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Entry
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- *603377 - SOLUTE CARRIER FAMILY 22 (ORGANIC CATION TRANSPORTER), MEMBER 5; SLC22A5
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- OMIM
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<p>
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<span class="h4">*603377</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="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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/603377">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>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000197375;t=ENST00000245407" 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=6584" 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=603377" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000197375;t=ENST00000245407" 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_001308122,NM_003060,XM_011543590,XM_017009778,XM_047417595,XM_047417596,XM_047417597,XM_047417598" 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_003060" 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=603377" 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=04539&isoform_id=04539_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/SLC22A5" 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/3242598,3273741,4126718,4507005,8928257,15147378,34536069,62088548,119582741,119582742,119582743,124271051,189053789,222070453,767936385,815890826,1034645877,2217356971,2217356973,2217356976,2217356978,2462603893,2462603895,2462603897,2462603899,2462603901,2462603903" 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/O76082" 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=6584" 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=ENSG00000197375;t=ENST00000245407" 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=SLC22A5" 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=SLC22A5" 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+6584" 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/SLC22A5" 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:6584" 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/6584" 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=chr5&hgg_gene=ENST00000245407.8&hgg_start=132369710&hgg_end=132395612&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:10969" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/slc22a5" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=603377[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
|
|
<span class="panel-title">
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<span class="small">
|
|
<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<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=603377[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/SLC22A5/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000197375" 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=SLC22A5" 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=SLC22A5" 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=SLC22A5" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.arup.utah.edu/database/OCTN2/OCTN2_welcome.php" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SLC22A5&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/PA333" 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:10969" 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/FBgn0019952.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/search?q=MGI:1329012 MGI:1929481" 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/SLC22A5#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/batch/summary?idType=MGI&ids=MGI:1329012 MGI:1929481" 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/6584/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=6584" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00003842;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-091012-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
|
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
|
|
<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:603377" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
|
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</span>
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</span>
|
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:6584" 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=SLC22A5&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>
|
|
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
|
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 21764004<br />
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<strong>ICD10CM:</strong> E71.41<br />
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<strong>ICD9CM:</strong> 277.81<br />
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">ICD+</a>
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</div>
|
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
603377
|
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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>
|
|
<h3>
|
|
<span class="mim-font">
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SOLUTE CARRIER FAMILY 22 (ORGANIC CATION TRANSPORTER), MEMBER 5; SLC22A5
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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>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
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</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
ORGANIC CATION TRANSPORTER 2; OCTN2
|
|
</span>
|
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</h4>
|
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</div>
|
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</div>
|
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SLC22A5" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SLC22A5</a></em></strong>
|
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</span>
|
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</p>
|
|
</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/5/448?start=-3&limit=10&highlight=448">5q31.1</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr5:132369710-132395612&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'})">5:132,369,710-132,395,612</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/5/448?start=-3&limit=10&highlight=448">
|
|
5q31.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Carnitine deficiency, systemic primary
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/212140"> 212140 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
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<p><a href="#31" class="mim-tip-reference" title="Wu, X., Prasad, P. D., Leibach, F. H., Ganapathy, V. <strong>cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family.</strong> Biochem. Biophys. Res. Commun. 246: 589-595, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618255</a>] [<a href="https://doi.org/10.1006/bbrc.1998.8669" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9618255">Wu et al. (1998)</a> cloned a full-length cDNA for OCTN2 (SLC22A5), a member of the organic cation transporter family, from a human placental trophoblast cell line. The OCTN2 cDNA encodes a predicted 557-amino acid protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9618255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Tamai, I., Ohashi, R., Nezu, J., Yabuuchi, H., Oku, A., Shimane, M., Sai, Y., Tsuji, A. <strong>Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2.</strong> J. Biol. Chem. 273: 20378-20382, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9685390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9685390</a>] [<a href="https://doi.org/10.1074/jbc.273.32.20378" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9685390">Tamai et al. (1998)</a> cloned OCTN2 from a human kidney cDNA library. The deduced protein shares 75.8% similarity with OCTN1 (<a href="/entry/604190">604190</a>). Northern blot analysis showed that OCTN2 is strongly expressed in kidney, skeletal muscle, heart, and placenta. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9685390" 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="#31" class="mim-tip-reference" title="Wu, X., Prasad, P. D., Leibach, F. H., Ganapathy, V. <strong>cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family.</strong> Biochem. Biophys. Res. Commun. 246: 589-595, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618255</a>] [<a href="https://doi.org/10.1006/bbrc.1998.8669" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9618255">Wu et al. (1998)</a> determined that the OCTN2 gene consists of 10 exons and spans approximately 26 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9618255" 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>Functional expression studies of OCTN2 in HEK293 cells by <a href="#21" class="mim-tip-reference" title="Tamai, I., Ohashi, R., Nezu, J., Yabuuchi, H., Oku, A., Shimane, M., Sai, Y., Tsuji, A. <strong>Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2.</strong> J. Biol. Chem. 273: 20378-20382, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9685390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9685390</a>] [<a href="https://doi.org/10.1074/jbc.273.32.20378" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9685390">Tamai et al. (1998)</a> indicated that OCTN2 is a physiologically important, high affinity carnitine transporter that shows significant sodium ion dependence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9685390" 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="Heintzman, H. D., Stuart, R. K., Hon, G., Fu, Y., Ching, C. W., Hawkins, R. D., Barrera, L. O., Van Calcar, S., Qu, C., Ching, K. A., Wang, W., Weng, Z., Green, R. D., Crawford, G. E., Ren, B. <strong>Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome.</strong> Nature Genet. 39: 311-318, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17277777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17277777</a>] [<a href="https://doi.org/10.1038/ng1966" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17277777">Heintzman et al. (2007)</a> determined the chromatin modification states in high resolution along 30 Mb of the human genome and found that active promoters are marked by trimethylation of lys4 of histone H3 (H3K4), whereas enhancers were marked by monomethylation, but not trimethylation, of H3K4. They developed computational algorithms using these distinct chromatin signatures to identify new regulatory elements, predicting over 200 promoters and 400 enhancers within the 30-Mb region. This approach accurately predicted the location and function of independently identified regulatory elements with high sensitivity and specificity and uncovered a novel functional enhancer for the carnitine transporter SLC22A5 (OCTN2). The results provided insight into the connections between chromatin modifications and transcriptional regulatory activity and provided a new tool for the functional annotation of the human genome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17277777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Primary Systemic Carnitine Deficiency</em></strong></p><p>
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Based on the observation that OCTN2 has the ability to transport carnitine in a sodium-dependent manner, <a href="#12" class="mim-tip-reference" title="Nezu, J., Tamai, I., Oku, A., Ohashi, R., Yabuuchi, H., Hashimoto, N., Nikaido, H., Sai, Y., Koizumi, A., Shoji, Y., Takada, G., Matsuishi, T., Yoshino, M., Kato, H., Ohura, T., Tsujimoto, G., Hayakawa, J., Shimane, M., Tsuji, A. <strong>Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter.</strong> Nature Genet. 21: 91-94, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9916797/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9916797</a>] [<a href="https://doi.org/10.1038/5030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9916797">Nezu et al. (1999)</a> searched for mutations in the gene encoding OCTN2, designated SLC22A5, both in the mouse model ('jvs') of primary systemic carnitine deficiency and in the human disorder (CDSP; <a href="/entry/212140">212140</a>). In the mouse model, they found a loss-of-function missense mutation, a substitution of a hydrophilic amino acid (arg) for a hydrophobic residue (leu) in a membrane-spanning region of the OCTN2 transporter. In 3 unrelated families with systemic carnitine deficiency, they found that CDSP patients were carrying mutations in the SLC22A5 gene (<a href="#0001">603377.0001</a>-<a href="#0004">603377.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9916797" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Lamhonwah, A.-M., Tein, I. <strong>Carnitine uptake defect: frameshift mutations in the human plasmalemmal carnitine transporter gene.</strong> Biochem. Biophys. Res. Commun. 252: 396-401, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9826541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9826541</a>] [<a href="https://doi.org/10.1006/bbrc.1998.9679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9826541">Lamhonwah and Tein (1998)</a> studied the expression of OCTN2 in cultured fibroblasts and lymphoblasts from 2 unrelated patients in whom they had previously documented a carnitine uptake defect (<a href="#25" class="mim-tip-reference" title="Tein, I., De Vivo, D. C., Bierman, F., Pulver, P., De Meirleir, L. J., Cvitanovic-Sojat, L., Pagon, R. A., Bertini, E., Dionisi-Vici, C., Servidei, S., Dimauro, S. <strong>Impaired skin fibroblast carnitine uptake in primary systemic carnitine deficiency manifested by childhood carnitine-responsive cardiomyopathy.</strong> Pediat. Res. 28: 247-255, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2235122/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2235122</a>] [<a href="https://doi.org/10.1203/00006450-199009000-00020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2235122">Tein et al., 1990</a>). In both patients, they found truncating mutations in the cDNA (<a href="#0005">603377.0005</a>-<a href="#0007">603377.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9826541+2235122" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Wang, Y., Ye, J., Ganapathy, V., Longo, N. <strong>Mutations in the organic cation/carnitine transporter OCTN2 in primary carnitine deficiency.</strong> Proc. Nat. Acad. Sci. 96: 2356-2360, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10051646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10051646</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10051646[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.5.2356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10051646">Wang et al. (1999)</a> identified mutations in the OCTN2 gene in 2 unrelated patients with CDSP, 1 homozygous and the other a compound heterozygous (<a href="#0008">603377.0008</a>-<a href="#0009">603377.0009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10051646" 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="#29" class="mim-tip-reference" title="Wang, Y., Taroni, F., Garavaglia, B., Longo, N. <strong>Functional analysis of mutations in the OCTN2 transporter causing primary carnitine deficiency: lack of genotype-phenotype correlation.</strong> Hum. Mutat. 16: 401-407, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11058897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11058897</a>] [<a href="https://doi.org/10.1002/1098-1004(200011)16:5<401::AID-HUMU4>3.0.CO;2-J" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11058897">Wang et al. (2000)</a> studied 4 European families with primary carnitine deficiency and found homozygosity for novel missense mutations in 3 patients. The fourth patient was compound heterozygous for R169W (<a href="#0014">603377.0014</a>) and W351R (<a href="#0015">603377.0015</a>). Further studies failed to indicate a correlation between residual carnitine transport and severity of the phenotype or age at presentation, which varies from early in life with hypoketotic hypoglycemia to later in life with skeletal myopathy or cardiomyopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11058897" 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="#28" class="mim-tip-reference" title="Wang, Y., Korman, S. H., Ye, J., Gargus, J. J., Gutman, A., Taroni, F., Garavaglia, B., Longo, N. <strong>Phenotype and genotype variation in primary carnitine deficiency.</strong> Genet. Med. 3: 387-392, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11715001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11715001</a>] [<a href="https://doi.org/10.1097/00125817-200111000-00002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11715001">Wang et al. (2001)</a> reported 4 novel mutations in the SLC22A5 gene causing primary carnitine deficiency. Alleles introducing premature stop codons reduced the levels of the mRNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11715001" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Lamhonwah, A.-M., Olpin, S. E., Pollitt, R. J., Vianey-Saban, C., Divry, P., Guffon, N., Besley, G. T. N., Onizuka, R., De Meirleir, L. J., Cvitanovic-Sojat, L., Baric, I., Dionisi-Vici, C., Fumic, K., Maradin, M., Tein, I. <strong>Novel OCTN2 mutations: no genotype-phenotype correlations: early carnitine therapy prevents cardiomyopathy.</strong> Am. J. Med. Genet. 111: 271-284, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12210323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12210323</a>] [<a href="https://doi.org/10.1002/ajmg.10585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12210323">Lamhonwah et al. (2002)</a> performed mutation screening of the OCTN2 gene in 11 individuals with CDSP by direct nucleotide sequencing of PCR products of all 10 exons. Carnitine uptake in cultured skin fibroblasts ranged from 1 to 20% of normal controls. Eleven mutations were described. No correlation between residual uptake and severity of clinical presentation was found, which suggested that the wide phenotypic variability was likely related to exogenous stressors that exacerbated carnitine deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12210323" 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="#15" class="mim-tip-reference" title="Rahbeeni, Z., Vaz, F. M., Al-Hussein, K., Bucknall, M. P., Ruiter, J., Wanders, R. J., Rashed, M. S. <strong>Identification of 2 novel mutations in OCTN2 from 2 Saudi patients with systemic carnitine deficiency.</strong> J. Inherit. Metab. Dis. 25: 363-369, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12408185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12408185</a>] [<a href="https://doi.org/10.1023/a:1020143632011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12408185">Rahbeeni et al. (2002)</a> reported 2 novel mutations in the OCTN2 gene from 2 Saudi patients with systemic carnitine deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12408185" 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="Dobrowolski, S. F., McKinney, J. T., di San Filippo, C. A., Sim, K. G., Wilcken, B., Longo, N. <strong>Validation of dye-binding/high-resolution thermal denaturation for the identification of mutations in the SLC22A5 gene.</strong> Hum. Mutat. 25: 306-313, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15714519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15714519</a>] [<a href="https://doi.org/10.1002/humu.20137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15714519">Dobrowolski et al. (2005)</a> validated the dye-binding/high-resolution thermal denaturation method for the identification of mutations in the SLC22A5 gene and expanded the mutational spectrum in primary carnitine deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15714519" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Amat di San Filippo, C., Pasquali, M., Longo, N. <strong>Pharmacological rescue of carnitine transport in primary carnitine deficiency.</strong> Hum. Mutat. 27: 513-523, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16652335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16652335</a>] [<a href="https://doi.org/10.1002/humu.20314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16652335">Amat di San Filippo et al. (2006)</a> found by confocal microscopy that several OCTN2 missense mutants matured normally to the plasma membrane. By contrast, other mutations caused significant retention of the mutant OCTN2 transporter in the cytoplasm. Failed maturation to the plasma membrane is a common mechanism in disorders affecting membrane transporters/ion channels, including cystic fibrosis. To correct this defect, <a href="#1" class="mim-tip-reference" title="Amat di San Filippo, C., Pasquali, M., Longo, N. <strong>Pharmacological rescue of carnitine transport in primary carnitine deficiency.</strong> Hum. Mutat. 27: 513-523, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16652335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16652335</a>] [<a href="https://doi.org/10.1002/humu.20314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16652335">Amat di San Filippo et al. (2006)</a> tested whether drugs reducing the efficiency of protein degradation in the endoplasmic reticulum (phenylbutyrate, curcumin) or capable of binding the OCTN2 carnitine transporter (verapamil, quinidine) could improve carnitine transport. Prolonged incubation with phenylbutyrate, quinidine, and verapamil partially stimulated carnitine transport, while curcumin was ineffective. Thus, pharmacologic therapy can be effective in partially restoring activity of mutant transporters. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16652335" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="El-Hattab, A. W., Li, F.-Y., Shen, J., Powell, B. R., Bawle, E. V., Adams, D. J., Wahl, E., Kobori, J. A., Graham, B., Scaglia, F., Wong, L.-J. <strong>Maternal systemic primary carnitine deficiency uncovered by newborn screening: clinical, biochemical, and molecular aspects.</strong> Genet. Med. 12: 19-24, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20027113/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20027113</a>] [<a href="https://doi.org/10.1097/GIM.0b013e3181c5e6f7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20027113">El-Hattab et al. (2010)</a> reported 5 families in which low free carnitine levels in the infants' newborn screen led to the diagnosis of maternal systemic primary carnitine deficiency. Affected mothers were compound heterozygotes or homozygotes for missense mutations. All infants were asymptomatic at the time of diagnosis, and 1 was found to have systemic primary carnitine deficiency. Three mothers were asymptomatic, one had decreased stamina during pregnancy, and the fifth had mild fatigability and developed preeclampsia. <a href="#4" class="mim-tip-reference" title="El-Hattab, A. W., Li, F.-Y., Shen, J., Powell, B. R., Bawle, E. V., Adams, D. J., Wahl, E., Kobori, J. A., Graham, B., Scaglia, F., Wong, L.-J. <strong>Maternal systemic primary carnitine deficiency uncovered by newborn screening: clinical, biochemical, and molecular aspects.</strong> Genet. Med. 12: 19-24, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20027113/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20027113</a>] [<a href="https://doi.org/10.1097/GIM.0b013e3181c5e6f7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20027113">El-Hattab et al. (2010)</a> concluded that these findings provided further evidence that systemic primary carnitine deficiency presents with a broad clinical spectrum from a metabolic decomposition in infancy to an asymptomatic adult. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20027113" 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>Inflammatory Bowel Disease 5</em></strong></p><p>
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For discussion of an association between variation in the SLC22A5 gene and inflammatory bowel disease-5, see <a href="/entry/606348">606348</a>.</p>
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<p><a href="#18" class="mim-tip-reference" title="Shekhawat, P. S., Srinivas, S. R., Matern, D., Bennett, M. J., Boriack, R., George, V., Xu, H., Prasad, P. D., Roon, P., Ganapathy, V. <strong>Spontaneous development of intestinal and colonic atrophy and inflammation in the carnitine-deficient jvs (OCTN2-/-) mice.</strong> Molec. Genet. Metab. 92: 315-324, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17884651/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17884651</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17884651[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ymgme.2007.08.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17884651">Shekhawat et al. (2007)</a> found that Octn2 +/- mice were viable and fertile, but Octn2 -/- mice survived only 4 to 5 weeks without carnitine supplementation. Octn2 -/- mice developed enlarged fatty liver, steatosis of other organs, and hypertrophic cardiomyopathy. In addition, Octn2 -/- mice developed intestinal villous atrophy and intestinal breakdown and inflammation with intense lymphocyte and macrophage infiltration, leading to ulcer formation and gut perforation. <a href="#18" class="mim-tip-reference" title="Shekhawat, P. S., Srinivas, S. R., Matern, D., Bennett, M. J., Boriack, R., George, V., Xu, H., Prasad, P. D., Roon, P., Ganapathy, V. <strong>Spontaneous development of intestinal and colonic atrophy and inflammation in the carnitine-deficient jvs (OCTN2-/-) mice.</strong> Molec. Genet. Metab. 92: 315-324, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17884651/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17884651</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17884651[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ymgme.2007.08.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17884651">Shekhawat et al. (2007)</a> observed increased apoptosis of Octn2 -/- gut epithelial cells and upregulation of Hsf1 (<a href="/entry/140580">140580</a>) and several heat shock proteins (e.g., HSPA1A; <a href="/entry/140550">140550</a>), which regulate OCTN2 gene expression. Intestinal and colonic epithelial cells in wildtype mice showed high expression and activity of enzymes of the beta-oxidation pathway (e.g., ADADM; <a href="/entry/607008">607008</a>). <a href="#18" class="mim-tip-reference" title="Shekhawat, P. S., Srinivas, S. R., Matern, D., Bennett, M. J., Boriack, R., George, V., Xu, H., Prasad, P. D., Roon, P., Ganapathy, V. <strong>Spontaneous development of intestinal and colonic atrophy and inflammation in the carnitine-deficient jvs (OCTN2-/-) mice.</strong> Molec. Genet. Metab. 92: 315-324, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17884651/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17884651</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17884651[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ymgme.2007.08.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17884651">Shekhawat et al. (2007)</a> concluded that carnitine-dependent oxidation of long-chain fatty acids in mitochondria is essential for normal gut function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17884651" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=603377[MIM]" class="btn btn-default mim-tip-hint" role="button" 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>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1554085861 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554085861;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=rs1554085861" 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=rs1554085861" 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=RCV000022287" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022287" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022287</a>
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<p>In 2 affected sibs with systemic carnitine deficiency (CDSP; <a href="/entry/212140">212140</a>) in a Japanese family reported by <a href="#11" class="mim-tip-reference" title="Matsuishi, T., Hirata, K., Terasawa, K., Kato, H., Yoshino, M., Ohtaki, E., Hirose, F., Nonaka, I., Sugiyama, N., Ohta, K. <strong>Successful carnitine treatment in two siblings having lipid storage myopathy with hypertrophic cardiomyopathy.</strong> Neuropediatrics 16: 6-12, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3974805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3974805</a>] [<a href="https://doi.org/10.1055/s-2008-1052536" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3974805">Matsuishi et al. (1985)</a>, <a href="#12" class="mim-tip-reference" title="Nezu, J., Tamai, I., Oku, A., Ohashi, R., Yabuuchi, H., Hashimoto, N., Nikaido, H., Sai, Y., Koizumi, A., Shoji, Y., Takada, G., Matsuishi, T., Yoshino, M., Kato, H., Ohura, T., Tsujimoto, G., Hayakawa, J., Shimane, M., Tsuji, A. <strong>Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter.</strong> Nature Genet. 21: 91-94, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9916797/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9916797</a>] [<a href="https://doi.org/10.1038/5030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9916797">Nezu et al. (1999)</a> found homozygosity for a 113-bp deletion in the SLC22A5 gene that encompassed the initiation codon in exon 1. The next available ATG in the correct frame was at codon 177, translation initiation at which would lead to loss of 2 transmembrane domains in the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9916797+3974805" 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 patient with primary systemic carnitine deficiency (CDSP; <a href="/entry/212140">212140</a>) reported by <a href="#19" class="mim-tip-reference" title="Shoji, Y., Koizumi, A., Kayo, T., Ohata, T., Takahashi, T., Harada, K., Takada, G. <strong>Evidence for linkage of human primary systemic carnitine deficiency with D5S436: a novel gene locus on chromosome 5q.</strong> Am. J. Hum. Genet. 63: 101-108, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9634512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9634512</a>] [<a href="https://doi.org/10.1086/301911" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9634512">Shoji et al. (1998)</a>, <a href="#12" class="mim-tip-reference" title="Nezu, J., Tamai, I., Oku, A., Ohashi, R., Yabuuchi, H., Hashimoto, N., Nikaido, H., Sai, Y., Koizumi, A., Shoji, Y., Takada, G., Matsuishi, T., Yoshino, M., Kato, H., Ohura, T., Tsujimoto, G., Hayakawa, J., Shimane, M., Tsuji, A. <strong>Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter.</strong> Nature Genet. 21: 91-94, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9916797/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9916797</a>] [<a href="https://doi.org/10.1038/5030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9916797">Nezu et al. (1999)</a> found compound heterozygosity for mutations in the SLC22A5 gene. One allele had a frameshift caused by a single cytosine insertion just after the start codon. The second allele had a single base substitution in codon 132 (the first codon of exon 2), which changed a tryptophan (TGG) to a stop codon (TGA) (W132X). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9916797+9634512" 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> rs72552727 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72552727;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/rs72552727?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=rs72552727" 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=rs72552727" 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=RCV000006780 OR RCV004589498" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006780, RCV004589498" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006780...</a>
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<p>See <a href="#0002">603377.0002</a> and <a href="#12" class="mim-tip-reference" title="Nezu, J., Tamai, I., Oku, A., Ohashi, R., Yabuuchi, H., Hashimoto, N., Nikaido, H., Sai, Y., Koizumi, A., Shoji, Y., Takada, G., Matsuishi, T., Yoshino, M., Kato, H., Ohura, T., Tsujimoto, G., Hayakawa, J., Shimane, M., Tsuji, A. <strong>Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter.</strong> Nature Genet. 21: 91-94, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9916797/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9916797</a>] [<a href="https://doi.org/10.1038/5030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9916797">Nezu et al. (1999)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9916797" 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 Chinese family with systemic primary carnitine deficiency (CDSP; <a href="/entry/212140">212140</a>) reported by <a href="#22" class="mim-tip-reference" title="Tang, N. L., Hui, J., Law, L. K., To, K. F., Ruiter, J. P., IJlst, L., Wanders, R. J., Ho, C. S., Fok, T. F., Yuen, P. M., Hjelm, N. M. <strong>Primary plasmalemmal carnitine transporter defect manifested with dicarboxylic aciduria and impaired fatty acid oxidation.</strong> J. Inherit. Metab. Dis. 21: 423-425, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9700600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9700600</a>] [<a href="https://doi.org/10.1023/a:1005314910623" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9700600">Tang et al. (1998)</a>, <a href="#23" class="mim-tip-reference" title="Tang, N. L. S., Ganapathy, V., Wu, X., Hui, J., Seth, P., Yuen, P. M. P., Fok, T. F., Hjelm, N. M. <strong>Mutations of OCTN2, an organic cation/carnitine transporter, lead to deficient cellular carnitine uptake in primary carnitine deficiency.</strong> Hum. Molec. Genet. 8: 655-660, 1999. Note: Erratum: Hum. Molec. Genet. 8: 943 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10072434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10072434</a>] [<a href="https://doi.org/10.1093/hmg/8.4.655" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10072434">Tang et al. (1999)</a> described compound heterozygosity for a truncating mutation (trp132 to ter) and a missense mutation (pro478 to leu; <a href="#0011">603377.0011</a>) in the SLC22A5 gene. Expression of mutant cDNAs revealed virtually no uptake activity for both mutations. The proband was the second child in the family. He was admitted with acute metabolic derangement at the age of 6 months, went into cardiac arrest, and succumbed shortly after admission. Peri-mortem serum free carnitine was very low with a normal free carnitine-to-acylcarnitine ratio. The diagnosis was established by measurement of carnitine uptake into fibroblasts, which was only 5% of normal. His elder sister had died after similar presentation. Physiologic studies in the parents indicated that both were heterozygotes for a defective carnitine transporter. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9700600+10072434" 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">rs386134224 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs386134224;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=rs386134224" 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=rs386134224" 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 5-year-old boy with systemic carnitine deficiency (CDSP; <a href="/entry/212140">212140</a>), <a href="#12" class="mim-tip-reference" title="Nezu, J., Tamai, I., Oku, A., Ohashi, R., Yabuuchi, H., Hashimoto, N., Nikaido, H., Sai, Y., Koizumi, A., Shoji, Y., Takada, G., Matsuishi, T., Yoshino, M., Kato, H., Ohura, T., Tsujimoto, G., Hayakawa, J., Shimane, M., Tsuji, A. <strong>Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter.</strong> Nature Genet. 21: 91-94, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9916797/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9916797</a>] [<a href="https://doi.org/10.1038/5030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9916797">Nezu et al. (1999)</a> found that the SLC22A5 gene carried an acceptor splice site mutation, a G-to-A transition in the last nucleotide of intron 8. The most likely consequence of this mutation, the joining of exon 8 with exon 10, was predicted to result in the creation of a premature stop codon after 2 residues. The patient had recurrent episodes of Reye syndrome, including encephalopathy, hyperammonemia, elevated liver enzymes, and liver steatosis, with hypoglycemia between ages 2 and 3 years. He had been taking carnitine orally without any recurrence of the episodes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9916797" 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 2 patients with carnitine uptake defect (CDSP; <a href="/entry/212140">212140</a>) reported by <a href="#25" class="mim-tip-reference" title="Tein, I., De Vivo, D. C., Bierman, F., Pulver, P., De Meirleir, L. J., Cvitanovic-Sojat, L., Pagon, R. A., Bertini, E., Dionisi-Vici, C., Servidei, S., Dimauro, S. <strong>Impaired skin fibroblast carnitine uptake in primary systemic carnitine deficiency manifested by childhood carnitine-responsive cardiomyopathy.</strong> Pediat. Res. 28: 247-255, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2235122/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2235122</a>] [<a href="https://doi.org/10.1203/00006450-199009000-00020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2235122">Tein et al. (1990)</a>, <a href="#8" class="mim-tip-reference" title="Lamhonwah, A.-M., Tein, I. <strong>Carnitine uptake defect: frameshift mutations in the human plasmalemmal carnitine transporter gene.</strong> Biochem. Biophys. Res. Commun. 252: 396-401, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9826541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9826541</a>] [<a href="https://doi.org/10.1006/bbrc.1998.9679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9826541">Lamhonwah and Tein (1998)</a> found compound heterozygosity for mutations in the SLC22A5 gene. Both patients showed a partial cDNA deletion of nucleotides 255-1649, resulting in a predicted truncated protein of 92 amino acids. In patient 1, the second mutant allele carried a 19-bp insertion between nucleotides 874 and 875, resulting in a frameshift and yielding a predicted truncated protein of 284 amino acids (<a href="#0006">603377.0006</a>); in patient 2, the second mutant allele had a deletion of nucleotides 875-1046, resulting in a predicted truncated protein of 237 amino acids (<a href="#0008">603377.0008</a>). Patient 1 was a male of Italian descent; patient 2 was a female of Mexican descent with a family history of an affected brother who had died of cardiomyopathy. Both children had early-onset myopathy, cardiomyopathy, and failure to thrive with less than 5% of control carnitine concentrations in muscle and had a dramatic improvement in growth, strength, and cardiac function following institution of high dose oral carnitine supplementation. Patient 1 had a striking decrease in renal reabsorption of carnitine (52%; normal greater than 95%) despite low serum carnitine concentrations. His muscle carnitine concentration increased to only 13% of control after carnitine supplementation; however, this was sufficient to result in a resolution of the lipid storage and a restoration of motor power. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9826541+2235122" 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">rs1554087461 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554087461;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=rs1554087461" 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=rs1554087461" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the 19-bp insertion between nucleotides 874 and 875 in the SLC22A5 gene that was found in compound heterozygous state in a patient with carnitine uptake defect (CDSP; <a href="/entry/212140">212140</a>) by <a href="#8" class="mim-tip-reference" title="Lamhonwah, A.-M., Tein, I. <strong>Carnitine uptake defect: frameshift mutations in the human plasmalemmal carnitine transporter gene.</strong> Biochem. Biophys. Res. Commun. 252: 396-401, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9826541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9826541</a>] [<a href="https://doi.org/10.1006/bbrc.1998.9679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9826541">Lamhonwah and Tein (1998)</a>, see <a href="#0005">603377.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9826541" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000006784" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006784" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006784</a>
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<p>For discussion of the 171-bp deletion of nucleotides 875-1046 in the SLC22A5 gene that was found in compound heterozygous state in a patient with carnitine uptake defect (CDSP; <a href="/entry/212140">212140</a>) by <a href="#8" class="mim-tip-reference" title="Lamhonwah, A.-M., Tein, I. <strong>Carnitine uptake defect: frameshift mutations in the human plasmalemmal carnitine transporter gene.</strong> Biochem. Biophys. Res. Commun. 252: 396-401, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9826541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9826541</a>] [<a href="https://doi.org/10.1006/bbrc.1998.9679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9826541">Lamhonwah and Tein (1998)</a>, see <a href="#0005">603377.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9826541" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908886 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908886;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/rs121908886?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=rs121908886" 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=rs121908886" 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=RCV000006785 OR RCV000579046 OR RCV004754250" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006785, RCV000579046, RCV004754250" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006785...</a>
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<p>In a patient with primary carnitine deficiency (CDSP; <a href="/entry/212140">212140</a>), <a href="#30" class="mim-tip-reference" title="Wang, Y., Ye, J., Ganapathy, V., Longo, N. <strong>Mutations in the organic cation/carnitine transporter OCTN2 in primary carnitine deficiency.</strong> Proc. Nat. Acad. Sci. 96: 2356-2360, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10051646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10051646</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10051646[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.5.2356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10051646">Wang et al. (1999)</a> found homozygosity for a C-to-T transition in exon 5 of the SLC22A5 gene, converting codon 282 from CGA (arg) to TGA (stop). Both parents were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10051646" 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="#26" class="mim-tip-reference" title="Vaz, F. M., Scholte, H. R., Ruiter, J., Hussaarts-Odijk, L. M., Rodrigues Pereira, R., Schweitzer, S., de Klerk, J. B. C., Waterham, H. R., Wanders, R. J. A. <strong>Identification of two novel mutations in OCTN2 of three patients with systemic carnitine deficiency.</strong> Hum. Genet. 105: 157-161, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10480371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10480371</a>] [<a href="https://doi.org/10.1007/s004399900105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10480371">Vaz et al. (1999)</a> found the R282X mutation in homozygous state in a patient with classic manifestations of systemic carnitine deficiency. Reintroduction of wildtype OCTN2 cDNA into fibroblasts of the patient by transient transfection restored the cellular carnitine uptake, confirming that mutation in OCTN2 was the cause of the systemic carnitine deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10480371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Burwinkel, B., Kreuder, J., Schweitzer, S., Vorgerd, M., Gempel, K., Gerbitz, K.-D., Kilimann, M. W. <strong>Carnitine transporter OCTN2 mutations in systemic primary carnitine deficiency: a novel Arg169Gln mutation and a recurrent Arg282ter mutation associated with an unconventional splicing abnormality.</strong> Biochem. Biophys. Res. Commun. 261: 484-487, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10425211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10425211</a>] [<a href="https://doi.org/10.1006/bbrc.1999.1060" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10425211">Burwinkel et al. (1999)</a> identified the R282X mutation in 2 German patients who had different haplotypes, suggesting that this mutation may either be recurrent or an ancient founder mutation. They also found that R282X was associated with a splicing abnormality at the intron 6/exon 7 junction. However, no mutations were present in exon 6, intron 6, or exon 7, suggesting that defective splicing of exon 7 on the R282X allele was due to an unconventional, long-distance mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10425211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
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SLC22A5, TYR401TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908887 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908887;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=rs121908887" 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=rs121908887" 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=RCV000006786 OR RCV000790705 OR RCV002226442" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006786, RCV000790705, RCV002226442" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006786...</a>
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<p>In a patient with primary carnitine deficiency (CDSP; <a href="/entry/212140">212140</a>), <a href="#30" class="mim-tip-reference" title="Wang, Y., Ye, J., Ganapathy, V., Longo, N. <strong>Mutations in the organic cation/carnitine transporter OCTN2 in primary carnitine deficiency.</strong> Proc. Nat. Acad. Sci. 96: 2356-2360, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10051646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10051646</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10051646[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.5.2356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10051646">Wang et al. (1999)</a> found compound heterozygosity for a paternal allele containing a 1-bp (A) insertion in exon 7, converting codon 401 from TAT (tyr) to TAA (stop), and a maternal allele containing a 1-bp (G) deletion in exon 8 (<a href="#0010">603377.0010</a>), causing a frameshift starting at codon 435 (gly) and resulting in a premature termination signal at codon 458. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10051646" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
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SLC22A5, 1-BP DEL, 1345G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs386134217 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs386134217;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=rs386134217" 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=rs386134217" 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=RCV000006787" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006787" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006787</a>
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<p>For discussion of the 1-bp deletion in the SLC22A5 gene that was found in compound heterozygous state in a patient with primary carnitine deficiency (CDSP; <a href="/entry/212140">212140</a>) by <a href="#30" class="mim-tip-reference" title="Wang, Y., Ye, J., Ganapathy, V., Longo, N. <strong>Mutations in the organic cation/carnitine transporter OCTN2 in primary carnitine deficiency.</strong> Proc. Nat. Acad. Sci. 96: 2356-2360, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10051646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10051646</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10051646[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.5.2356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10051646">Wang et al. (1999)</a>, see <a href="#0009">603377.0009</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10051646" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
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SLC22A5, PRO478LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs72552735 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72552735;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=rs72552735" 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=rs72552735" 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=RCV000006788" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006788" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006788</a>
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<p>For discussion of the pro478-to-leu (P478L) mutation in the SLC22A5 gene that was found in compound heterozygous state in a family with systemic primary carnitine deficiency (CDSP; <a href="/entry/212140">212140</a>) by <a href="#23" class="mim-tip-reference" title="Tang, N. L. S., Ganapathy, V., Wu, X., Hui, J., Seth, P., Yuen, P. M. P., Fok, T. F., Hjelm, N. M. <strong>Mutations of OCTN2, an organic cation/carnitine transporter, lead to deficient cellular carnitine uptake in primary carnitine deficiency.</strong> Hum. Molec. Genet. 8: 655-660, 1999. Note: Erratum: Hum. Molec. Genet. 8: 943 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10072434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10072434</a>] [<a href="https://doi.org/10.1093/hmg/8.4.655" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10072434">Tang et al. (1999)</a>, see <a href="#0003">603377.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10072434" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
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SLC22A5, TYR211CYS
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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> rs121908888 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908888;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/rs121908888?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=rs121908888" 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=rs121908888" 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=RCV000006789 OR RCV000186136 OR RCV002226443" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006789, RCV000186136, RCV002226443" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006789...</a>
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<p>In 2 unrelated patients with classic systemic carnitine deficiency (CDSP; <a href="/entry/212140">212140</a>), <a href="#26" class="mim-tip-reference" title="Vaz, F. M., Scholte, H. R., Ruiter, J., Hussaarts-Odijk, L. M., Rodrigues Pereira, R., Schweitzer, S., de Klerk, J. B. C., Waterham, H. R., Wanders, R. J. A. <strong>Identification of two novel mutations in OCTN2 of three patients with systemic carnitine deficiency.</strong> Hum. Genet. 105: 157-161, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10480371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10480371</a>] [<a href="https://doi.org/10.1007/s004399900105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10480371">Vaz et al. (1999)</a> found homozygosity for the same missense mutation, 632A-G, which changes the tyrosine at amino acid position 211 into a cysteine (Y211C). The first patient had been reported by <a href="#16" class="mim-tip-reference" title="Rodrigues Pereira, R., Scholte, H. R., Luyt-Houwen, I. E. M., Vaandrager-Verduin, M. H. M. <strong>Cardiomyopathy associated with carnitine loss in kidneys and small intestine.</strong> Europ. J. Pediat. 148: 193-197, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3215194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3215194</a>] [<a href="https://doi.org/10.1007/BF00441399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3215194">Rodrigues Pereira et al. (1988)</a> and by <a href="#17" class="mim-tip-reference" title="Scholte, H. R., Rodrigues Pereira, R., de Jonge, P. C., Luyt-Houwen, I. E. M., Hedwig, M., Verduin, M., Ross, J. D. <strong>Primary carnitine deficiency.</strong> J. Clin. Chem. Clin. Biochem. 28: 351-357, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2199596/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2199596</a>]" pmid="2199596">Scholte et al. (1990)</a>. The second patient was admitted to hospital at 7 months of age because of failure to thrive. Physical examination showed dilated cardiomyopathy. Cardiac decompensation had existed from the age of 5 months. Treatment with digoxin and diuretics was started. At the age of 20 months, she presented with lowered consciousness, respiratory insufficiency, hypoglycemia, hyperammonemia, elevated transaminases, and low plasma carnitine concentrations. With carnitine therapy, improvement of the echocardiographic findings was noted by the age of 2 years. At the age of 5.5 years, the echocardiograph was almost normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10480371+3215194+2199596" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908889 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908889;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/rs121908889?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=rs121908889" 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=rs121908889" 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=RCV000006790 OR RCV000186134" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006790, RCV000186134" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006790...</a>
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<p>On 1 of 4 chromosomes from 2 unrelated German patients with systemic primary carnitine deficiency (CDSP; <a href="/entry/212140">212140</a>), <a href="#2" class="mim-tip-reference" title="Burwinkel, B., Kreuder, J., Schweitzer, S., Vorgerd, M., Gempel, K., Gerbitz, K.-D., Kilimann, M. W. <strong>Carnitine transporter OCTN2 mutations in systemic primary carnitine deficiency: a novel Arg169Gln mutation and a recurrent Arg282ter mutation associated with an unconventional splicing abnormality.</strong> Biochem. Biophys. Res. Commun. 261: 484-487, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10425211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10425211</a>] [<a href="https://doi.org/10.1006/bbrc.1999.1060" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10425211">Burwinkel et al. (1999)</a> identified a G-to-A transition at nucleotide 506 of the SLC22A5 gene, resulting in an arg169-to-gln (R169Q) substitution. The mutation involved an arginine residue absolutely conserved in the entire transporter superfamily to which SLC22A5 belongs. On the 3 other chromosomes, they identified an arg282-to-ter mutation in exon 5 of the gene (R282X; <a href="#0008">603377.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10425211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908890 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908890;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/rs121908890?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=rs121908890" 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=rs121908890" 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=RCV000006791" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006791" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006791</a>
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<p><a href="#29" class="mim-tip-reference" title="Wang, Y., Taroni, F., Garavaglia, B., Longo, N. <strong>Functional analysis of mutations in the OCTN2 transporter causing primary carnitine deficiency: lack of genotype-phenotype correlation.</strong> Hum. Mutat. 16: 401-407, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11058897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11058897</a>] [<a href="https://doi.org/10.1002/1098-1004(200011)16:5<401::AID-HUMU4>3.0.CO;2-J" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11058897">Wang et al. (2000)</a> described compound heterozygosity for arg169 to trp (R169W) and trp351 to arg (W351R; <a href="#0015">603377.0015</a>) in a patient with systemic primary carnitine deficiency (CDSP; <a href="/entry/212140">212140</a>). The patient had presented at 5 years of age with acute metabolic decompensation. The parents were unrelated. This C-to-T transition in exon 2 occurred in a CpG region; therefore, it was not surprising that another patient had a different mutation (R169Q; <a href="#0013">603377.0013</a>) in the same residue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11058897" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0015 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs68018207 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs68018207;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=rs68018207" 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=rs68018207" 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=RCV000006792" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006792" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006792</a>
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<p>For discussion of the trp351-to-arg (W351R) mutation in the SLC22A5 gene that was found in compound heterozygous state in a patient with systemic primary carnitine deficiency (CDSP; <a href="/entry/212140">212140</a>) by <a href="#29" class="mim-tip-reference" title="Wang, Y., Taroni, F., Garavaglia, B., Longo, N. <strong>Functional analysis of mutations in the OCTN2 transporter causing primary carnitine deficiency: lack of genotype-phenotype correlation.</strong> Hum. Mutat. 16: 401-407, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11058897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11058897</a>] [<a href="https://doi.org/10.1002/1098-1004(200011)16:5<401::AID-HUMU4>3.0.CO;2-J" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11058897">Wang et al. (2000)</a>, see <a href="#0014">603377.0014</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11058897" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0016 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908891 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908891;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/rs121908891?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=rs121908891" 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=rs121908891" 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=RCV000006793 OR RCV001532526 OR RCV002226444" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006793, RCV001532526, RCV002226444" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006793...</a>
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<p><a href="#28" class="mim-tip-reference" title="Wang, Y., Korman, S. H., Ye, J., Gargus, J. J., Gutman, A., Taroni, F., Garavaglia, B., Longo, N. <strong>Phenotype and genotype variation in primary carnitine deficiency.</strong> Genet. Med. 3: 387-392, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11715001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11715001</a>] [<a href="https://doi.org/10.1097/00125817-200111000-00002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11715001">Wang et al. (2001)</a> reported Iranian Jewish sibs with systemic primary carnitine deficiency (CDSP; <a href="/entry/212140">212140</a>) who were homozygous for a G-to-A transition at nucleotide 1196 in exon 7 of the SLC22A5 gene, resulting in an arginine-to-glutamine substitution at codon 399 (R399Q). Both parents were heterozygous for this mutation. The first sib presented at 2 years of age in coma during an episode of gastroenteritis, while her older sister had weakness of the proximal limb girdle musculature requiring physical therapy, and developmental delays involving language skills, concentration, and attention span. Starting her on carnitine resulted in marked improvement of muscle tone, general mood, alertness, activity, and concentration span. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11715001" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0017 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs2631367 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2631367;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/rs2631367?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=rs2631367" 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=rs2631367" 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=RCV000023299" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023299" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023299</a>
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<p>This variant, formerly titled INFLAMMATORY BOWEL DISEASE 5, ASSOCIATION WITH, has been reclassified based on the findings of <a href="#10" class="mim-tip-reference" title="Martinez, A., Martin, M. C., Mendoza, J. L., Taxonera, C., Diaz-Rubio, M., de la Concha, E. G., Urcelay, E. <strong>Association of the organic cation transporter OCTN genes with Crohn's disease in the Spanish population.</strong> Europ. J. Hum. Genet. 14: 222-226, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16333318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16333318</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201529" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16333318">Martinez et al. (2006)</a> and <a href="#20" class="mim-tip-reference" title="Silverberg, M. S., Duerr, R. H., Brant, S. R., Bromfield, G., Datta, L. W., Jani, N., Kane, S. V., Rotter, J. I., Schumm, L. P., Steinhart, A. H., Taylor, K. D., Yang, H., Cho, J. H., Rioux, J. D., Daly, M. J. <strong>Refined genomic localization and ethnic differences observed for the IBD5 association with Crohn's disease.</strong> Europ. J. Hum. Genet. 15: 328-335, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17213842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17213842</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201756" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17213842">Silverberg et al. (2007)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16333318+17213842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Peltekova, V. D., Wintle, R. F., Rubin, L. A., Amos, C. I., Huang, Q., Gu, X., Newman, B., Van Oene, M., Cescon, D., Greenberg, G., Griffiths, A. M., St George-Hyslop, P. H., Siminovitch, K. A. <strong>Functional variants of OCTN cation transporter genes are associated with Crohn disease.</strong> Nature Genet. 36: 471-475, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15107849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15107849</a>] [<a href="https://doi.org/10.1038/ng1339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15107849">Peltekova et al. (2004)</a> found a 2-allele haplotype enriched in individuals with Crohn disease (IBD5; <a href="/entry/606348">606348</a>) involving a SNP in SLC22A4 (1672C-T; <a href="/entry/604190#0002">604190.0002</a>) and G-to-C transversion in the SLC22A5 promoter (-207G-C). The 2-allele risk haplotype was referred to as TC for the nucleotides involved in Crohn disease risk. The TC haplotype was not enriched in individuals with ulcerative colitis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15107849" 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 case-control study of 309 Spanish patients with Crohn disease and 408 controls, <a href="#10" class="mim-tip-reference" title="Martinez, A., Martin, M. C., Mendoza, J. L., Taxonera, C., Diaz-Rubio, M., de la Concha, E. G., Urcelay, E. <strong>Association of the organic cation transporter OCTN genes with Crohn's disease in the Spanish population.</strong> Europ. J. Hum. Genet. 14: 222-226, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16333318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16333318</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201529" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16333318">Martinez et al. (2006)</a> found conflicting evidence for the role of the SLC22A4 1672C-T and the SLC22A5 -207G-C polymorphisms. Separate analysis for each variant showed no disease association, whereas a combination of the 2 variants showed a mildly increased disease risk. The authors suggested that certain haplotypes in defined populations may confer susceptibility or protection to Crohn disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16333318" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Silverberg, M. S., Duerr, R. H., Brant, S. R., Bromfield, G., Datta, L. W., Jani, N., Kane, S. V., Rotter, J. I., Schumm, L. P., Steinhart, A. H., Taylor, K. D., Yang, H., Cho, J. H., Rioux, J. D., Daly, M. J. <strong>Refined genomic localization and ethnic differences observed for the IBD5 association with Crohn's disease.</strong> Europ. J. Hum. Genet. 15: 328-335, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17213842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17213842</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201756" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17213842">Silverberg et al. (2007)</a> evaluated 1,879 affected offspring and parents ascertained by a North American IBD Genetics Consortium for 6 IDB5 SNPs. The findings rejected the previously reported -207G-C SNP as the potential causative variant for Crohn disease susceptibility, although it did not compromise the observation that this SNP may alter SLC22A5 expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17213842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0018 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908892 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908892;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/rs121908892?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=rs121908892" 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=rs121908892" 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=RCV000006794" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006794" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006794</a>
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<p><a href="#3" class="mim-tip-reference" title="Dobrowolski, S. F., McKinney, J. T., di San Filippo, C. A., Sim, K. G., Wilcken, B., Longo, N. <strong>Validation of dye-binding/high-resolution thermal denaturation for the identification of mutations in the SLC22A5 gene.</strong> Hum. Mutat. 25: 306-313, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15714519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15714519</a>] [<a href="https://doi.org/10.1002/humu.20137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15714519">Dobrowolski et al. (2005)</a> demonstrated a 3G-T transversion in the SLC22A5 gene, predicted to produce a met1-to-ile substitution (M1I), as the cause of systemic primary carnitine deficiency (CDSP; <a href="/entry/212140">212140</a>). The causative role of this missense mutation was confirmed by expression in Chinese hamster ovary (CHO) cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15714519" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0019 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908893 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908893;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/rs121908893?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=rs121908893" 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=rs121908893" 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=RCV000006795 OR RCV000490002 OR RCV000506929" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006795, RCV000490002, RCV000506929" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006795...</a>
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<p>In 2 unrelated Chinese patients with systemic primary carnitine deficiency (CDSP; <a href="/entry/212140">212140</a>), one of whom had previously been described by <a href="#9" class="mim-tip-reference" title="Marques, J. S. <strong>Dilated cardiomyopathy caused by plasma membrane carnitine transport defect.</strong> J. Inherit. Metab. Dis. 21: 428-429, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9700603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9700603</a>] [<a href="https://doi.org/10.1023/a:1005371028370" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9700603">Marques (1998)</a>, <a href="#24" class="mim-tip-reference" title="Tang, N. L. S., Hwu, W. L., Chan, R. T., Law, L. K., Fung, L. M., Zhang, W. M. <strong>A founder mutation (R254X) of SLC22A5 (OCTN2) in Chinese primary carnitine deficiency patients. (Abstract)</strong> Hum. Mutat. 20: 232 only, 2002. Note: Full article online."None>Tang et al. (2002)</a> identified homozygosity for a 981C-T transition in exon 4 of the SLC22A5 gene, resulting in an arg254-to-ter (R254X) substitution. The predicted protein has only 5 of the 12 transmembrane domains and is a loss-of-function mutant. Both patients had presented with acute heart failure and dilated cardiomyopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9700603" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Yamak, A. A., Bitar, F., Karam, P., Nemer, G. <strong>Exclusive cardiac dysfunction in familial primary carnitine deficiency cases: a genotype-phenotype correlation.</strong> Clin. Genet. 72: 59-62, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17594400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17594400</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00814.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17594400">Yamak et al. (2007)</a> identified homozygosity for the R254X mutation in affected members of 2 Lebanese families segregating for primary systemic carnitine deficiency. Their patients shared a common haplotype with the 2 Chinese patients reported by <a href="#24" class="mim-tip-reference" title="Tang, N. L. S., Hwu, W. L., Chan, R. T., Law, L. K., Fung, L. M., Zhang, W. M. <strong>A founder mutation (R254X) of SLC22A5 (OCTN2) in Chinese primary carnitine deficiency patients. (Abstract)</strong> Hum. Mutat. 20: 232 only, 2002. Note: Full article online."None>Tang et al. (2002)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17594400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Lamhonwah, A.-M., Onizuka, R., Olpin, S. E., Muntoni, F., Tein, I. <strong>OCTN2 mutation (R254X) found in Saudi Arabian kindred: recurrent mutation or ancient founder mutation?</strong> J. Inherit. Metab. Dis. 27: 473-476, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15303004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15303004</a>] [<a href="https://doi.org/10.1023/B:BOLI.0000037339.25821.87" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15303004">Lamhonwah et al. (2004)</a> identified homozygosity for the R254X mutation in a Saudi Arabian girl with systemic carnitine deficiency. Laboratory studies showed impaired fatty acid oxidation and decreased carnitine uptake in skin fibroblasts (less than 1% of control values). Western blot analysis showed absence of the protein. <a href="#7" class="mim-tip-reference" title="Lamhonwah, A.-M., Onizuka, R., Olpin, S. E., Muntoni, F., Tein, I. <strong>OCTN2 mutation (R254X) found in Saudi Arabian kindred: recurrent mutation or ancient founder mutation?</strong> J. Inherit. Metab. Dis. 27: 473-476, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15303004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15303004</a>] [<a href="https://doi.org/10.1023/B:BOLI.0000037339.25821.87" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15303004">Lamhonwah et al. (2004)</a> stated that the substitution resulted from a 760C-T transition in exon 4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15303004" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0020 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs267607054 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607054;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/rs267607054?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=rs267607054" 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=rs267607054" 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=RCV000006796 OR RCV000186144" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006796, RCV000186144" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006796...</a>
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<p>In an African American family in which an infant was identified as having low carnitine in newborn screening, subsequent analysis showed that the asymptomatic mother actually had systemic carnitine deficiency (CDSP; <a href="/entry/212140">212140</a>), with a free plasma carnitine level of 1 micromol/L and a total plasma carnitine of 2 micromol/L. She was found to be compound heterozygous for a C-to-T transversion at nucleotide 1195 of the SLC22A5 gene, resulting in an arg-to-trp substitution at codon 399 (R399W), and a second missense mutation (A442I; <a href="#0021">603377.0021</a>).</p>
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<strong>.0021 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
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<p>In an African American family in which an infant was identified as having low carnitine in newborn screening, subsequent analysis showed that the asymptomatic mother actually had systemic carnitine deficiency (CDSP; <a href="/entry/212140">212140</a>). She was found to be compound heterozygous for a GC-to-AT substitution at nucleotides 1324/1325 of the SLC22A5 gene, resulting in an ala-to-ile substitution at codon 442 (A442I), and another missense mutation (R399W; <a href="#0020">603377.0020</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> rs267607052 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607052;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/rs267607052?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=rs267607052" 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=rs267607052" 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=RCV000006798 OR RCV000186150" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006798, RCV000186150" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006798...</a>
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<p><a href="#4" class="mim-tip-reference" title="El-Hattab, A. W., Li, F.-Y., Shen, J., Powell, B. R., Bawle, E. V., Adams, D. J., Wahl, E., Kobori, J. A., Graham, B., Scaglia, F., Wong, L.-J. <strong>Maternal systemic primary carnitine deficiency uncovered by newborn screening: clinical, biochemical, and molecular aspects.</strong> Genet. Med. 12: 19-24, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20027113/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20027113</a>] [<a href="https://doi.org/10.1097/GIM.0b013e3181c5e6f7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20027113">El-Hattab et al. (2010)</a> identified low carnitine in an Indian infant by newborn screening. Subsequent analysis revealed that his mother had primary carnitine deficiency (CDSP; <a href="/entry/212140">212140</a>) with a free plasma carnitine level of 3 micromol/L and total plasma carnitine of 7 micromol/L. She was completely asymptomatic at the age of 33 years. She was homozygous for a G-to-T transversion at nucleotide 43 of the SLC22A5 gene, resulting in a gly-to-trp substitution at codon 15 (G15W). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20027113" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0023 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
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SLC22A5, -149G-A
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs57262206 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs57262206;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/rs57262206?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=rs57262206" 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=rs57262206" 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=RCV000022286 OR RCV001268199 OR RCV003407353 OR RCV004955257" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022286, RCV001268199, RCV003407353, RCV004955257" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022286...</a>
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<p>After finding low carnitine in 2 sibs and their maternal first cousin by newborn screening, <a href="#27" class="mim-tip-reference" title="Verbeeten, K. C., Lamhonwah, A.-M., Bulman, D., Faghfoury, H., Chakraborty, P., Tein, I., Geraghty, M. T. <strong>Carnitine uptake defect due to a 5-prime UTR mutation in a pedigree with false positives and false negatives on newborn screening.</strong> Molec. Genet. Metab. 129: 213-218, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31864849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31864849</a>] [<a href="https://doi.org/10.1016/j.ymgme.2019.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31864849">Verbeeten et al. (2020)</a> found that their mothers, who were sisters, and a maternal uncle had primary carnitine deficiency (CDSP; <a href="/entry/212140">212140</a>) with low plasma carnitine and increased fractional excretion of free carnitine in the urine. Next-generation sequencing identified a homozygous c.-149G-A transition (c.-149G-A, NM_003060) in the SLC22A5 gene in the 3 affected individuals and carrier status in the 3 infants. Skin fibroblast studies from the affected male showed deficient carnitine uptake at less than 6% of control values. <a href="#27" class="mim-tip-reference" title="Verbeeten, K. C., Lamhonwah, A.-M., Bulman, D., Faghfoury, H., Chakraborty, P., Tein, I., Geraghty, M. T. <strong>Carnitine uptake defect due to a 5-prime UTR mutation in a pedigree with false positives and false negatives on newborn screening.</strong> Molec. Genet. Metab. 129: 213-218, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31864849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31864849</a>] [<a href="https://doi.org/10.1016/j.ymgme.2019.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31864849">Verbeeten et al. (2020)</a> also found that the wife of the affected male was a carrier for the mutation and that 2 of their children were homozygous for the mutation and diagnosed with carnitine uptake deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31864849" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0024 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs72552722 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72552722;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/rs72552722?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=rs72552722" 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=rs72552722" 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=RCV000022293 OR RCV003398556" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022293, RCV003398556" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022293...</a>
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<p>In a Pakistani girl, born to first-cousin parents, with primary carnitine deficiency (CDSP; <a href="/entry/212140">212140</a>), <a href="#14" class="mim-tip-reference" title="Perrier, S., Gauquelin, L., Tetreault, M., Tran, L. T., Webb, N., Srour, M., Mitchell, J. J., Brunel-Guitton, C., Majewski, J., Long, V., Keller, S., Gambello, M. J., Simons, C., Care4Rare Canada Consortium, Vanderver, A. <strong>Recessive mutations in NDUFA2 cause mitochondrial leukoencephalopathy.</strong> Clin. Genet. 93: 396-400, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28857146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28857146</a>] [<a href="https://doi.org/10.1111/cge.13126" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28857146">Perrier et al. (2018)</a> identified a homozygous c.12C-G transversion in the SLC22A5 gene, resulting in a tyr4-to-ter (Y4X) substitution. The mutation was identified by gene sequencing. The patient also had a homozygous mutation in the NDUFA2 gene (<a href="/entry/602137#0002">602137.0002</a>) and an additional diagnosis of mitochondrial complex I deficiency nuclear type 13 (MC1DN13; <a href="/entry/618235">618235</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28857146" 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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Amat di San Filippo, C., Pasquali, M., Longo, N.
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<strong>Pharmacological rescue of carnitine transport in primary carnitine deficiency.</strong>
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Hum. Mutat. 27: 513-523, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16652335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16652335</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16652335" 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.20314" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17884651/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17884651</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17884651[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=17884651" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2007.08.002" target="_blank">Full Text</a>]
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<strong>Evidence for linkage of human primary systemic carnitine deficiency with D5S436: a novel gene locus on chromosome 5q.</strong>
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[<a href="https://doi.org/10.1086/301911" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5201756" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.273.32.20378" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1023/a:1005314910623" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/8.4.655" target="_blank">Full Text</a>]
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Tein, I., De Vivo, D. C., Bierman, F., Pulver, P., De Meirleir, L. J., Cvitanovic-Sojat, L., Pagon, R. A., Bertini, E., Dionisi-Vici, C., Servidei, S., Dimauro, S.
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[<a href="https://doi.org/10.1203/00006450-199009000-00020" target="_blank">Full Text</a>]
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<a id="Vaz1999" class="mim-anchor"></a>
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Vaz, F. M., Scholte, H. R., Ruiter, J., Hussaarts-Odijk, L. M., Rodrigues Pereira, R., Schweitzer, S., de Klerk, J. B. C., Waterham, H. R., Wanders, R. J. A.
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[<a href="https://doi.org/10.1007/s004399900105" target="_blank">Full Text</a>]
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<a id="Verbeeten2020" class="mim-anchor"></a>
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Verbeeten, K. C., Lamhonwah, A.-M., Bulman, D., Faghfoury, H., Chakraborty, P., Tein, I., Geraghty, M. T.
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[<a href="https://doi.org/10.1016/j.ymgme.2019.12.006" target="_blank">Full Text</a>]
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<a id="Wang2001" class="mim-anchor"></a>
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Wang, Y., Korman, S. H., Ye, J., Gargus, J. J., Gutman, A., Taroni, F., Garavaglia, B., Longo, N.
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[<a href="https://doi.org/10.1097/00125817-200111000-00002" target="_blank">Full Text</a>]
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Wang, Y., Taroni, F., Garavaglia, B., Longo, N.
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[<a href="https://doi.org/10.1002/1098-1004(200011)16:5<401::AID-HUMU4>3.0.CO;2-J" target="_blank">Full Text</a>]
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<a id="Wang1999" class="mim-anchor"></a>
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Wang, Y., Ye, J., Ganapathy, V., Longo, N.
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[<a href="https://doi.org/10.1073/pnas.96.5.2356" target="_blank">Full Text</a>]
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<a id="Wu1998" class="mim-anchor"></a>
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Wu, X., Prasad, P. D., Leibach, F. H., Ganapathy, V.
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<strong>cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family.</strong>
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[<a href="https://doi.org/10.1006/bbrc.1998.8669" target="_blank">Full Text</a>]
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<a id="Yamak2007" class="mim-anchor"></a>
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Yamak, A. A., Bitar, F., Karam, P., Nemer, G.
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<strong>Exclusive cardiac dysfunction in familial primary carnitine deficiency cases: a genotype-phenotype correlation.</strong>
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Clin. Genet. 72: 59-62, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17594400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17594400</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17594400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2007.00814.x" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 09/17/2020
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 05/22/2020<br>Ada Hamosh - updated : 5/27/2010<br>Cassandra L. Kniffin - updated : 5/13/2009<br>Marla J. F. O'Neill - updated : 10/17/2008<br>Patricia A. Hartz - updated : 9/11/2008<br>Marla J. F. O'Neill - updated : 11/28/2007<br>Kelly A. Przylepa - updated : 9/21/2007<br>Victor A. McKusick - updated : 4/4/2007<br>Victor A. McKusick - updated : 7/12/2006<br>Cassandra L. Kniffin - updated : 2/17/2006<br>Victor A. McKusick - updated : 4/1/2005<br>Victor A. McKusick - updated : 4/26/2004<br>Ada Hamosh - updated : 10/6/2003<br>Victor A. McKusick - updated : 9/19/2002<br>Ada Hamosh - updated : 1/9/2002<br>Victor A. McKusick - updated : 11/29/2000<br>Victor A. McKusick - updated : 10/5/1999<br>Victor A. McKusick - updated : 8/23/1999<br>Victor A. McKusick - updated : 5/14/1999<br>Victor A. McKusick - updated : 3/23/1999<br>Victor A. McKusick - updated : 2/25/1999
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 12/22/1998
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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alopez : 06/27/2022
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alopez : 03/17/2021<br>carol : 09/17/2020<br>carol : 05/22/2020<br>alopez : 09/26/2018<br>alopez : 04/29/2015<br>mcolton : 4/17/2015<br>alopez : 8/7/2012<br>carol : 5/17/2011<br>alopez : 6/2/2010<br>terry : 5/27/2010<br>terry : 5/18/2009<br>carol : 5/15/2009<br>carol : 5/14/2009<br>ckniffin : 5/13/2009<br>carol : 4/3/2009<br>carol : 10/17/2008<br>carol : 10/17/2008<br>mgross : 9/12/2008<br>terry : 9/11/2008<br>carol : 8/15/2008<br>carol : 8/15/2008<br>carol : 8/15/2008<br>wwang : 11/28/2007<br>carol : 9/21/2007<br>alopez : 4/9/2007<br>terry : 4/4/2007<br>terry : 7/12/2006<br>wwang : 2/23/2006<br>ckniffin : 2/17/2006<br>wwang : 4/14/2005<br>wwang : 4/5/2005<br>terry : 4/1/2005<br>alopez : 5/3/2004<br>alopez : 4/27/2004<br>terry : 4/26/2004<br>cwells : 11/12/2003<br>cwells : 10/6/2003<br>tkritzer : 9/19/2002<br>tkritzer : 9/19/2002<br>alopez : 1/17/2002<br>terry : 1/9/2002<br>mcapotos : 12/19/2000<br>mcapotos : 12/14/2000<br>terry : 11/29/2000<br>carol : 7/18/2000<br>alopez : 11/23/1999<br>mgross : 10/27/1999<br>terry : 10/5/1999<br>psherman : 9/30/1999<br>jlewis : 9/17/1999<br>jlewis : 9/3/1999<br>terry : 8/23/1999<br>mgross : 5/27/1999<br>mgross : 5/20/1999<br>terry : 5/14/1999<br>mgross : 4/7/1999<br>mgross : 4/6/1999<br>terry : 3/23/1999<br>carol : 3/9/1999<br>terry : 2/25/1999<br>alopez : 1/6/1999<br>alopez : 12/23/1998<br>alopez : 12/23/1998<br>alopez : 12/22/1998
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<span class="mim-font">
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<strong>*</strong> 603377
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<h3>
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SOLUTE CARRIER FAMILY 22 (ORGANIC CATION TRANSPORTER), MEMBER 5; SLC22A5
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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ORGANIC CATION TRANSPORTER 2; OCTN2
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SLC22A5</em></strong>
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<strong>SNOMEDCT:</strong> 21764004;
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<strong>ICD10CM:</strong> E71.41;
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<strong>ICD9CM:</strong> 277.81;
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<strong>
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<em>
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Cytogenetic location: 5q31.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 5:132,369,710-132,395,612 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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5q31.1
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<span class="mim-font">
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Carnitine deficiency, systemic primary
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<span class="mim-font">
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212140
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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<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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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</h4>
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<span class="mim-text-font">
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<p>Wu et al. (1998) cloned a full-length cDNA for OCTN2 (SLC22A5), a member of the organic cation transporter family, from a human placental trophoblast cell line. The OCTN2 cDNA encodes a predicted 557-amino acid protein. </p><p>Tamai et al. (1998) cloned OCTN2 from a human kidney cDNA library. The deduced protein shares 75.8% similarity with OCTN1 (604190). Northern blot analysis showed that OCTN2 is strongly expressed in kidney, skeletal muscle, heart, and placenta. </p>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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<span class="mim-text-font">
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<p>Wu et al. (1998) determined that the OCTN2 gene consists of 10 exons and spans approximately 26 kb. </p>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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<span class="mim-text-font">
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<p>Functional expression studies of OCTN2 in HEK293 cells by Tamai et al. (1998) indicated that OCTN2 is a physiologically important, high affinity carnitine transporter that shows significant sodium ion dependence. </p><p>Heintzman et al. (2007) determined the chromatin modification states in high resolution along 30 Mb of the human genome and found that active promoters are marked by trimethylation of lys4 of histone H3 (H3K4), whereas enhancers were marked by monomethylation, but not trimethylation, of H3K4. They developed computational algorithms using these distinct chromatin signatures to identify new regulatory elements, predicting over 200 promoters and 400 enhancers within the 30-Mb region. This approach accurately predicted the location and function of independently identified regulatory elements with high sensitivity and specificity and uncovered a novel functional enhancer for the carnitine transporter SLC22A5 (OCTN2). The results provided insight into the connections between chromatin modifications and transcriptional regulatory activity and provided a new tool for the functional annotation of the human genome. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Primary Systemic Carnitine Deficiency</em></strong></p><p>
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Based on the observation that OCTN2 has the ability to transport carnitine in a sodium-dependent manner, Nezu et al. (1999) searched for mutations in the gene encoding OCTN2, designated SLC22A5, both in the mouse model ('jvs') of primary systemic carnitine deficiency and in the human disorder (CDSP; 212140). In the mouse model, they found a loss-of-function missense mutation, a substitution of a hydrophilic amino acid (arg) for a hydrophobic residue (leu) in a membrane-spanning region of the OCTN2 transporter. In 3 unrelated families with systemic carnitine deficiency, they found that CDSP patients were carrying mutations in the SLC22A5 gene (603377.0001-603377.0004). </p><p>Lamhonwah and Tein (1998) studied the expression of OCTN2 in cultured fibroblasts and lymphoblasts from 2 unrelated patients in whom they had previously documented a carnitine uptake defect (Tein et al., 1990). In both patients, they found truncating mutations in the cDNA (603377.0005-603377.0007). </p><p>Wang et al. (1999) identified mutations in the OCTN2 gene in 2 unrelated patients with CDSP, 1 homozygous and the other a compound heterozygous (603377.0008-603377.0009). </p><p>Wang et al. (2000) studied 4 European families with primary carnitine deficiency and found homozygosity for novel missense mutations in 3 patients. The fourth patient was compound heterozygous for R169W (603377.0014) and W351R (603377.0015). Further studies failed to indicate a correlation between residual carnitine transport and severity of the phenotype or age at presentation, which varies from early in life with hypoketotic hypoglycemia to later in life with skeletal myopathy or cardiomyopathy. </p><p>Wang et al. (2001) reported 4 novel mutations in the SLC22A5 gene causing primary carnitine deficiency. Alleles introducing premature stop codons reduced the levels of the mRNA. </p><p>Lamhonwah et al. (2002) performed mutation screening of the OCTN2 gene in 11 individuals with CDSP by direct nucleotide sequencing of PCR products of all 10 exons. Carnitine uptake in cultured skin fibroblasts ranged from 1 to 20% of normal controls. Eleven mutations were described. No correlation between residual uptake and severity of clinical presentation was found, which suggested that the wide phenotypic variability was likely related to exogenous stressors that exacerbated carnitine deficiency. </p><p>Rahbeeni et al. (2002) reported 2 novel mutations in the OCTN2 gene from 2 Saudi patients with systemic carnitine deficiency. </p><p>Dobrowolski et al. (2005) validated the dye-binding/high-resolution thermal denaturation method for the identification of mutations in the SLC22A5 gene and expanded the mutational spectrum in primary carnitine deficiency. </p><p>Amat di San Filippo et al. (2006) found by confocal microscopy that several OCTN2 missense mutants matured normally to the plasma membrane. By contrast, other mutations caused significant retention of the mutant OCTN2 transporter in the cytoplasm. Failed maturation to the plasma membrane is a common mechanism in disorders affecting membrane transporters/ion channels, including cystic fibrosis. To correct this defect, Amat di San Filippo et al. (2006) tested whether drugs reducing the efficiency of protein degradation in the endoplasmic reticulum (phenylbutyrate, curcumin) or capable of binding the OCTN2 carnitine transporter (verapamil, quinidine) could improve carnitine transport. Prolonged incubation with phenylbutyrate, quinidine, and verapamil partially stimulated carnitine transport, while curcumin was ineffective. Thus, pharmacologic therapy can be effective in partially restoring activity of mutant transporters. </p><p>El-Hattab et al. (2010) reported 5 families in which low free carnitine levels in the infants' newborn screen led to the diagnosis of maternal systemic primary carnitine deficiency. Affected mothers were compound heterozygotes or homozygotes for missense mutations. All infants were asymptomatic at the time of diagnosis, and 1 was found to have systemic primary carnitine deficiency. Three mothers were asymptomatic, one had decreased stamina during pregnancy, and the fifth had mild fatigability and developed preeclampsia. El-Hattab et al. (2010) concluded that these findings provided further evidence that systemic primary carnitine deficiency presents with a broad clinical spectrum from a metabolic decomposition in infancy to an asymptomatic adult. </p><p><strong><em>Inflammatory Bowel Disease 5</em></strong></p><p>
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For discussion of an association between variation in the SLC22A5 gene and inflammatory bowel disease-5, see 606348.</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Shekhawat et al. (2007) found that Octn2 +/- mice were viable and fertile, but Octn2 -/- mice survived only 4 to 5 weeks without carnitine supplementation. Octn2 -/- mice developed enlarged fatty liver, steatosis of other organs, and hypertrophic cardiomyopathy. In addition, Octn2 -/- mice developed intestinal villous atrophy and intestinal breakdown and inflammation with intense lymphocyte and macrophage infiltration, leading to ulcer formation and gut perforation. Shekhawat et al. (2007) observed increased apoptosis of Octn2 -/- gut epithelial cells and upregulation of Hsf1 (140580) and several heat shock proteins (e.g., HSPA1A; 140550), which regulate OCTN2 gene expression. Intestinal and colonic epithelial cells in wildtype mice showed high expression and activity of enzymes of the beta-oxidation pathway (e.g., ADADM; 607008). Shekhawat et al. (2007) concluded that carnitine-dependent oxidation of long-chain fatty acids in mitochondria is essential for normal gut function. </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>ALLELIC VARIANTS</strong>
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</span>
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<strong>24 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</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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SLC22A5, 113-BP DEL
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<br />
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SNP: rs1554085861,
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ClinVar: RCV000022287
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 affected sibs with systemic carnitine deficiency (CDSP; 212140) in a Japanese family reported by Matsuishi et al. (1985), Nezu et al. (1999) found homozygosity for a 113-bp deletion in the SLC22A5 gene that encompassed the initiation codon in exon 1. The next available ATG in the correct frame was at codon 177, translation initiation at which would lead to loss of 2 transmembrane domains in the protein. </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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<h4>
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<span class="mim-font">
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<strong>.0002 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</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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SLC22A5, 1-BP INS, 226C
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<br />
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SNP: rs377767443,
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ClinVar: RCV000006779
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<div>
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<span class="mim-text-font">
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<p>In a patient with primary systemic carnitine deficiency (CDSP; 212140) reported by Shoji et al. (1998), Nezu et al. (1999) found compound heterozygosity for mutations in the SLC22A5 gene. One allele had a frameshift caused by a single cytosine insertion just after the start codon. The second allele had a single base substitution in codon 132 (the first codon of exon 2), which changed a tryptophan (TGG) to a stop codon (TGA) (W132X). </p>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</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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SLC22A5, TRP132TER
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<br />
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SNP: rs72552727,
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gnomAD: rs72552727,
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ClinVar: RCV000006780, RCV004589498
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</div>
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<div>
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<span class="mim-text-font">
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<p>See 603377.0002 and Nezu et al. (1999). </p><p>In a Chinese family with systemic primary carnitine deficiency (CDSP; 212140) reported by Tang et al. (1998), Tang et al. (1999) described compound heterozygosity for a truncating mutation (trp132 to ter) and a missense mutation (pro478 to leu; 603377.0011) in the SLC22A5 gene. Expression of mutant cDNAs revealed virtually no uptake activity for both mutations. The proband was the second child in the family. He was admitted with acute metabolic derangement at the age of 6 months, went into cardiac arrest, and succumbed shortly after admission. Peri-mortem serum free carnitine was very low with a normal free carnitine-to-acylcarnitine ratio. The diagnosis was established by measurement of carnitine uptake into fibroblasts, which was only 5% of normal. His elder sister had died after similar presentation. Physiologic studies in the parents indicated that both were heterozygotes for a defective carnitine transporter. </p>
|
|
</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
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|
SLC22A5, IVS8AS, G-A, -1
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|
<br />
|
|
|
|
SNP: rs386134224,
|
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|
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|
|
|
|
ClinVar: RCV000022385
|
|
|
|
|
|
</span>
|
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 5-year-old boy with systemic carnitine deficiency (CDSP; 212140), Nezu et al. (1999) found that the SLC22A5 gene carried an acceptor splice site mutation, a G-to-A transition in the last nucleotide of intron 8. The most likely consequence of this mutation, the joining of exon 8 with exon 10, was predicted to result in the creation of a premature stop codon after 2 residues. The patient had recurrent episodes of Reye syndrome, including encephalopathy, hyperammonemia, elevated liver enzymes, and liver steatosis, with hypoglycemia between ages 2 and 3 years. He had been taking carnitine orally without any recurrence of the episodes. </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>.0005 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</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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SLC22A5, 1394-BP DEL
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|
<br />
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|
|
|
ClinVar: RCV000006782
|
|
|
|
|
|
</span>
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|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 patients with carnitine uptake defect (CDSP; 212140) reported by Tein et al. (1990), Lamhonwah and Tein (1998) found compound heterozygosity for mutations in the SLC22A5 gene. Both patients showed a partial cDNA deletion of nucleotides 255-1649, resulting in a predicted truncated protein of 92 amino acids. In patient 1, the second mutant allele carried a 19-bp insertion between nucleotides 874 and 875, resulting in a frameshift and yielding a predicted truncated protein of 284 amino acids (603377.0006); in patient 2, the second mutant allele had a deletion of nucleotides 875-1046, resulting in a predicted truncated protein of 237 amino acids (603377.0008). Patient 1 was a male of Italian descent; patient 2 was a female of Mexican descent with a family history of an affected brother who had died of cardiomyopathy. Both children had early-onset myopathy, cardiomyopathy, and failure to thrive with less than 5% of control carnitine concentrations in muscle and had a dramatic improvement in growth, strength, and cardiac function following institution of high dose oral carnitine supplementation. Patient 1 had a striking decrease in renal reabsorption of carnitine (52%; normal greater than 95%) despite low serum carnitine concentrations. His muscle carnitine concentration increased to only 13% of control after carnitine supplementation; however, this was sufficient to result in a resolution of the lipid storage and a restoration of motor power. </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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|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
|
|
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC22A5, 19-BP INS, NT874
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs1554087461,
|
|
|
|
|
|
|
|
ClinVar: RCV000006783
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 19-bp insertion between nucleotides 874 and 875 in the SLC22A5 gene that was found in compound heterozygous state in a patient with carnitine uptake defect (CDSP; 212140) by Lamhonwah and Tein (1998), see 603377.0005. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
|
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC22A5, 171-BP DEL, NT875
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000006784
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 171-bp deletion of nucleotides 875-1046 in the SLC22A5 gene that was found in compound heterozygous state in a patient with carnitine uptake defect (CDSP; 212140) by Lamhonwah and Tein (1998), see 603377.0005. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC22A5, ARG282TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908886,
|
|
|
|
|
|
gnomAD: rs121908886,
|
|
|
|
|
|
ClinVar: RCV000006785, RCV000579046, RCV004754250
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with primary carnitine deficiency (CDSP; 212140), Wang et al. (1999) found homozygosity for a C-to-T transition in exon 5 of the SLC22A5 gene, converting codon 282 from CGA (arg) to TGA (stop). Both parents were heterozygous for the mutation. </p><p>Vaz et al. (1999) found the R282X mutation in homozygous state in a patient with classic manifestations of systemic carnitine deficiency. Reintroduction of wildtype OCTN2 cDNA into fibroblasts of the patient by transient transfection restored the cellular carnitine uptake, confirming that mutation in OCTN2 was the cause of the systemic carnitine deficiency. </p><p>Burwinkel et al. (1999) identified the R282X mutation in 2 German patients who had different haplotypes, suggesting that this mutation may either be recurrent or an ancient founder mutation. They also found that R282X was associated with a splicing abnormality at the intron 6/exon 7 junction. However, no mutations were present in exon 6, intron 6, or exon 7, suggesting that defective splicing of exon 7 on the R282X allele was due to an unconventional, long-distance mechanism. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC22A5, TYR401TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908887,
|
|
|
|
|
|
|
|
ClinVar: RCV000006786, RCV000790705, RCV002226442
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with primary carnitine deficiency (CDSP; 212140), Wang et al. (1999) found compound heterozygosity for a paternal allele containing a 1-bp (A) insertion in exon 7, converting codon 401 from TAT (tyr) to TAA (stop), and a maternal allele containing a 1-bp (G) deletion in exon 8 (603377.0010), causing a frameshift starting at codon 435 (gly) and resulting in a premature termination signal at codon 458. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC22A5, 1-BP DEL, 1345G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs386134217,
|
|
|
|
|
|
|
|
ClinVar: RCV000006787
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 1-bp deletion in the SLC22A5 gene that was found in compound heterozygous state in a patient with primary carnitine deficiency (CDSP; 212140) by Wang et al. (1999), see 603377.0009. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC22A5, PRO478LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs72552735,
|
|
|
|
|
|
|
|
ClinVar: RCV000006788
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the pro478-to-leu (P478L) mutation in the SLC22A5 gene that was found in compound heterozygous state in a family with systemic primary carnitine deficiency (CDSP; 212140) by Tang et al. (1999), see 603377.0003. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC22A5, TYR211CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908888,
|
|
|
|
|
|
gnomAD: rs121908888,
|
|
|
|
|
|
ClinVar: RCV000006789, RCV000186136, RCV002226443
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated patients with classic systemic carnitine deficiency (CDSP; 212140), Vaz et al. (1999) found homozygosity for the same missense mutation, 632A-G, which changes the tyrosine at amino acid position 211 into a cysteine (Y211C). The first patient had been reported by Rodrigues Pereira et al. (1988) and by Scholte et al. (1990). The second patient was admitted to hospital at 7 months of age because of failure to thrive. Physical examination showed dilated cardiomyopathy. Cardiac decompensation had existed from the age of 5 months. Treatment with digoxin and diuretics was started. At the age of 20 months, she presented with lowered consciousness, respiratory insufficiency, hypoglycemia, hyperammonemia, elevated transaminases, and low plasma carnitine concentrations. With carnitine therapy, improvement of the echocardiographic findings was noted by the age of 2 years. At the age of 5.5 years, the echocardiograph was almost normal. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC22A5, ARG169GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908889,
|
|
|
|
|
|
gnomAD: rs121908889,
|
|
|
|
|
|
ClinVar: RCV000006790, RCV000186134
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>On 1 of 4 chromosomes from 2 unrelated German patients with systemic primary carnitine deficiency (CDSP; 212140), Burwinkel et al. (1999) identified a G-to-A transition at nucleotide 506 of the SLC22A5 gene, resulting in an arg169-to-gln (R169Q) substitution. The mutation involved an arginine residue absolutely conserved in the entire transporter superfamily to which SLC22A5 belongs. On the 3 other chromosomes, they identified an arg282-to-ter mutation in exon 5 of the gene (R282X; 603377.0008). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC22A5, ARG169TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908890,
|
|
|
|
|
|
gnomAD: rs121908890,
|
|
|
|
|
|
ClinVar: RCV000006791
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Wang et al. (2000) described compound heterozygosity for arg169 to trp (R169W) and trp351 to arg (W351R; 603377.0015) in a patient with systemic primary carnitine deficiency (CDSP; 212140). The patient had presented at 5 years of age with acute metabolic decompensation. The parents were unrelated. This C-to-T transition in exon 2 occurred in a CpG region; therefore, it was not surprising that another patient had a different mutation (R169Q; 603377.0013) in the same residue. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC22A5, TRP351ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs68018207,
|
|
|
|
|
|
|
|
ClinVar: RCV000006792
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the trp351-to-arg (W351R) mutation in the SLC22A5 gene that was found in compound heterozygous state in a patient with systemic primary carnitine deficiency (CDSP; 212140) by Wang et al. (2000), see 603377.0014. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC22A5, ARG399GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908891,
|
|
|
|
|
|
gnomAD: rs121908891,
|
|
|
|
|
|
ClinVar: RCV000006793, RCV001532526, RCV002226444
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Wang et al. (2001) reported Iranian Jewish sibs with systemic primary carnitine deficiency (CDSP; 212140) who were homozygous for a G-to-A transition at nucleotide 1196 in exon 7 of the SLC22A5 gene, resulting in an arginine-to-glutamine substitution at codon 399 (R399Q). Both parents were heterozygous for this mutation. The first sib presented at 2 years of age in coma during an episode of gastroenteritis, while her older sister had weakness of the proximal limb girdle musculature requiring physical therapy, and developmental delays involving language skills, concentration, and attention span. Starting her on carnitine resulted in marked improvement of muscle tone, general mood, alertness, activity, and concentration span. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0017 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SLC22A5, -207G-C
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<br />
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SNP: rs2631367,
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gnomAD: rs2631367,
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ClinVar: RCV000023299
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>This variant, formerly titled INFLAMMATORY BOWEL DISEASE 5, ASSOCIATION WITH, has been reclassified based on the findings of Martinez et al. (2006) and Silverberg et al. (2007). </p><p>Peltekova et al. (2004) found a 2-allele haplotype enriched in individuals with Crohn disease (IBD5; 606348) involving a SNP in SLC22A4 (1672C-T; 604190.0002) and G-to-C transversion in the SLC22A5 promoter (-207G-C). The 2-allele risk haplotype was referred to as TC for the nucleotides involved in Crohn disease risk. The TC haplotype was not enriched in individuals with ulcerative colitis. </p><p>In a case-control study of 309 Spanish patients with Crohn disease and 408 controls, Martinez et al. (2006) found conflicting evidence for the role of the SLC22A4 1672C-T and the SLC22A5 -207G-C polymorphisms. Separate analysis for each variant showed no disease association, whereas a combination of the 2 variants showed a mildly increased disease risk. The authors suggested that certain haplotypes in defined populations may confer susceptibility or protection to Crohn disease. </p><p>Silverberg et al. (2007) evaluated 1,879 affected offspring and parents ascertained by a North American IBD Genetics Consortium for 6 IDB5 SNPs. The findings rejected the previously reported -207G-C SNP as the potential causative variant for Crohn disease susceptibility, although it did not compromise the observation that this SNP may alter SLC22A5 expression. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0018 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</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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SLC22A5, MET1ILE
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<br />
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SNP: rs121908892,
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gnomAD: rs121908892,
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ClinVar: RCV000006794
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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>Dobrowolski et al. (2005) demonstrated a 3G-T transversion in the SLC22A5 gene, predicted to produce a met1-to-ile substitution (M1I), as the cause of systemic primary carnitine deficiency (CDSP; 212140). The causative role of this missense mutation was confirmed by expression in Chinese hamster ovary (CHO) cells. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0019 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</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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SLC22A5, ARG254TER
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<br />
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SNP: rs121908893,
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gnomAD: rs121908893,
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ClinVar: RCV000006795, RCV000490002, RCV000506929
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 unrelated Chinese patients with systemic primary carnitine deficiency (CDSP; 212140), one of whom had previously been described by Marques (1998), Tang et al. (2002) identified homozygosity for a 981C-T transition in exon 4 of the SLC22A5 gene, resulting in an arg254-to-ter (R254X) substitution. The predicted protein has only 5 of the 12 transmembrane domains and is a loss-of-function mutant. Both patients had presented with acute heart failure and dilated cardiomyopathy. </p><p>Yamak et al. (2007) identified homozygosity for the R254X mutation in affected members of 2 Lebanese families segregating for primary systemic carnitine deficiency. Their patients shared a common haplotype with the 2 Chinese patients reported by Tang et al. (2002). </p><p>Lamhonwah et al. (2004) identified homozygosity for the R254X mutation in a Saudi Arabian girl with systemic carnitine deficiency. Laboratory studies showed impaired fatty acid oxidation and decreased carnitine uptake in skin fibroblasts (less than 1% of control values). Western blot analysis showed absence of the protein. Lamhonwah et al. (2004) stated that the substitution resulted from a 760C-T transition in exon 4. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0020 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</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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SLC22A5, ARG399TRP
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<br />
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SNP: rs267607054,
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gnomAD: rs267607054,
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ClinVar: RCV000006796, RCV000186144
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an African American family in which an infant was identified as having low carnitine in newborn screening, subsequent analysis showed that the asymptomatic mother actually had systemic carnitine deficiency (CDSP; 212140), with a free plasma carnitine level of 1 micromol/L and a total plasma carnitine of 2 micromol/L. She was found to be compound heterozygous for a C-to-T transversion at nucleotide 1195 of the SLC22A5 gene, resulting in an arg-to-trp substitution at codon 399 (R399W), and a second missense mutation (A442I; 603377.0021).</p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0021 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</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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SLC22A5, ALA442ILE
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<br />
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|
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SNP: rs267607053,
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|
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|
|
ClinVar: RCV000006797, RCV000186157, RCV004955252
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In an African American family in which an infant was identified as having low carnitine in newborn screening, subsequent analysis showed that the asymptomatic mother actually had systemic carnitine deficiency (CDSP; 212140). She was found to be compound heterozygous for a GC-to-AT substitution at nucleotides 1324/1325 of the SLC22A5 gene, resulting in an ala-to-ile substitution at codon 442 (A442I), and another missense mutation (R399W; 603377.0020).</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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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
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|
|
SLC22A5, GLY15TRP
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<br />
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|
|
SNP: rs267607052,
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|
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|
|
gnomAD: rs267607052,
|
|
|
|
|
|
ClinVar: RCV000006798, RCV000186150
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>El-Hattab et al. (2010) identified low carnitine in an Indian infant by newborn screening. Subsequent analysis revealed that his mother had primary carnitine deficiency (CDSP; 212140) with a free plasma carnitine level of 3 micromol/L and total plasma carnitine of 7 micromol/L. She was completely asymptomatic at the age of 33 years. She was homozygous for a G-to-T transversion at nucleotide 43 of the SLC22A5 gene, resulting in a gly-to-trp substitution at codon 15 (G15W). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC22A5, -149G-A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs57262206,
|
|
|
|
|
|
gnomAD: rs57262206,
|
|
|
|
|
|
ClinVar: RCV000022286, RCV001268199, RCV003407353, RCV004955257
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>After finding low carnitine in 2 sibs and their maternal first cousin by newborn screening, Verbeeten et al. (2020) found that their mothers, who were sisters, and a maternal uncle had primary carnitine deficiency (CDSP; 212140) with low plasma carnitine and increased fractional excretion of free carnitine in the urine. Next-generation sequencing identified a homozygous c.-149G-A transition (c.-149G-A, NM_003060) in the SLC22A5 gene in the 3 affected individuals and carrier status in the 3 infants. Skin fibroblast studies from the affected male showed deficient carnitine uptake at less than 6% of control values. Verbeeten et al. (2020) also found that the wife of the affected male was a carrier for the mutation and that 2 of their children were homozygous for the mutation and diagnosed with carnitine uptake deficiency. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 CARNITINE DEFICIENCY, SYSTEMIC PRIMARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC22A5, TYR4TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs72552722,
|
|
|
|
|
|
gnomAD: rs72552722,
|
|
|
|
|
|
ClinVar: RCV000022293, RCV003398556
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Pakistani girl, born to first-cousin parents, with primary carnitine deficiency (CDSP; 212140), Perrier et al. (2018) identified a homozygous c.12C-G transversion in the SLC22A5 gene, resulting in a tyr4-to-ter (Y4X) substitution. The mutation was identified by gene sequencing. The patient also had a homozygous mutation in the NDUFA2 gene (602137.0002) and an additional diagnosis of mitochondrial complex I deficiency nuclear type 13 (MC1DN13; 618235). </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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</div>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Amat di San Filippo, C., Pasquali, M., Longo, N.
|
|
<strong>Pharmacological rescue of carnitine transport in primary carnitine deficiency.</strong>
|
|
Hum. Mutat. 27: 513-523, 2006.
|
|
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|
|
[PubMed: 16652335]
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[Full Text: https://doi.org/10.1002/humu.20314]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Burwinkel, B., Kreuder, J., Schweitzer, S., Vorgerd, M., Gempel, K., Gerbitz, K.-D., Kilimann, M. W.
|
|
<strong>Carnitine transporter OCTN2 mutations in systemic primary carnitine deficiency: a novel Arg169Gln mutation and a recurrent Arg282ter mutation associated with an unconventional splicing abnormality.</strong>
|
|
Biochem. Biophys. Res. Commun. 261: 484-487, 1999.
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|
[PubMed: 10425211]
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[Full Text: https://doi.org/10.1006/bbrc.1999.1060]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Dobrowolski, S. F., McKinney, J. T., di San Filippo, C. A., Sim, K. G., Wilcken, B., Longo, N.
|
|
<strong>Validation of dye-binding/high-resolution thermal denaturation for the identification of mutations in the SLC22A5 gene.</strong>
|
|
Hum. Mutat. 25: 306-313, 2005.
|
|
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|
|
[PubMed: 15714519]
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[Full Text: https://doi.org/10.1002/humu.20137]
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</p>
|
|
</li>
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|
<li>
|
|
<p class="mim-text-font">
|
|
El-Hattab, A. W., Li, F.-Y., Shen, J., Powell, B. R., Bawle, E. V., Adams, D. J., Wahl, E., Kobori, J. A., Graham, B., Scaglia, F., Wong, L.-J.
|
|
<strong>Maternal systemic primary carnitine deficiency uncovered by newborn screening: clinical, biochemical, and molecular aspects.</strong>
|
|
Genet. Med. 12: 19-24, 2010.
|
|
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|
|
[PubMed: 20027113]
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[Full Text: https://doi.org/10.1097/GIM.0b013e3181c5e6f7]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Heintzman, H. D., Stuart, R. K., Hon, G., Fu, Y., Ching, C. W., Hawkins, R. D., Barrera, L. O., Van Calcar, S., Qu, C., Ching, K. A., Wang, W., Weng, Z., Green, R. D., Crawford, G. E., Ren, B.
|
|
<strong>Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome.</strong>
|
|
Nature Genet. 39: 311-318, 2007.
|
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|
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|
|
[PubMed: 17277777]
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|
|
[Full Text: https://doi.org/10.1038/ng1966]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Lamhonwah, A.-M., Olpin, S. E., Pollitt, R. J., Vianey-Saban, C., Divry, P., Guffon, N., Besley, G. T. N., Onizuka, R., De Meirleir, L. J., Cvitanovic-Sojat, L., Baric, I., Dionisi-Vici, C., Fumic, K., Maradin, M., Tein, I.
|
|
<strong>Novel OCTN2 mutations: no genotype-phenotype correlations: early carnitine therapy prevents cardiomyopathy.</strong>
|
|
Am. J. Med. Genet. 111: 271-284, 2002.
|
|
|
|
|
|
[PubMed: 12210323]
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|
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[Full Text: https://doi.org/10.1002/ajmg.10585]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Lamhonwah, A.-M., Onizuka, R., Olpin, S. E., Muntoni, F., Tein, I.
|
|
<strong>OCTN2 mutation (R254X) found in Saudi Arabian kindred: recurrent mutation or ancient founder mutation?</strong>
|
|
J. Inherit. Metab. Dis. 27: 473-476, 2004.
|
|
|
|
|
|
[PubMed: 15303004]
|
|
|
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|
|
[Full Text: https://doi.org/10.1023/B:BOLI.0000037339.25821.87]
|
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</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Lamhonwah, A.-M., Tein, I.
|
|
<strong>Carnitine uptake defect: frameshift mutations in the human plasmalemmal carnitine transporter gene.</strong>
|
|
Biochem. Biophys. Res. Commun. 252: 396-401, 1998.
|
|
|
|
|
|
[PubMed: 9826541]
|
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|
|
|
[Full Text: https://doi.org/10.1006/bbrc.1998.9679]
|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Marques, J. S.
|
|
<strong>Dilated cardiomyopathy caused by plasma membrane carnitine transport defect.</strong>
|
|
J. Inherit. Metab. Dis. 21: 428-429, 1998.
|
|
|
|
|
|
[PubMed: 9700603]
|
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|
|
[Full Text: https://doi.org/10.1023/a:1005371028370]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
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Hilary J. Vernon - updated : 09/17/2020<br>Hilary J. Vernon - updated : 05/22/2020<br>Ada Hamosh - updated : 5/27/2010<br>Cassandra L. Kniffin - updated : 5/13/2009<br>Marla J. F. O'Neill - updated : 10/17/2008<br>Patricia A. Hartz - updated : 9/11/2008<br>Marla J. F. O'Neill - updated : 11/28/2007<br>Kelly A. Przylepa - updated : 9/21/2007<br>Victor A. McKusick - updated : 4/4/2007<br>Victor A. McKusick - updated : 7/12/2006<br>Cassandra L. Kniffin - updated : 2/17/2006<br>Victor A. McKusick - updated : 4/1/2005<br>Victor A. McKusick - updated : 4/26/2004<br>Ada Hamosh - updated : 10/6/2003<br>Victor A. McKusick - updated : 9/19/2002<br>Ada Hamosh - updated : 1/9/2002<br>Victor A. McKusick - updated : 11/29/2000<br>Victor A. McKusick - updated : 10/5/1999<br>Victor A. McKusick - updated : 8/23/1999<br>Victor A. McKusick - updated : 5/14/1999<br>Victor A. McKusick - updated : 3/23/1999<br>Victor A. McKusick - updated : 2/25/1999
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Victor A. McKusick : 12/22/1998
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OMIM<sup>®</sup> and Online Mendelian Inheritance in Man<sup>®</sup> are registered trademarks of the Johns Hopkins University.
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