phosphate lyase deficiency causes Charcot-Marie-Tooth neuropathy.</strong> Neurology 88: 533-542, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28077491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28077491</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28077491[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/10.1212/WNL.0000000000003595" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28077491">Atkinson et al. (2017)</a> described 2 Serbian sibs with acute or subacute onset of axonal peripheral neuropathy and episodes of recurrent mononeuropathy, which the authors called autosomal recessive Charcot-Marie-Tooth disease, who were compound heterozygous for mutations in the SGPL1 gene: c.551T-C, resulting in an ile184-to-thr (I184T) substitution, and c.1082C-G in exon 12 (of 15), resulting in a ser361-to-ter (S361X) substitution. The mutations cosegregated with the phenotype in the family. Plasma levels of sphingosine 1-phosophate and the sphingosine/sphinganine ratio were elevated in the patients, consistent with decreased sphingosine-1-phosphate lyase activity. The S361X variant appeared to result in nonsense-mediated decay based on the absence of the c.1082C-G allele on Sanger sequencing of SGPL1 cDNA from lymphoblasts. SGPL1 protein levels were nearly undetectable based on immunoblotting. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28077491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#5" class="mim-tip-reference" title="Prasad, R., Hadjidemetriou, I., Maharaj, A. Meimaridou, E., Buonocore, F., Saleem, M., Hurcombe, J., Bierzynska, A., Barbagelata, E., Bergada, I., Cassinelli, H., Das, U., and 16 others. <strong>Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome.</strong> J. Clin. Invest. 127: 942-953, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28165343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28165343</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28165343[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/JCI90171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28165343">Prasad et al. (2017)</a> found that adrenal cortical zonation was compromised in Sgpl1-null mice. Steroidogenesis also appeared to be disrupted. Kidneys from mutant mice showed mesangial hypercellularity and glomerular fibrosis, which recapitulated the main characteristics of NPHS14. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28165343" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Lovric, S., Goncalves, S., Gee, H. Y., Oskouian, B., Srinivas, H., Choi, W.-I., Shril, S., Ashraf, S., Tan, W., Rao, J., Airik, M., Schapiro, D., and 53 others. <strong>Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency.</strong> J. Clin. Invest. 127: 912-928, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28165339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28165339</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28165339[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/JCI89626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28165339">Lovric et al. (2017)</a> found that the kidneys of Sgpl1-null mice showed complete foot process effacement and absence of slit diaphragms. Mutant mice also showed hypoalbuminemia and increased urinary albumin/creatinine ratio. Cultured podocytes from Sgpl1-null mice did not show evidence of increased apoptosis or abnormalities in cell migration. Knockdown of Sgpl1 in rat mesangial cells did not affect apoptosis or proliferation, but did have reduced migration. Certain S1PR antagonists partially rescued the migration defect. Studies of Drosophila with deficiency of the Sply ortholog of Sgpl1 showed a reduction of nephrocyte foot process density and reduced albumin uptake compared to controls. Mutant flies also showed evidence of altered lipid metabolism due to disruption of the sphingolipid catabolic pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28165339" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 3 members of a highly consanguineous Pakistani family with RENI syndrome (RENI; <a href="/entry/617575">617575</a>), originally reported by <a href="#6" class="mim-tip-reference" title="Ram, N., Asghar, A., Islam, N. <strong>A case report: familial glucocorticoid deficiency associated with familial focal segmental glomerulosclerosis.</strong> BMC Endocr. Disord. 12: 32, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23232022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23232022</a>] [<a href="https://doi.org/10.1186/1472-6823-12-32" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23232022">Ram et al. (2012)</a>, <a href="#5" class="mim-tip-reference" title="Prasad, R., Hadjidemetriou, I., Maharaj, A. Meimaridou, E., Buonocore, F., Saleem, M., Hurcombe, J., Bierzynska, A., Barbagelata, E., Bergada, I., Cassinelli, H., Das, U., and 16 others. <strong>Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome.</strong> J. Clin. Invest. 127: 942-953, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28165343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28165343</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28165343[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/JCI90171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28165343">Prasad et al. (2017)</a> identified a homozygous c.665G-A transition (chr10:72,628,151G-A) in the SGPL1 gene, resulting in an arg222-to-gln (R222Q) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found in heterozygous state in 2 of 120,744 alleles in the ExAC database (frequency of 1.7 x 10(-5)). No homozygotes were found in the dbSNP, Exome Variant Server, or ExAC databases. Subsequently, the same mutation was found in a similarly affected individual, born of consanguineous Saudi parents, but haplotype analysis excluded a founder effect. Cellular expression assays showed that the mutation resulted in decreased stability of the protein and almost complete absence of enzyme activity, consistent with a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28165343+23232022" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Lovric, S., Goncalves, S., Gee, H. Y., Oskouian, B., Srinivas, H., Choi, W.-I., Shril, S., Ashraf, S., Tan, W., Rao, J., Airik, M., Schapiro, D., and 53 others. <strong>Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency.</strong> J. Clin. Invest. 127: 912-928, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28165339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28165339</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28165339[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/JCI89626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28165339">Lovric et al. (2017)</a> identified homozygosity for the R222Q mutation in the SGPL1 gene in 3 members of a consanguineous Pakistani family (A280) with RENI syndrome. The mutation was found by a combination of homozygosity mapping and whole-exome sequencing. Cellular expression studies showed that the mutation resulted in decreased protein levels and strongly decreased enzyme activity compared to wildtype, as well as formation of abnormal cytoplasmic SGPL1 aggregates. The mutant protein also failed to rescue growth defects in DPL1-deficient yeast, consistent with a loss of function. One of the patients had unusually late onset of renal disease at age 19 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28165339" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 5.5-year-old boy, born to consanguineous Saudi Arabian parents, with RENI syndrome, and in his 15-year-old first cousin, <a href="#10" class="mim-tip-reference" title="Settas, N., Persky, R., Faucz, F. R., Sheanon, N., Voutetakis, A., Lodish, M., Metherell, L. A., Stratakis, C. A. <strong>SGPL1 deficiency: a rare cause of primary adrenal insufficiency.</strong> J. Clin. Endocr. Metab. 104: 1484-1490, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30517686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30517686</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30517686[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1210/jc.2018-02238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30517686">Settas et al. (2019)</a> identified homozygosity for a G-A transition (c.665G-A) in the SGPL1 gene, resulting in an arg222-to-gln (R222Q) substitution. The 15-year-old first cousin had amblyopia of the right eye, right-sided hearing loss, and right arm paralysis and developed kidney failure requiring hemodialysis; no further information on his phenotype was available. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30517686" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs1131692252 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1131692252;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=rs1131692252" 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=rs1131692252" 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 female Turkish patient with RENI syndrome (RENI; <a href="/entry/617575">617575</a>), <a href="#5" class="mim-tip-reference" title="Prasad, R., Hadjidemetriou, I., Maharaj, A. Meimaridou, E., Buonocore, F., Saleem, M., Hurcombe, J., Bierzynska, A., Barbagelata, E., Bergada, I., Cassinelli, H., Das, U., and 16 others. <strong>Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome.</strong> J. Clin. Invest. 127: 942-953, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28165343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28165343</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28165343[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/JCI90171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28165343">Prasad et al. (2017)</a> identified a homozygous in-frame 3-bp deletion (c.1633_1635delTTC) in the SGPL1 gene, resulting in the deletion of highly conserved residue Phe545. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. It was not present in public databases. Cellular expression assays showed that the mutation resulted in decreased stability of the protein and almost complete absence of enzyme activity, consistent with a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28165343" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs1131692253 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1131692253;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=rs1131692253" 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=rs1131692253" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 sibs, born of consanguineous Peruvian parents, with RENI syndrome (RENI; <a href="/entry/617575">617575</a>), <a href="#5" class="mim-tip-reference" title="Prasad, R., Hadjidemetriou, I., Maharaj, A. Meimaridou, E., Buonocore, F., Saleem, M., Hurcombe, J., Bierzynska, A., Barbagelata, E., Bergada, I., Cassinelli, H., Das, U., and 16 others. <strong>Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome.</strong> J. Clin. Invest. 127: 942-953, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28165343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28165343</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28165343[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/JCI90171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28165343">Prasad et al. (2017)</a> identified a homozygous G-to-A transition (c.261+1G-A) in the SGPL1 gene, resulting in a splice site defect and predicting premature termination (Ser65ArgfsTer6). The mutant transcript was likely degraded by nonsense-mediated mRNA decay, resulting in a loss of function. The mutation segregated with the disorder in the family and was not found in any databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28165343" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 set of Chinese identical twin girls with RENI syndrome, <a href="#11" class="mim-tip-reference" title="Yang, S., He, Y., Zhou, J., Yuan, H., Qiu, L. <strong>Steroid-resistant nephrotic syndrome associated with certain SGPL1 variants in a family: case report and literature review.</strong> Front. Pediat. 11: 1079758, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36873630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36873630</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36873630[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/10.3389/fped.2023.1079758" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36873630">Yang et al. (2023)</a> identified compound heterozygous splicing mutations in the SGPL1 gene: c.261+1G-A (c.261+1G-A, NM_003901.4) in intron 4 and c.1298+6T-C (<a href="#0009">603729.0009</a>) in intron 12. The mutations were found by exome sequencing, and each parent carried one of the mutations. The girls had steroid-resistant nephrotic syndrome with no extrarenal manifestations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36873630" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs1131692254 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1131692254;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=rs1131692254" 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=rs1131692254" 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, born of consanguineous Spanish parents, with RENI syndrome (RENI; <a href="/entry/617575">617575</a>), <a href="#5" class="mim-tip-reference" title="Prasad, R., Hadjidemetriou, I., Maharaj, A. Meimaridou, E., Buonocore, F., Saleem, M., Hurcombe, J., Bierzynska, A., Barbagelata, E., Bergada, I., Cassinelli, H., Das, U., and 16 others. <strong>Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome.</strong> J. Clin. Invest. 127: 942-953, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28165343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28165343</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28165343[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/JCI90171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28165343">Prasad et al. (2017)</a> identified a homozygous 1-bp duplication (c.7dupA) in the SGPL1 gene, resulting in a frameshift and premature termination (Ser3LysfsTer11). The mutation was not found in the ExAC database. The mutant transcript was likely degraded by nonsense-mediated mRNA decay, resulting in a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28165343" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 3 affected members of a consanguineous Spanish Roma family (A5444) with RENI syndrome, <a href="#3" class="mim-tip-reference" title="Lovric, S., Goncalves, S., Gee, H. Y., Oskouian, B., Srinivas, H., Choi, W.-I., Shril, S., Ashraf, S., Tan, W., Rao, J., Airik, M., Schapiro, D., and 53 others. <strong>Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency.</strong> J. Clin. Invest. 127: 912-928, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28165339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28165339</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28165339[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/JCI89626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28165339">Lovric et al. (2017)</a> identified a homozygous c.7dupA mutation in exon 2 of the SGPL1 gene. The mutation was found by whole-exome sequencing and segregated with the disorder in the family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28165339" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs1131692255 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1131692255;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/rs1131692255?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=rs1131692255" 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=rs1131692255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 4 members of a consanguineous Turkish family (EB) with RENI syndrome (RENI; <a href="/entry/617575">617575</a>), <a href="#3" class="mim-tip-reference" title="Lovric, S., Goncalves, S., Gee, H. Y., Oskouian, B., Srinivas, H., Choi, W.-I., Shril, S., Ashraf, S., Tan, W., Rao, J., Airik, M., Schapiro, D., and 53 others. <strong>Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency.</strong> J. Clin. Invest. 127: 912-928, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28165339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28165339</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28165339[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/JCI89626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28165339">Lovric et al. (2017)</a> identified a homozygous c.664C-T transition in exon 8 of the SGPL1 gene, resulting in an arg222-to-trp (R222W) substitution at a highly conserved residue in the PLP-dependent transferase domain. The mutation was not found in the ExAC database. Functional studies of the variant were not performed, but a different mutation in the same codon was found in another family with NPHS14 (R222Q; <a href="#0001">603729.0001</a>). Patients in the EB family had a severe form of the disorder, with congenital nephrotic syndrome resulting in fetal demise or death in the first months of life. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28165339" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs1131692256 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1131692256;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=rs1131692256" 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=rs1131692256" 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=RCV000495968 OR RCV001849386" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000495968, RCV001849386" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000495968...</a>
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<p>In affected members of a large consanguineous Moroccan kindred (B46/B56) with RENI syndrome (RENI; <a href="/entry/617575">617575</a>), <a href="#3" class="mim-tip-reference" title="Lovric, S., Goncalves, S., Gee, H. Y., Oskouian, B., Srinivas, H., Choi, W.-I., Shril, S., Ashraf, S., Tan, W., Rao, J., Airik, M., Schapiro, D., and 53 others. <strong>Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency.</strong> J. Clin. Invest. 127: 912-928, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28165339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28165339</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28165339[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/JCI89626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28165339">Lovric et al. (2017)</a> identified a homozygous c.1037G-T transversion in exon 11 of the SGPL1 gene, resulting in a ser346-to-ile (S346I) substitution at a highly conserved residue in the PLP-dependent transferase domain. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was not found in the ExAC database. Cellular expression studies showed that the mutation resulted in decreased protein levels and enzyme activity compared to wildtype, as well as formation of abnormal cytoplasmic SGPL1 aggregates. The mutant protein also failed to rescue growth defects in DPL1-deficient yeast, consistent with a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28165339" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a male patient from a large consanguineous family of Arab descent with RENI syndrome (RENI; <a href="/entry/617575">617575</a>), <a href="#2" class="mim-tip-reference" title="Janecke, A. R., Xu, R., Steichen-Gersdorf, E., Waldegger, S., Entenmann, A., Giner, T., Krainer, I., Huber, L. A., Hess, M. W., Frishberg, Y., Barash, H., Tzur, S., Schreyer-Shafir, N., Sukenik-Halevy, R., Zehavi, T., Raas-Rothschild, A., Mao, C., Muller, T. <strong>Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications.</strong> Hum. Mutat. 38: 365-372, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28181337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28181337</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28181337[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.23192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28181337">Janecke et al. (2017)</a> identified a homozygous c.1513C-T transition (c.1513C-T, NM_003901.3) in the SGPL1 gene, resulting in an arg505-to-ter (R505X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP, Exome Sequencing Project, or ExAC databases. The mutation was predicted to result in nonsense-mediated mRNA decay and a loss of function. A similarly affected patient from the same family died at age 7 weeks; material from that patient was not available for study. The family had previously been reported by <a href="#8" class="mim-tip-reference" title="Schreyer-Shafir, N., Sukenik-Halevy, R., Tepper, R., Amon, S., Litmanovitch, I., Eliakim, A., Pommeranz, A., Ludman, M. D., Raas-Rothschild, A. <strong>Prenatal bilateral adrenal calcifications, hypogonadism, and nephrotic syndrome: beyond Wolman disease.</strong> Prenatal Diag. 34: 608-611, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24777844/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24777844</a>] [<a href="https://doi.org/10.1002/pd.4344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24777844">Schreyer-Shafir et al. (2014)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28181337+24777844" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs1131692235 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1131692235;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=rs1131692235" 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=rs1131692235" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a male patient, born of consanguineous parents, with RENI syndrome (RENI; <a href="/entry/617575">617575</a>), <a href="#2" class="mim-tip-reference" title="Janecke, A. R., Xu, R., Steichen-Gersdorf, E., Waldegger, S., Entenmann, A., Giner, T., Krainer, I., Huber, L. A., Hess, M. W., Frishberg, Y., Barash, H., Tzur, S., Schreyer-Shafir, N., Sukenik-Halevy, R., Zehavi, T., Raas-Rothschild, A., Mao, C., Muller, T. <strong>Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications.</strong> Hum. Mutat. 38: 365-372, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28181337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28181337</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28181337[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.23192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28181337">Janecke et al. (2017)</a> identified a homozygous 1-bp deletion (c.934delC, NM_003901.3) in the SGPL1 gene, resulting in a frameshift and premature termination (Leu312PhefsTer30). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP, Exome Sequencing Project, or ExAC databases. The mutation was predicted to result in nonsense-mediated mRNA decay and a loss of function. The levels of SGPL1 substrates, S1P, and sphingosine were markedly increased in the patient's blood and fibroblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28181337" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>For discussion of the c.1298+6C-T mutation (c.1298+6C-T, NM_003901.4) in the SGPL1 gene that was found in compound heterozygous state in Chinese identical twin girls with RENI syndrome (RENI; <a href="/entry/617575">617575</a>) by <a href="#11" class="mim-tip-reference" title="Yang, S., He, Y., Zhou, J., Yuan, H., Qiu, L. <strong>Steroid-resistant nephrotic syndrome associated with certain SGPL1 variants in a family: case report and literature review.</strong> Front. Pediat. 11: 1079758, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36873630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36873630</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36873630[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/10.3389/fped.2023.1079758" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36873630">Yang et al. (2023)</a>, see <a href="#0003">603729.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36873630" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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Atkinson, D., Nikodinovic Glumac, J., Asselbergh, B., Ermanoska, B., Blocquel, D., Steiner, R., Estrada-Cuzcano, A., Peeters, K., Ooms, T., De Vriendt, E., Yang, X. L., Hornemann, T., Milic Rasic, V., Jordanova, A.
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<strong>Sphingosine 1-phosphate lyase deficiency causes Charcot-Marie-Tooth neuropathy.</strong>
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Neurology 88: 533-542, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28077491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28077491</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28077491[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=28077491" 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/WNL.0000000000003595" target="_blank">Full Text</a>]
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<a id="Janecke2017" class="mim-anchor"></a>
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Janecke, A. R., Xu, R., Steichen-Gersdorf, E., Waldegger, S., Entenmann, A., Giner, T., Krainer, I., Huber, L. A., Hess, M. W., Frishberg, Y., Barash, H., Tzur, S., Schreyer-Shafir, N., Sukenik-Halevy, R., Zehavi, T., Raas-Rothschild, A., Mao, C., Muller, T.
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<strong>Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications.</strong>
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Hum. Mutat. 38: 365-372, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28181337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28181337</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28181337[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=28181337" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.23192" target="_blank">Full Text</a>]
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<a id="Lovric2017" class="mim-anchor"></a>
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<div class="">
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Lovric, S., Goncalves, S., Gee, H. Y., Oskouian, B., Srinivas, H., Choi, W.-I., Shril, S., Ashraf, S., Tan, W., Rao, J., Airik, M., Schapiro, D., and 53 others.
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<strong>Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28165339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28165339</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28165339[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=28165339" 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/JCI89626" target="_blank">Full Text</a>]
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<a id="Maharaj2022" class="mim-anchor"></a>
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Maharaj, A., Guran, T., Buonocore, F., Achermann, J. C., Metherell, L., Prasad, R., Cetinkaya, S.
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<strong>Insights from long-term follow-up of a girl with adrenal insufficiency and sphingosine-1-phosphate lyase deficiency.</strong>
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J. Endocr. Soc. 6: bvac020, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35308304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35308304</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35308304[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=35308304" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jendso/bvac020" target="_blank">Full Text</a>]
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Prasad, R., Hadjidemetriou, I., Maharaj, A. Meimaridou, E., Buonocore, F., Saleem, M., Hurcombe, J., Bierzynska, A., Barbagelata, E., Bergada, I., Cassinelli, H., Das, U., and 16 others.
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<strong>Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome.</strong>
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J. Clin. Invest. 127: 942-953, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28165343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28165343</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28165343[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=28165343" 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/JCI90171" target="_blank">Full Text</a>]
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Ram, N., Asghar, A., Islam, N.
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<strong>A case report: familial glucocorticoid deficiency associated with familial focal segmental glomerulosclerosis.</strong>
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BMC Endocr. Disord. 12: 32, 2012. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23232022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23232022</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23232022" 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/10.1186/1472-6823-12-32" target="_blank">Full Text</a>]
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Saba, J. D., Nara, F., Bielawska, A., Garrett, S., Hannun, Y. A.
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<strong>The BST1 gene of Saccharomyces cerevisiae is the sphingosine-1-phosphate lyase.</strong>
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J. Biol. Chem. 272: 26087-26090, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9334171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9334171</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9334171" 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.272.42.26087" target="_blank">Full Text</a>]
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<a id="Schreyer-Shafir2014" class="mim-anchor"></a>
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Schreyer-Shafir, N., Sukenik-Halevy, R., Tepper, R., Amon, S., Litmanovitch, I., Eliakim, A., Pommeranz, A., Ludman, M. D., Raas-Rothschild, A.
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<strong>Prenatal bilateral adrenal calcifications, hypogonadism, and nephrotic syndrome: beyond Wolman disease.</strong>
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Prenatal Diag. 34: 608-611, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24777844/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24777844</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24777844" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/pd.4344" target="_blank">Full Text</a>]
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<a id="Schwab2005" class="mim-anchor"></a>
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Schwab, S. R., Pereira, J. P., Matloubian, M., Xu, Y., Huang, Y., Cyster, J. G.
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<strong>Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients.</strong>
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Science 309: 1735-1739, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16151014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16151014</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16151014" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1113640" target="_blank">Full Text</a>]
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<a id="Settas2019" class="mim-anchor"></a>
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Settas, N., Persky, R., Faucz, F. R., Sheanon, N., Voutetakis, A., Lodish, M., Metherell, L. A., Stratakis, C. A.
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<strong>SGPL1 deficiency: a rare cause of primary adrenal insufficiency.</strong>
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J. Clin. Endocr. Metab. 104: 1484-1490, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30517686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30517686</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30517686[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=30517686" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jc.2018-02238" target="_blank">Full Text</a>]
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Yang, S., He, Y., Zhou, J., Yuan, H., Qiu, L.
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<strong>Steroid-resistant nephrotic syndrome associated with certain SGPL1 variants in a family: case report and literature review.</strong>
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Front. Pediat. 11: 1079758, 2023.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36873630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36873630</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36873630[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=36873630" 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/10.3389/fped.2023.1079758" target="_blank">Full Text</a>]
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Zhou, J., Saba, J. D.
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<strong>Identification of the first mammalian sphingosine phosphate lyase gene and its functional expression in yeast.</strong>
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Biochem. Biophys. Res. Commun. 242: 502-507, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9464245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9464245</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9464245" 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/10.1006/bbrc.1997.7993" target="_blank">Full Text</a>]
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Sonja A. Rasmussen - updated : 08/24/2023
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Cassandra L. Kniffin - updated : 07/20/2017<br>Ada Hamosh - updated : 9/27/2005
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Sheryl A. Jankowski : 4/13/1999
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carol : 07/18/2018<br>carol : 12/18/2017<br>carol : 07/24/2017<br>carol : 07/21/2017<br>ckniffin : 07/20/2017<br>alopez : 09/29/2005<br>terry : 9/27/2005<br>psherman : 4/13/1999
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SPHINGOSINE-1-PHOSPHATE LYASE 1; SGPL1
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 10q22.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 10:70,815,948-70,881,184 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
|
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Inheritance
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</th>
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<th>
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|
Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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|
10q22.1
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</span>
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</td>
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<td>
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<span class="mim-font">
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RENI syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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617575
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Description</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The SGPL1 gene encodes sphingosine-1-phosphate lyase-1, an endoplasmic reticulum (ER) enzyme that is involved in sphingolipid catabolism. It catalyzes the final step of the sphingolipid breakdown pathway, initiating irreversible cleavage of the lipid-signaling molecule sphingosine-1-phosphate (S1P) (summary by Prasad et al., 2017). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Sphingosine-1-phosphate (SPP) participates in the proliferative signal transduction pathways of mammalian cells. SPP synthesis is catalyzed by sphingosine kinase (603730), and SPP degradation is catalyzed by SPP lyase (SPL). The first SPL gene cloned, BST1 ('bestowed of sphingosine tolerance'), was isolated from budding yeast (Saba et al., 1997). A yeast mutant strain containing a deletion of the entire BST1 coding region is sensitive to the growth-inhibitory effects of D-erythro-sphingosine, due to its inability to degrade SPP. Zhou and Saba (1998) identified a mouse cDNA encoding a protein, which they named Spl, that has 59% sequence similarity to the BST1 gene product. They showed that this cDNA can functionally complement the yeast BST1 deletion, restoring a sphingosine-resistant phenotype. Northern blot analysis detected Spl expression in several mouse tissues, with the highest level found in the liver. </p><p>Prasad et al. (2017) found ubiquitous expression of SGPL1 in human tissues, with moderate levels of expression in the adrenal cortex and kidneys and high levels of expression in the testes and thyroid. </p><p>In mouse kidney, Lovric et al. (2017) found expression of Sgpl1 in podocytes, as well as in other renal glomerular cell types, including mesangial and endothelial cells. Sgpl1 colocalized with ER markers. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using interspecific backcross mapping, Zhou and Saba (1998) localized the mouse Spl gene to chromosome 10, between the Eif4ebp2 (602224) and Egr2 (129010) genes. By homology of synteny, they mapped the human homolog of Spl, SGPL1, to 10q21. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Lymphocyte egress from the thymus and from peripheral lymphoid organs depends on sphingosine 1-phosphate (S1P) receptor-1 (601974) and is thought to occur in response to circulatory S1P. To further define gene egress requirements, Schwab et al. (2005) addressed why treatment with the food colorant 2-acetyl-4-tetrahydroxybutylimidazole (THI) induces lymphopenia. Schwab et al. (2005) found that S1P abundance in lymphoid tissues of mice is normally low but increases more than 100-fold after TH1 treatment and that this treatment inhibits the S1P-degrading enzyme sphingosine 1-phosphate lyase (SGPL1). Schwab et al. (2005) concluded that lymphocyte egress is mediated by S1P gradients that are established by S1P lyase activity and that the lyase may represent a novel immunosuppressant drug target. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
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<p>In 8 patients from 5 unrelated families with RENI syndrome (RENI; 617575), Prasad et al. (2017) identified homozygous loss-of-function mutations in the SGPL1 gene (see, e.g., 603729.0001-603729.0004). All but 1 of the families were consanguineous. The mutations were found by whole-exome or Sanger sequencing and segregated with the disorder in the families. Cellular expression assays of 2 of the mutations (R222Q, 603729.0001 and F545del, 603729.0002) showed that they resulted in decreased stability of the protein and almost complete absence of enzyme activity, consistent with a loss of function. </p><p>In patients from 7 unrelated, mostly consanguineous families of various ethnic origins with RENI syndrome, Lovric et al. (2017) identified homozygous or compound heterozygous mutations in the SGPL1 gene (see, e.g., 603729.0001; 603729.0004-603729.0006). The mutation in the first family was found by a combination of homozygosity mapping and whole-exome sequencing; subsequent mutations were found by whole-exome sequencing or Sanger sequencing. All mutations segregated with the disorder in the families. The mutation spectrum included frameshift, splice site, and missense mutations, and all were associated with reduced or absent SGPL1 protein and/or enzyme activity as measured in patient fibroblasts or transfected cells. Detailed functional studies of 2 of the missense mutations (R222Q and S346I, 603729.0006) showed a loss-of-function effect, with reduced protein levels, enzyme activity, impaired degradation of long-chain sphingoid bases, and altered subcellular localization. Disease-associated variants were unable to rescue growth defects in yeast or abnormalities in Drosophila deficient in Sgpl1. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, and patient fibroblasts showed reduced cell migration compared to controls. </p><p>In 2 unrelated male patients, both born of consanguineous parents, with RENI syndrome, Janecke et al. (2017) identified homozygous truncating mutations in the SGPL1 gene (603729.0007 and 603729.0008). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The levels of SGPL1 substrates, S1P, and sphingosine were markedly increased in blood and fibroblasts from one of the patients. </p><p>Settas et al. (2019) screened 21 patients with clinical features of primary adrenal insufficiency for variants in the SGPL1 gene and identified 2 patients with homozygosity and 2 with heterozygosity. The 2 patients with homozygosity were a 5.5-year-old proband, born of consanguineous parents, with RENI syndrome and his 15-year-old first cousin with the previously identified R222Q mutation (603729.0001). The 2 patients with heterozygosity had a missense variant (c.61G-T; V21L) that had an allele frequency of 0.09 in ExAC; the authors posited that this variant was unrelated to their adrenal insufficiency. </p><p>In a 15-year-old girl, born to consanguineous Turkish parents, with RENI syndrome, Maharaj et al. (2022) identified a homozygous missense mutation in the SGPL1 gene (c.1049A-G, chr10:72631733A-G, D350G). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. Examination of SGPL1 protein levels in the patient by immunoblotting showed decreased expression of the D350G variant. CRISPR-engineered human adrenocortical cells with SGPL1 knockout showed minimal cortisol output. </p><p>In a set of Chinese identical twin girls with RENI syndrome, Yang et al. (2023) identified compound heterozygous intronic mutations in the SGPL1 gene (603729.0003 and 603729.0009). The mutations were found by exome sequencing and segregated with the disorder in the family. Yang et al. (2023) conducted a review of 31 patients in the literature with SGPL1 variants causing nephrotic syndrome, including their 2 patients. Twenty-five patients (80.6%) had homozygous mutations (15 missense, 8 frameshift, and 2 truncation) and 6 patients (19.4%) had compound heterozygous mutations. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
|
|
Atkinson et al. (2017) described 2 Serbian sibs with acute or subacute onset of axonal peripheral neuropathy and episodes of recurrent mononeuropathy, which the authors called autosomal recessive Charcot-Marie-Tooth disease, who were compound heterozygous for mutations in the SGPL1 gene: c.551T-C, resulting in an ile184-to-thr (I184T) substitution, and c.1082C-G in exon 12 (of 15), resulting in a ser361-to-ter (S361X) substitution. The mutations cosegregated with the phenotype in the family. Plasma levels of sphingosine 1-phosophate and the sphingosine/sphinganine ratio were elevated in the patients, consistent with decreased sphingosine-1-phosphate lyase activity. The S361X variant appeared to result in nonsense-mediated decay based on the absence of the c.1082C-G allele on Sanger sequencing of SGPL1 cDNA from lymphoblasts. SGPL1 protein levels were nearly undetectable based on immunoblotting. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Prasad et al. (2017) found that adrenal cortical zonation was compromised in Sgpl1-null mice. Steroidogenesis also appeared to be disrupted. Kidneys from mutant mice showed mesangial hypercellularity and glomerular fibrosis, which recapitulated the main characteristics of NPHS14. </p><p>Lovric et al. (2017) found that the kidneys of Sgpl1-null mice showed complete foot process effacement and absence of slit diaphragms. Mutant mice also showed hypoalbuminemia and increased urinary albumin/creatinine ratio. Cultured podocytes from Sgpl1-null mice did not show evidence of increased apoptosis or abnormalities in cell migration. Knockdown of Sgpl1 in rat mesangial cells did not affect apoptosis or proliferation, but did have reduced migration. Certain S1PR antagonists partially rescued the migration defect. Studies of Drosophila with deficiency of the Sply ortholog of Sgpl1 showed a reduction of nephrocyte foot process density and reduced albumin uptake compared to controls. Mutant flies also showed evidence of altered lipid metabolism due to disruption of the sphingolipid catabolic pathway. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
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|
|
|
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</div>
|
|
|
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>9 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 RENI SYNDROME</strong>
|
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</span>
|
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SGPL1, ARG222GLN
|
|
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|
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<br />
|
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|
|
SNP: rs769259446,
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|
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gnomAD: rs769259446,
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|
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ClinVar: RCV000495961, RCV001849385, RCV001851363
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|
|
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</span>
|
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</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 members of a highly consanguineous Pakistani family with RENI syndrome (RENI; 617575), originally reported by Ram et al. (2012), Prasad et al. (2017) identified a homozygous c.665G-A transition (chr10:72,628,151G-A) in the SGPL1 gene, resulting in an arg222-to-gln (R222Q) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found in heterozygous state in 2 of 120,744 alleles in the ExAC database (frequency of 1.7 x 10(-5)). No homozygotes were found in the dbSNP, Exome Variant Server, or ExAC databases. Subsequently, the same mutation was found in a similarly affected individual, born of consanguineous Saudi parents, but haplotype analysis excluded a founder effect. Cellular expression assays showed that the mutation resulted in decreased stability of the protein and almost complete absence of enzyme activity, consistent with a loss of function. </p><p>Lovric et al. (2017) identified homozygosity for the R222Q mutation in the SGPL1 gene in 3 members of a consanguineous Pakistani family (A280) with RENI syndrome. The mutation was found by a combination of homozygosity mapping and whole-exome sequencing. Cellular expression studies showed that the mutation resulted in decreased protein levels and strongly decreased enzyme activity compared to wildtype, as well as formation of abnormal cytoplasmic SGPL1 aggregates. The mutant protein also failed to rescue growth defects in DPL1-deficient yeast, consistent with a loss of function. One of the patients had unusually late onset of renal disease at age 19 years. </p><p>In a 5.5-year-old boy, born to consanguineous Saudi Arabian parents, with RENI syndrome, and in his 15-year-old first cousin, Settas et al. (2019) identified homozygosity for a G-A transition (c.665G-A) in the SGPL1 gene, resulting in an arg222-to-gln (R222Q) substitution. The 15-year-old first cousin had amblyopia of the right eye, right-sided hearing loss, and right arm paralysis and developed kidney failure requiring hemodialysis; no further information on his phenotype was available. </p>
|
|
</span>
|
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</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 RENI SYNDROME</strong>
|
|
</span>
|
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</h4>
|
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</div>
|
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<div>
|
|
<span class="mim-text-font">
|
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SGPL1, 3-BP DEL, 1633TTC
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<br />
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|
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SNP: rs1131692252,
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|
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ClinVar: RCV000495964
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|
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</span>
|
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</div>
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a female Turkish patient with RENI syndrome (RENI; 617575), Prasad et al. (2017) identified a homozygous in-frame 3-bp deletion (c.1633_1635delTTC) in the SGPL1 gene, resulting in the deletion of highly conserved residue Phe545. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. It was not present in public databases. Cellular expression assays showed that the mutation resulted in decreased stability of the protein and almost complete absence of enzyme activity, consistent with a loss of function. </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>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 RENI SYNDROME</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
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|
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SGPL1, IVSDS, G-A, +1
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<br />
|
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|
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SNP: rs1131692253,
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|
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ClinVar: RCV000495967
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs, born of consanguineous Peruvian parents, with RENI syndrome (RENI; 617575), Prasad et al. (2017) identified a homozygous G-to-A transition (c.261+1G-A) in the SGPL1 gene, resulting in a splice site defect and predicting premature termination (Ser65ArgfsTer6). The mutant transcript was likely degraded by nonsense-mediated mRNA decay, resulting in a loss of function. The mutation segregated with the disorder in the family and was not found in any databases. </p><p>In a set of Chinese identical twin girls with RENI syndrome, Yang et al. (2023) identified compound heterozygous splicing mutations in the SGPL1 gene: c.261+1G-A (c.261+1G-A, NM_003901.4) in intron 4 and c.1298+6T-C (603729.0009) in intron 12. The mutations were found by exome sequencing, and each parent carried one of the mutations. The girls had steroid-resistant nephrotic syndrome with no extrarenal manifestations. </p>
|
|
</span>
|
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</div>
|
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0004 RENI SYNDROME</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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SGPL1, 1-BP DUP, 7A
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<br />
|
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|
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SNP: rs1131692254,
|
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|
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|
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|
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ClinVar: RCV000495963
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|
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|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient, born of consanguineous Spanish parents, with RENI syndrome (RENI; 617575), Prasad et al. (2017) identified a homozygous 1-bp duplication (c.7dupA) in the SGPL1 gene, resulting in a frameshift and premature termination (Ser3LysfsTer11). The mutation was not found in the ExAC database. The mutant transcript was likely degraded by nonsense-mediated mRNA decay, resulting in a loss of function. </p><p>In 3 affected members of a consanguineous Spanish Roma family (A5444) with RENI syndrome, Lovric et al. (2017) identified a homozygous c.7dupA mutation in exon 2 of the SGPL1 gene. The mutation was found by whole-exome sequencing and segregated with the disorder in the family. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 RENI SYNDROME</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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SGPL1, ARG222TRP
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<br />
|
|
|
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SNP: rs1131692255,
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|
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gnomAD: rs1131692255,
|
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|
|
|
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ClinVar: RCV000495965
|
|
|
|
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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 4 members of a consanguineous Turkish family (EB) with RENI syndrome (RENI; 617575), Lovric et al. (2017) identified a homozygous c.664C-T transition in exon 8 of the SGPL1 gene, resulting in an arg222-to-trp (R222W) substitution at a highly conserved residue in the PLP-dependent transferase domain. The mutation was not found in the ExAC database. Functional studies of the variant were not performed, but a different mutation in the same codon was found in another family with NPHS14 (R222Q; 603729.0001). Patients in the EB family had a severe form of the disorder, with congenital nephrotic syndrome resulting in fetal demise or death in the first months of life. </p>
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<strong>.0006 RENI SYNDROME</strong>
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SGPL1, SER346ILE
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SNP: rs1131692256,
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ClinVar: RCV000495968, RCV001849386
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<p>In affected members of a large consanguineous Moroccan kindred (B46/B56) with RENI syndrome (RENI; 617575), Lovric et al. (2017) identified a homozygous c.1037G-T transversion in exon 11 of the SGPL1 gene, resulting in a ser346-to-ile (S346I) substitution at a highly conserved residue in the PLP-dependent transferase domain. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was not found in the ExAC database. Cellular expression studies showed that the mutation resulted in decreased protein levels and enzyme activity compared to wildtype, as well as formation of abnormal cytoplasmic SGPL1 aggregates. The mutant protein also failed to rescue growth defects in DPL1-deficient yeast, consistent with a loss of function. </p>
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<span class="mim-font">
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<strong>.0007 RENI SYNDROME</strong>
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SGPL1, ARG505TER
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<br />
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SNP: rs746887949,
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gnomAD: rs746887949,
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ClinVar: RCV000495962
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<p>In a male patient from a large consanguineous family of Arab descent with RENI syndrome (RENI; 617575), Janecke et al. (2017) identified a homozygous c.1513C-T transition (c.1513C-T, NM_003901.3) in the SGPL1 gene, resulting in an arg505-to-ter (R505X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP, Exome Sequencing Project, or ExAC databases. The mutation was predicted to result in nonsense-mediated mRNA decay and a loss of function. A similarly affected patient from the same family died at age 7 weeks; material from that patient was not available for study. The family had previously been reported by Schreyer-Shafir et al. (2014). </p>
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<span class="mim-font">
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<strong>.0008 RENI SYNDROME</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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SGPL1, 1-BP DEL, 934C
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SNP: rs1131692235,
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ClinVar: RCV000495966
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<span class="mim-text-font">
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<p>In a male patient, born of consanguineous parents, with RENI syndrome (RENI; 617575), Janecke et al. (2017) identified a homozygous 1-bp deletion (c.934delC, NM_003901.3) in the SGPL1 gene, resulting in a frameshift and premature termination (Leu312PhefsTer30). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP, Exome Sequencing Project, or ExAC databases. The mutation was predicted to result in nonsense-mediated mRNA decay and a loss of function. The levels of SGPL1 substrates, S1P, and sphingosine were markedly increased in the patient's blood and fibroblasts. </p>
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<span class="mim-font">
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<strong>.0009 RENI SYNDROME</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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SGPL1, IVS12, C-T, +6
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<br />
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ClinVar: RCV003324601
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<span class="mim-text-font">
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<p>For discussion of the c.1298+6C-T mutation (c.1298+6C-T, NM_003901.4) in the SGPL1 gene that was found in compound heterozygous state in Chinese identical twin girls with RENI syndrome (RENI; 617575) by Yang et al. (2023), see 603729.0003. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<ol>
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<li>
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<p class="mim-text-font">
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Atkinson, D., Nikodinovic Glumac, J., Asselbergh, B., Ermanoska, B., Blocquel, D., Steiner, R., Estrada-Cuzcano, A., Peeters, K., Ooms, T., De Vriendt, E., Yang, X. L., Hornemann, T., Milic Rasic, V., Jordanova, A.
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<strong>Sphingosine 1-phosphate lyase deficiency causes Charcot-Marie-Tooth neuropathy.</strong>
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Neurology 88: 533-542, 2017.
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[PubMed: 28077491]
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[Full Text: https://doi.org/10.1212/WNL.0000000000003595]
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</li>
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<li>
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<p class="mim-text-font">
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Janecke, A. R., Xu, R., Steichen-Gersdorf, E., Waldegger, S., Entenmann, A., Giner, T., Krainer, I., Huber, L. A., Hess, M. W., Frishberg, Y., Barash, H., Tzur, S., Schreyer-Shafir, N., Sukenik-Halevy, R., Zehavi, T., Raas-Rothschild, A., Mao, C., Muller, T.
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<strong>Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications.</strong>
|
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Hum. Mutat. 38: 365-372, 2017.
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[PubMed: 28181337]
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[Full Text: https://doi.org/10.1002/humu.23192]
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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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Lovric, S., Goncalves, S., Gee, H. Y., Oskouian, B., Srinivas, H., Choi, W.-I., Shril, S., Ashraf, S., Tan, W., Rao, J., Airik, M., Schapiro, D., and 53 others.
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<strong>Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency.</strong>
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J. Clin. Invest. 127: 912-928, 2017.
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[PubMed: 28165339]
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[Full Text: https://doi.org/10.1172/JCI89626]
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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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Maharaj, A., Guran, T., Buonocore, F., Achermann, J. C., Metherell, L., Prasad, R., Cetinkaya, S.
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<strong>Insights from long-term follow-up of a girl with adrenal insufficiency and sphingosine-1-phosphate lyase deficiency.</strong>
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J. Endocr. Soc. 6: bvac020, 2022.
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[PubMed: 35308304]
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[Full Text: https://doi.org/10.1210/jendso/bvac020]
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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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Prasad, R., Hadjidemetriou, I., Maharaj, A. Meimaridou, E., Buonocore, F., Saleem, M., Hurcombe, J., Bierzynska, A., Barbagelata, E., Bergada, I., Cassinelli, H., Das, U., and 16 others.
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<strong>Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome.</strong>
|
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J. Clin. Invest. 127: 942-953, 2017.
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[PubMed: 28165343]
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[Full Text: https://doi.org/10.1172/JCI90171]
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</li>
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<li>
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<p class="mim-text-font">
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Ram, N., Asghar, A., Islam, N.
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<strong>A case report: familial glucocorticoid deficiency associated with familial focal segmental glomerulosclerosis.</strong>
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BMC Endocr. Disord. 12: 32, 2012. Note: Electronic Article.
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[PubMed: 23232022]
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[Full Text: https://doi.org/10.1186/1472-6823-12-32]
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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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Saba, J. D., Nara, F., Bielawska, A., Garrett, S., Hannun, Y. A.
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<strong>The BST1 gene of Saccharomyces cerevisiae is the sphingosine-1-phosphate lyase.</strong>
|
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J. Biol. Chem. 272: 26087-26090, 1997.
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[PubMed: 9334171]
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[Full Text: https://doi.org/10.1074/jbc.272.42.26087]
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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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Schreyer-Shafir, N., Sukenik-Halevy, R., Tepper, R., Amon, S., Litmanovitch, I., Eliakim, A., Pommeranz, A., Ludman, M. D., Raas-Rothschild, A.
|
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<strong>Prenatal bilateral adrenal calcifications, hypogonadism, and nephrotic syndrome: beyond Wolman disease.</strong>
|
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Prenatal Diag. 34: 608-611, 2014.
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[PubMed: 24777844]
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[Full Text: https://doi.org/10.1002/pd.4344]
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<li>
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<p class="mim-text-font">
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Schwab, S. R., Pereira, J. P., Matloubian, M., Xu, Y., Huang, Y., Cyster, J. G.
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<strong>Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients.</strong>
|
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Science 309: 1735-1739, 2005.
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[PubMed: 16151014]
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[Full Text: https://doi.org/10.1126/science.1113640]
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</li>
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<li>
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<p class="mim-text-font">
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Settas, N., Persky, R., Faucz, F. R., Sheanon, N., Voutetakis, A., Lodish, M., Metherell, L. A., Stratakis, C. A.
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<strong>SGPL1 deficiency: a rare cause of primary adrenal insufficiency.</strong>
|
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J. Clin. Endocr. Metab. 104: 1484-1490, 2019.
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[PubMed: 30517686]
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[Full Text: https://doi.org/10.1210/jc.2018-02238]
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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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Yang, S., He, Y., Zhou, J., Yuan, H., Qiu, L.
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<strong>Steroid-resistant nephrotic syndrome associated with certain SGPL1 variants in a family: case report and literature review.</strong>
|
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Front. Pediat. 11: 1079758, 2023.
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[PubMed: 36873630]
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[Full Text: https://doi.org/10.3389/fped.2023.1079758]
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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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Zhou, J., Saba, J. D.
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<strong>Identification of the first mammalian sphingosine phosphate lyase gene and its functional expression in yeast.</strong>
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Biochem. Biophys. Res. Commun. 242: 502-507, 1998.
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[PubMed: 9464245]
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[Full Text: https://doi.org/10.1006/bbrc.1997.7993]
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</li>
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</ol>
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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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Sonja A. Rasmussen - updated : 08/24/2023<br>Cassandra L. Kniffin - updated : 07/20/2017<br>Ada Hamosh - updated : 9/27/2005
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</span>
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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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Sheryl A. Jankowski : 4/13/1999
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carol : 08/24/2023<br>carol : 07/18/2018<br>carol : 12/18/2017<br>carol : 07/24/2017<br>carol : 07/21/2017<br>ckniffin : 07/20/2017<br>alopez : 09/29/2005<br>terry : 9/27/2005<br>psherman : 4/13/1999
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