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- *300231 - SOLUTE CARRIER FAMILY 9, MEMBER 6; SLC9A6
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*300231</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</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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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/300231">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</nav>
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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=ENSG00000198689;t=ENST00000630721" 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=10479" 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=300231" 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=ENSG00000198689;t=ENST00000630721" 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_001042537,NM_001177651,NM_001330652,NM_001379110,NM_001400909,NM_001400910,NM_001400911,NM_001400912,NM_001400913,NM_006359,XM_047441765" 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_001379110" 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=300231" 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=02208&isoform_id=02208_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/SLC9A6" 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/1665827,2944233,5454070,16923281,29351609,73909067,110227626,119608887,119608888,158260573,194383078,194386274,194390866,221045898,294997330,1061899928,1823682895,2185407685,2185408353,2185408634,2185411359,2185415290,2194521878,2217390873,2450958303,2462628027" 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/Q92581" 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=10479" 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=ENSG00000198689;t=ENST00000630721" 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=SLC9A6" 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=SLC9A6" 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+10479" 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/SLC9A6" 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:10479" 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/10479" 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=chrX&hgg_gene=ENST00000630721.3&hgg_start=135973837&hgg_end=136047269&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/gene-dosage/HGNC:11079" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:11079" 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/slc9a6" 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=300231[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=300231[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/SLC9A6/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/ENSG00000198689" 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.gwascentral.org/search?q=SLC9A6" 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=SLC9A6" 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.LOVD.nl/SLC9A6" 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=SLC9A6&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/PA35935" 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:11079" 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/FBgn0028703.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:2443511" 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/SLC9A6#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:2443511" 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/10479/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=10479" 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=WBGene00003733;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-070424-104" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<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:10479" 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=SLC9A6&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 702354007<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
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300231
|
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
|
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SOLUTE CARRIER FAMILY 9, MEMBER 6; SLC9A6
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</span>
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</h3>
|
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</div>
|
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
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<p>
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<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
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</span>
|
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</p>
|
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</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
SODIUM/HYDROGEN EXCHANGER 6; NHE6
|
|
</span>
|
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</h4>
|
|
</div>
|
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</div>
|
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SLC9A6" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SLC9A6</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/X/716?start=-3&limit=10&highlight=716">Xq26.3</a>
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:135973837-136047269&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'})">X:135,973,837-136,047,269</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
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</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=300243,301142" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/X/716?start=-3&limit=10&highlight=716">
|
|
Xq26.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Intellectual developmental disorder, X-linked syndromic, Christianson type
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/300243"> 300243 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked">XL</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
</span>
|
|
</td>
|
|
|
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|
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</tr>
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|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Neurodegenerative disorder, X-linked, female-restricted, with parkinsonism and cognitive impairement
|
|
|
|
</span>
|
|
</td>
|
|
<td>
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<p>The SLC9A6 gene encodes a monovalent sodium-selective sodium/hydrogen exchanger (NHE) that is found in the membranes of intracellular organelles such as mitochondria and endosomes. NHEs participate in a wide array of essential cellular processes, including control of intracellular pH, maintenance of cellular volume, and reabsorption of sodium across renal, intestinal, and other epithelia (summary by <a href="#10" class="mim-tip-reference" title="Numata, M., Petrecca, K., Lake, N., Orlowski, J. <strong>Identification of a mitochondrial Na+/H+ exchanger.</strong> J. Biol. Chem. 273: 6951-6959, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9507001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9507001</a>] [<a href="https://doi.org/10.1074/jbc.273.12.6951" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9507001">Numata et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9507001" 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>By sequencing random cDNAs corresponding to relatively long transcripts from the human immature myeloid cell line KG-1, <a href="#8" class="mim-tip-reference" title="Nagase, T., Seki, N., Ishikawa, K., Ohira, M., Kawarabayasi, Y., Ohara, O., Tanaka, A., Kotani, H., Miyajima, N., Nomura, N. <strong>Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain.</strong> DNA Res. 3: 321-329, 1996. Note: Supplement: DNA Res. 3: 341-354, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9039502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9039502</a>] [<a href="https://doi.org/10.1093/dnares/3.5.321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9039502">Nagase et al. (1996)</a> identified a cDNA, which they called KIAA0267, that encodes SLC9A6. The cDNA represents at least 90% of the full-length SLC9A6 transcript; however, since it lacks an in-frame stop codon upstream of the first ATG, it may be missing 5-prime coding sequence. The 666-amino acid protein deduced from the SLC9A6 cDNA sequence contains predicted transmembrane domains. SLC9A6 shares 29% amino acid sequence identity with human NHE2 (SLC9A2; <a href="/entry/600530">600530</a>) across 418 amino acids. Northern blot analysis detected SLC9A6 expression in all human tissues tested, with the highest expression in brain and skeletal muscle, and lower expression in heart, lung, liver, pancreas, small intestine, colon, kidney, spleen, thymus, peripheral blood leukocytes, prostate, testis, ovary, and placenta. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9039502" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By searching sequence databases for proteins with sequence similarity to the S. cerevisiae mitochondrial sodium/hydrogen exchanger Nha2, <a href="#10" class="mim-tip-reference" title="Numata, M., Petrecca, K., Lake, N., Orlowski, J. <strong>Identification of a mitochondrial Na+/H+ exchanger.</strong> J. Biol. Chem. 273: 6951-6959, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9507001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9507001</a>] [<a href="https://doi.org/10.1074/jbc.273.12.6951" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9507001">Numata et al. (1998)</a> identified the deduced protein product of the KIAA0267 cDNA (<a href="#8" class="mim-tip-reference" title="Nagase, T., Seki, N., Ishikawa, K., Ohira, M., Kawarabayasi, Y., Ohara, O., Tanaka, A., Kotani, H., Miyajima, N., Nomura, N. <strong>Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain.</strong> DNA Res. 3: 321-329, 1996. Note: Supplement: DNA Res. 3: 341-354, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9039502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9039502</a>] [<a href="https://doi.org/10.1093/dnares/3.5.321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9039502">Nagase et al., 1996</a>), SLC9A6. The KIAA0267-encoded protein shares 30% amino acid sequence identity with S. cerevisiae Nha2, and approximately 20 to 24% identity with the mammalian NHE isoforms NHE1 to NHE5 (see SLC9A5; <a href="/entry/600477">600477</a>). <a href="#10" class="mim-tip-reference" title="Numata, M., Petrecca, K., Lake, N., Orlowski, J. <strong>Identification of a mitochondrial Na+/H+ exchanger.</strong> J. Biol. Chem. 273: 6951-6959, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9507001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9507001</a>] [<a href="https://doi.org/10.1074/jbc.273.12.6951" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9507001">Numata et al. (1998)</a>, who concluded that the KIAA0267 cDNA lacks 5-prime coding sequence, isolated a human cDNA containing the complete coding sequence of SLC9A6, which they called NHE6. The deduced 669-amino acid SLC9A6 protein has 12 putative membrane-spanning segments within the N-terminal region, and a hydrophilic C terminus, similar to the topologies predicted for other NHEs. In addition, SLC9A6 has a putative mitochondrial inner membrane targeting signal at its N terminus. Northern blot analysis detected an approximately 5.5-kb SLC9A6 transcript that was ubiquitously expressed, with the most abundant expression in mitochondrion-rich tissues such as brain, skeletal muscle, and heart. Fluorescence microscopy suggested that SLC9A6 localizes to mitochondria. <a href="#10" class="mim-tip-reference" title="Numata, M., Petrecca, K., Lake, N., Orlowski, J. <strong>Identification of a mitochondrial Na+/H+ exchanger.</strong> J. Biol. Chem. 273: 6951-6959, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9507001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9507001</a>] [<a href="https://doi.org/10.1074/jbc.273.12.6951" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9507001">Numata et al. (1998)</a> deleted the S. cerevisiae NHA2 gene by homologous disruption and found that benzamil-inhibitable, acid-activated sodium uptake into mitochondria was abolished in the mutant strain. The mutant strain also showed retarded growth on nonfermentable carbon sources and severely reduced survival during the stationary phase of the cell cycle compared with the parental strain, consistent with a defect in aerobic metabolism. The authors suggested that Nha2 and SLC9A6 are homologous sodium/hydrogen exchangers that are important for mitochondrial function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9507001+9039502" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Ohgaki, R., Matsushita, M., Kanazawa, H., Ogihara, S., Hoekstra, D., van IJzendoorn, S. C. D. <strong>The Na+/H+ exchanger NHE6 in the endosomal recycling system is involved in the development of apical bile canalicular surface domains in HepG2 cells.</strong> Molec. Biol. Cell 21: 1293-1304, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20130086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20130086</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20130086[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/10.1091/mbc.e09-09-0767" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20130086">Ohgaki et al. (2010)</a> reported that SLC9A6 is expressed as 2 splice variants, which they called NHE6.0 and NHE6.1. Western blot analysis and N-glycosidase treatment of HepG2 polarized human hepatoma cells revealed that mature NHE6 is a highly glycosylated protein with an apparent molecular mass of 86 kD; it also appeared as oligomers of over 200 kD. NHE6.1 localized to all compartments of the endosomal recycling system in HepG2 cells: early sorting endosomes, common recycling endosomes, and apical recycling endosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20130086" 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="Ouyang, Q., Lizarraga, S. B., Schmidt, M., Yang, U., Gong, J., Ellisor, D., Kauer, J. A., Morrow, E. M. <strong>Christianson syndrome protein NHE6 modulates TrkB endosomal signaling required for neuronal circuit development.</strong> Neuron 80: 97-112, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24035762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24035762</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24035762[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.neuron.2013.07.043" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24035762">Ouyang et al. (2013)</a> found that Nhe6 was expressed in the perinuclear region, as well as in axons and dendrites and their branch points, during mouse embryonic development. Nhe6 showed a similar pattern of expression in cultured hippocampal neurons, with localization in the perinuclear region, in axons and dendrites and their branch points, and within growing neurite tips. Nhe6 colocalized with markers of early, recycling, and late endosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24035762" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#8" class="mim-tip-reference" title="Nagase, T., Seki, N., Ishikawa, K., Ohira, M., Kawarabayasi, Y., Ohara, O., Tanaka, A., Kotani, H., Miyajima, N., Nomura, N. <strong>Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain.</strong> DNA Res. 3: 321-329, 1996. Note: Supplement: DNA Res. 3: 341-354, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9039502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9039502</a>] [<a href="https://doi.org/10.1093/dnares/3.5.321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9039502">Nagase et al. (1996)</a> mapped the SLC9A6 gene to chromosome X using a radiation hybrid mapping panel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9039502" 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="Gilfillan, G. D., Selmer, K. K., Roxrud, I., Smith, R., Kyllerman, M., Eiklid, K., Kroken, M., Mattingsdal, M., Egeland, T., Stenmark, H., Sjoholm, H., Server, A., and 15 others. <strong>SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome.</strong> Am. J. Hum. Genet. 82: 1003-1010, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18342287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18342287</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18342287[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.ajhg.2008.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18342287">Gilfillan et al. (2008)</a> reported that the SLC9A6 gene maps to chromosome Xq26.3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18342287" 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="#6" class="mim-tip-reference" title="Hill, J. K., Brett, C. L., Chyou, A., Kallay, L. M., Sakaguchi, M., Rao, R., Gillespie, P. G. <strong>Vestibular hair bundles control pH with (Na+, K+)/H+ exchangers NHE6 and NHE9.</strong> J. Neurosci. 26: 9944-9955, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17005858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17005858</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17005858[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/10.1523/JNEUROSCI.2990-06.2006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17005858">Hill et al. (2006)</a> demonstrated that bullfrog saccular hair bundles regulate pH independently of the cell body using a mechanism that operates in the presence of K+, and identified NHE6 and NHE9 (SLC9A9; <a href="/entry/608396">608396</a>) as strong candidates for the bundle H+ extrusion mechanism. NHE6 was identified in a subset of hair bundles, and NHE9 in all bundles. RT-PCR detected NHE6, NHE7 (SLC9A7; <a href="/entry/300368">300368</a>), NHE8 (SLC9A8; <a href="/entry/612730">612730</a>), and NHE9 in mouse brain, kidney, and inner ear. <a href="#6" class="mim-tip-reference" title="Hill, J. K., Brett, C. L., Chyou, A., Kallay, L. M., Sakaguchi, M., Rao, R., Gillespie, P. G. <strong>Vestibular hair bundles control pH with (Na+, K+)/H+ exchangers NHE6 and NHE9.</strong> J. Neurosci. 26: 9944-9955, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17005858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17005858</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17005858[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/10.1523/JNEUROSCI.2990-06.2006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17005858">Hill et al. (2006)</a> found that heterologous expression of NHE6 and NHE9 in yeast strains lacking endogenous cation/proton exchangers conferred pH-dependent tolerance to high levels of KCl and NaCl. Cation tolerance growth assays in yeast suggested that K+ and Na+ were good substrates for NHE6 and NHE9, consistent with the efficacy of these ions in promoting pH recovery in hair bundles, and that both NHE6 and NHE9 function as K+ (Na+)/H+ exchangers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17005858" 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>To identify interacting proteins that may regulate intracellular NHEs, <a href="#11" class="mim-tip-reference" title="Ohgaki, R., Fukura, N., Matsushita, M., Mitsui, K., Kanazawa, H. <strong>Cell surface levels of organellar Na+/H+ exchanger isoform 6 are regulated by interaction with RACK1.</strong> J. Biol. Chem. 283: 4417-4429, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18057008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18057008</a>] [<a href="https://doi.org/10.1074/jbc.M705146200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18057008">Ohgaki et al. (2008)</a> conducted a yeast 2-hybrid screen using the C terminus of NHE9 as bait. They detected an interaction between NHE9 and receptor for activated C kinase-1 (RACK1; <a href="/entry/176981">176981</a>), a cytoplasmic scaffold protein, and localized the NHE9 binding region to the central C terminus. Pull-down assays detected interaction of NHE6 and NHE7, but not NHE8, with RACK1. Endogenous association of RACK1 and NHE6 was confirmed by coimmunoprecipitation and colocalization in HeLa cells. The luminal pH of the recycling endosome was elevated in RACK1 knockdown cells, accompanied by a decrease in the amount of NHE6 on the cell surface, although the total level of NHE6 was not decreased. These results indicated that RACK1 plays a role in regulating the distribution of NHE6 between endosomes and the plasma membrane and contributes to maintaining luminal pH of the endocytic recycling compartment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18057008" 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 HeLa cells, <a href="#16" class="mim-tip-reference" title="Roxrud, I., Raiborg, C., Gilfillan, G. D., Stromme, P., Stenmark, H. <strong>Dual degradation mechanisms ensure disposal of NHE6 mutant protein associated with neurological disease.</strong> Exp. Cell Res. 315: 3014-3027, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19619532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19619532</a>] [<a href="https://doi.org/10.1016/j.yexcr.2009.07.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19619532">Roxrud et al. (2009)</a> found that NHE6 localized to early endosomes, recycling endosomes, and the plasma membrane. Knockdown of both NHE6 and NHE9 using siRNA resulted in more acidified early endosomes, although this did not appear to alter endosomal function. Knockdown of NHE6 alone had no detectable effect on endosomal pH. The findings suggested that these proteins release H(+) out of the endosomal lumen, thus regulating endosomal pH, and likely have redundant actions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19619532" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Ohgaki, R., Matsushita, M., Kanazawa, H., Ogihara, S., Hoekstra, D., van IJzendoorn, S. C. D. <strong>The Na+/H+ exchanger NHE6 in the endosomal recycling system is involved in the development of apical bile canalicular surface domains in HepG2 cells.</strong> Molec. Biol. Cell 21: 1293-1304, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20130086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20130086</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20130086[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/10.1091/mbc.e09-09-0767" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20130086">Ohgaki et al. (2010)</a> found that knockdown and overexpression of NHE6.1 reduced and elevated endosomal pH, respectively. Both knockdown and overexpression of NHE6.1 inhibited the maintenance, but not formation, of apical, bile canalicular plasma membranes. Knockdown of NHE6.1 did not inhibit basolateral-to-apical transcytosis of bulk membrane lipids, but permitted their progressive loss from the apical surface, leaving cells unable to efficiently retain bulk membrane and bile canalicular proteins at the apical surface. <a href="#12" class="mim-tip-reference" title="Ohgaki, R., Matsushita, M., Kanazawa, H., Ogihara, S., Hoekstra, D., van IJzendoorn, S. C. D. <strong>The Na+/H+ exchanger NHE6 in the endosomal recycling system is involved in the development of apical bile canalicular surface domains in HepG2 cells.</strong> Molec. Biol. Cell 21: 1293-1304, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20130086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20130086</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20130086[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/10.1091/mbc.e09-09-0767" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20130086">Ohgaki et al. (2010)</a> concluded that NHE6.1 secures the polarized distribution of membrane lipids at the apical surface of HepG2 cells and maintains cell polarity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20130086" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using transfected COS-7 cells, <a href="#3" class="mim-tip-reference" title="Fukura, N., Ohgaki, R., Matsushita, M., Nakamura, N., Mitsui, K., Kanazawa, H. <strong>A membrane-proximal region in the C-terminal tail of NHE7 is required for its distribution in the trans-Golgi network, distinct from NHE6 localization at endosomes.</strong> J. Membr. Biol. 234: 149-158, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20364249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20364249</a>] [<a href="https://doi.org/10.1007/s00232-010-9242-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20364249">Fukura et al. (2010)</a> independently showed that epitope-tagged human NHE6 colocalized with fluorescent-labeled transferrin (<a href="/entry/190000">190000</a>), a marker of early and recycling endosomes. NHE7 (SLC9A7; <a href="/entry/300368">300368</a>) localizes to the trans-Golgi network (TGN) and mid-trans-Golgi stacks. Using chimeric NHE6 and NHE7 constructs, they showed that 2 short sequences in the most membrane-proximal region of the C-terminal domain of NHE7 was responsible for TGN localization, whereas the membrane-proximal region of NHE6 did not contribute to endosomal localization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20364249" 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="mim-changed mim-change"><p><strong><em>X-linked Syndromic Christianson-type Intellectual Developmental Disorder</em></strong>
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<div class="mim-changed mim-change"><p>In affected males from 4 unrelated families with X-linked syndromic Christianson-type intellectual developmental disorder (MRXSCH; <a href="/entry/300243">300243</a>), <a href="#5" class="mim-tip-reference" title="Gilfillan, G. D., Selmer, K. K., Roxrud, I., Smith, R., Kyllerman, M., Eiklid, K., Kroken, M., Mattingsdal, M., Egeland, T., Stenmark, H., Sjoholm, H., Server, A., and 15 others. <strong>SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome.</strong> Am. J. Hum. Genet. 82: 1003-1010, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18342287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18342287</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18342287[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.ajhg.2008.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18342287">Gilfillan et al. (2008)</a> identified 4 different hemizygous mutations in the SLC9A6 gene (<a href="#0001">300231.0001</a>-<a href="#0004">300231.0004</a>). Variants included an in-frame deletion, a nonsense mutation, a splice site mutation, and a frameshift. The phenotype was characterized by profoundly impaired intellectual development, epilepsy, ataxia, and microcephaly, and showed phenotypic overlap with Angelman syndrome (AS; <a href="/entry/105830">105830</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18342287" 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></div>
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<p><a href="#2" class="mim-tip-reference" title="Fichou, Y., Bahi-Buisson, N., Nectoux, J., Chelly, J., Heron, D., Cuisset, L., Bienvenu, T. <strong>Mutation in the SLC9A6 gene is not a frequent cause of sporadic Angelman-like syndrome. (Letter)</strong> Europ. J. Hum. Genet. 17: 1378-1380, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19471312/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19471312</a>] [<a href="https://doi.org/10.1038/ejhg.2009.82" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19471312">Fichou et al. (2009)</a> did not find any unambiguous pathogenic mutations in the SLC9A6 gene among 59 unrelated boys with a diagnosis consistent with Angelman syndrome who did not have known molecular anomalies, suggesting that mutations in this gene are not a common cause of Angelman syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19471312" 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="#19" class="mim-tip-reference" title="Tarpey, P. S., Smith, R., Pleasance, E., Whibley, A., Edkins, S., Hardy, C., O'Meara, S., Latimer, C., Dicks, E., Menzies, A., Stephens, P., Blow, M., and 67 others. <strong>A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation.</strong> Nature Genet. 41: 535-543, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19377476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19377476</a>] [<a href="https://doi.org/10.1038/ng.367" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19377476">Tarpey et al. (2009)</a> sequenced the coding exons of the X chromosome in 208 families with X-linked intellectual developmental disorder. They identified 2 independent nonrecurring truncating mutations in SLC9A6 that segregated precisely with the phenotype. In addition to X-linked impaired intellectual development, affected individuals had epilepsy and ataxia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19377476" 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 affected members of a family with MRXSCH, <a href="#4" class="mim-tip-reference" title="Garbern, J. Y., Neumann, M., Trojanowski, J. Q., Lee, V. M.-Y., Feldman, G., Norris, J. W., Friez, M. J., Schwartz, C. E., Stevenson, R., Sima, A. A. F. <strong>A mutation affecting the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition.</strong> Brain 133: 1391-1402, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20395263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20395263</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20395263[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awq071" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20395263">Garbern et al. (2010)</a> identified a mutation in the SLC9A6 gene (<a href="#0005">300231.0005</a>). Neuropathologic findings of 2 affected adult brothers showed numerous tau (MAPT; <a href="/entry/157140">157140</a>)-positive intracellular inclusions in the glial cells throughout the white matter and strongly tau-positive tangle-like inclusions in neurons of the substantia nigra, locus ceruleus, pontine nuclei, basal ganglia, thalami, and cranial nerve nuclei. Tau-positive neurons were also found in the cerebral cortex and hippocampus. The tau proteins were predominantly of the 4R type, were insoluble, and highly phosphorylated. <a href="#4" class="mim-tip-reference" title="Garbern, J. Y., Neumann, M., Trojanowski, J. Q., Lee, V. M.-Y., Feldman, G., Norris, J. W., Friez, M. J., Schwartz, C. E., Stevenson, R., Sima, A. A. F. <strong>A mutation affecting the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition.</strong> Brain 133: 1391-1402, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20395263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20395263</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20395263[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awq071" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20395263">Garbern et al. (2010)</a> suggested that the pathogenesis of this disorder resulted from aberrant MAPT processing, suggesting a possible interaction between the SLC9A6 function and cytoskeletal elements involved in vesicular transport. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20395263" 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="mim-changed mim-change"><p>In 3 affected males of a German family (family 1) with MRXSCH, <a href="#15" class="mim-tip-reference" title="Riess, A., Rossier, E., Kruger, R., Dufke, A., Beck-Woedl, S., Horber, V., Alber, M., Glaser, D., Riess, O., Tzschach, A. <strong>Novel SLC9A6 mutations in two families with Christianson syndrome.</strong> Clin. Genet. 83: 596-597, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22931061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22931061</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2012.01948.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22931061">Riess et al. (2013)</a> identified a hemizygous frameshift mutation in the SLC9A6 gene (<a href="#0008">300231.0008</a>). The mutation was present in the unaffected mother of the proband who had random X-inactivation (54:46). The grandmother of the proband and her mother, who were thought to be obligate carriers, developed late-onset parkinsonism. The male proband of a second German family (family 2) carried a hemizygous splice site mutation in the SLC9A6 gene that was inherited from his unaffected mother, who had non-skewed X-inactivation (58:42). Functional studies of the variants were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22931061" 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></div>
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<div class="mim-changed mim-change"><p><strong><em>X-Linked Female-Restricted Neurodegenerative Disorder With Parkinsonism And Cognitive Impairment</em></strong>
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<div class="mim-changed mim-change"><p>In 3 females spanning 2 generations of a Japanese family with X-linked female-restricted neurodegenerative disorder with parkinsonism and cognitive impairment (NDPACX; <a href="/entry/301142">301142</a>), <a href="#9" class="mim-tip-reference" title="Nan, H., Kim, Y.-J., Tsuchiya, M., Ishida, A., Haro, H., Hiraide, M., Ohtsuka, T., Takiyama, Y. <strong>Novel SLC9A6 variation in female carriers with intellectual disability and atypical parkinsonism.</strong> Neurol. Genet. 8: e651, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35198730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35198730</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35198730[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/NXG.0000000000000651" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35198730">Nan et al. (2022)</a> identified a heterozygous missense mutation in the SLC9A6 gene (W89R; <a href="#0009">300231.0009</a>). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in public databases, including dbSNP, 1000 Genomes, and gnomAD. The variant was classified as likely pathogenic according to ACMG standards. Expression of the mutation in HEK293 cells showed that the mutant protein was expressed normally, but showed increased localization to the early endosome and recycling endosome compared to wildtype, suggesting that it may affect membrane trafficking processes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35198730" 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></div>
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<div class="mim-changed mim-change"><p>In a Japanese woman (P1) with onset of Parkinson disease in her mid-forties, <a href="#20" class="mim-tip-reference" title="Yamamoto, Y., Takahata, K., Seki, M., Okusa, S., Tatebe, H., Ueda, R., Endo, H., Tagai, K., Moriguchi, S., Kurose, S., Ichihashi, M., Matsuura, S., Kawamura, K., Zhang, M.-R., Ueno, Y., Takiyama, Y., Tokuda, T., Higuchi, M., Ito, D. <strong>SLC9A6-linked parkinson syndrome in female heterozygotes is associated with PET-detectable tau pathology.</strong> Neurol. Genet. 11: e200235, 2025.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/39810750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">39810750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=39810750[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/NXG.0000000000200235" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="39810750">Yamamoto et al. (2025)</a> identified a heterozygous 3-bp in-frame deletion in the SLC9A6 gene (Met453del; <a href="#0010">300231.0010</a>). Her son, who inherited it as a hemizygous mutation, had Christianson-type X-linked syndromic intellectual developmental disorder (MRXSCH; <a href="/entry/300243">300243</a>). The mutation, which was found by whole-exome sequencing, was not present in public databases, including dbSNP, ClinVar, and the Human Gene Mutation Database. Functional studies of the variant and studies of patient cells were not performed. Tau-tagged PET imaging of their patient and the 2 sisters reported by <a href="#9" class="mim-tip-reference" title="Nan, H., Kim, Y.-J., Tsuchiya, M., Ishida, A., Haro, H., Hiraide, M., Ohtsuka, T., Takiyama, Y. <strong>Novel SLC9A6 variation in female carriers with intellectual disability and atypical parkinsonism.</strong> Neurol. Genet. 8: e651, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35198730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35198730</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35198730[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/NXG.0000000000000651" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35198730">Nan et al. (2022)</a> showed evidence of focal tau accumulation primarily in the striatum. Noting that some affected females have cognitive impairment since birth, <a href="#20" class="mim-tip-reference" title="Yamamoto, Y., Takahata, K., Seki, M., Okusa, S., Tatebe, H., Ueda, R., Endo, H., Tagai, K., Moriguchi, S., Kurose, S., Ichihashi, M., Matsuura, S., Kawamura, K., Zhang, M.-R., Ueno, Y., Takiyama, Y., Tokuda, T., Higuchi, M., Ito, D. <strong>SLC9A6-linked parkinson syndrome in female heterozygotes is associated with PET-detectable tau pathology.</strong> Neurol. Genet. 11: e200235, 2025.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/39810750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">39810750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=39810750[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/NXG.0000000000200235" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="39810750">Yamamoto et al. (2025)</a> hypothesized that such a developmental defect could be a result of disrupted endosomal/lysosomal trafficking caused by SLC9A6 mutations rather than the tau pathology. Adult-onset neurodegenerative features could result from pathologic tau accumulation, which also may be a result of dysfunctional SLC9A6. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=39810750+35198730" 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></div>
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<p><a href="#13" class="mim-tip-reference" title="Ouyang, Q., Lizarraga, S. B., Schmidt, M., Yang, U., Gong, J., Ellisor, D., Kauer, J. A., Morrow, E. M. <strong>Christianson syndrome protein NHE6 modulates TrkB endosomal signaling required for neuronal circuit development.</strong> Neuron 80: 97-112, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24035762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24035762</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24035762[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.neuron.2013.07.043" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24035762">Ouyang et al. (2013)</a> found that, although Nhe6 -/- mice appeared normal, 10 to 20% died within the first month of life. Hippocampal slices of Nhe6 -/- mice showed reduced numbers of synapses and mature synaptic spines and reduced complexity of neuronal arborization. Extracellular recordings revealed reduced extracellular synaptic potential compared with wildtype. Cultured Nhe6 -/- hippocampal pyramidal neurons showed significantly reduced axon and dendrite complexity and fewer numbers of dendrites. Defects were rescued by wildtype human NHE6, but not by a cation exchange-defective mutant protein. Neuronal endosomes normally show a gradient of pH, with more proximal endosomes having low pH, and distal endosomes in axons and dendrites having a higher pH. <a href="#13" class="mim-tip-reference" title="Ouyang, Q., Lizarraga, S. B., Schmidt, M., Yang, U., Gong, J., Ellisor, D., Kauer, J. A., Morrow, E. M. <strong>Christianson syndrome protein NHE6 modulates TrkB endosomal signaling required for neuronal circuit development.</strong> Neuron 80: 97-112, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24035762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24035762</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24035762[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.neuron.2013.07.043" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24035762">Ouyang et al. (2013)</a> found that endosomes of Nhe6 -/- neurons were overacidified, with low-pH endosomes along axons and dendrites at distances about twice that of wildtype. Abnormal acidification of endosomes resulted in activation of lysosomal enzymes and degradation of endocytosed Trkb (NTRK2; <a href="/entry/600456">600456</a>), a receptor for brain-derived neurotrophic factor (BDNF; <a href="/entry/113505">113505</a>). Consequently, reduced Trkb availability impaired Bdnf signaling in Nhe6 -/- neurons. Inhibition of lysosomal enzymes prior to treatment of Nhe6 -/- cultures with Bdnf partially rescued Trkb expression. Treatment of Nhe6 -/- cultures with exogenous Bdnf rescued neuronal arborization. <a href="#13" class="mim-tip-reference" title="Ouyang, Q., Lizarraga, S. B., Schmidt, M., Yang, U., Gong, J., Ellisor, D., Kauer, J. A., Morrow, E. M. <strong>Christianson syndrome protein NHE6 modulates TrkB endosomal signaling required for neuronal circuit development.</strong> Neuron 80: 97-112, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24035762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24035762</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24035762[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.neuron.2013.07.043" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24035762">Ouyang et al. (2013)</a> concluded that NHE6 has a role in neurotrophic BDNF-TRKB signaling by supporting a leak current that causes alkalization of endosomes, resulting in uptake, but not degradation, of ligand-bound TRKB at axons and dendrites. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24035762" 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="mim-changed mim-change"><p><a href="#18" class="mim-tip-reference" title="Stromme, P., Dobrenis, K., Sillitoe, R. V., Gulinello, M., Ali, N. F., Davidson, C., Micsenyi, M. C., Stephney, G., Ellevog, L., Klungland, A., Walkley, S. U. <strong>X-linked Angelman-like syndrome caused by Slc9a6 knockout in mice exhibits evidence of endosomal-lysosomal dysfunction.</strong> Brain 134: 3369-3383, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21964919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21964919</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21964919[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awr250" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21964919">Stromme et al. (2011)</a> found that homozygous loss of Slc9a6 in female mice and hemizygous loss of Slc9A6 in male mice caused progressive accumulation of GM2 ganglioside and unesterified cholesterol in late endosome and lysosomes within neurons in selective brain regions. The amygdala was particularly affected, followed by the CA3 and CA4 regions of the hippocampus and the hypothalamus. This abnormalities were associated with little or undetectable activity of the GM2-degradative lysosomal hydrolase beta-hexosaminidase (HEXB; <a href="/entry/606873">606873</a>), indicating disturbed endosomal/lysosomal function. Cerebellar Purkinje cells showed extensive degeneration in the absence of GM2 ganglioside accumulation. Soluble brain fractions from both hemizygous male and homozygous-null female mice showed small elevations of hyperphosphorylated tau compared to controls. Mutant mice were hyperactive and showed coordination deficits. <a href="#18" class="mim-tip-reference" title="Stromme, P., Dobrenis, K., Sillitoe, R. V., Gulinello, M., Ali, N. F., Davidson, C., Micsenyi, M. C., Stephney, G., Ellevog, L., Klungland, A., Walkley, S. U. <strong>X-linked Angelman-like syndrome caused by Slc9a6 knockout in mice exhibits evidence of endosomal-lysosomal dysfunction.</strong> Brain 134: 3369-3383, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21964919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21964919</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21964919[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awr250" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21964919">Stromme et al. (2011)</a> concluded that this disorder is similar to a lysosomal storage disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21964919" 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></div>
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<p>In 3 affected males from a Norwegian family with the Christianson type of X-linked syndromic intellectual developmental disorder (MRXSCH; <a href="/entry/300243">300243</a>), <a href="#5" class="mim-tip-reference" title="Gilfillan, G. D., Selmer, K. K., Roxrud, I., Smith, R., Kyllerman, M., Eiklid, K., Kroken, M., Mattingsdal, M., Egeland, T., Stenmark, H., Sjoholm, H., Server, A., and 15 others. <strong>SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome.</strong> Am. J. Hum. Genet. 82: 1003-1010, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18342287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18342287</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18342287[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.ajhg.2008.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18342287">Gilfillan et al. (2008)</a> identified a 6-bp deletion in the SLC9A6 gene, resulting in the loss of 2 highly conserved residues from the Na+/H+ exchanger domain of the protein. Unaffected carrier females also carried the deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18342287" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The 6-bp deletion (764_769del) results in the deletion of glu255 and ser256 in a highly conserved region of transmembrane domain-7 of the SLC9A6 protein. In HeLa cells, <a href="#16" class="mim-tip-reference" title="Roxrud, I., Raiborg, C., Gilfillan, G. D., Stromme, P., Stenmark, H. <strong>Dual degradation mechanisms ensure disposal of NHE6 mutant protein associated with neurological disease.</strong> Exp. Cell Res. 315: 3014-3027, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19619532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19619532</a>] [<a href="https://doi.org/10.1016/j.yexcr.2009.07.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19619532">Roxrud et al. (2009)</a> found that the 6-bp deletion mutant protein was unstable and rapidly degraded. The mutant protein accumulated in the ER after synthesis and did not localize to recycling endosomes, as did the wildtype protein. However, some mutant protein was found in early endosomes via a dynamin (DNM1; <a href="/entry/602377">602377</a>)-dependent mechanism. Degradation of the mutant protein occurred by 2 mechanisms: the ER-associated proteosomal pathway and, for those mutant proteins that escape the ER, ubiquitination and targeting to lysosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19619532" 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 affected males from a Swedish family with the Christianson type of X-linked syndromic intellectual developmental disorder (MRXSCH; <a href="/entry/300243">300243</a>), <a href="#5" class="mim-tip-reference" title="Gilfillan, G. D., Selmer, K. K., Roxrud, I., Smith, R., Kyllerman, M., Eiklid, K., Kroken, M., Mattingsdal, M., Egeland, T., Stenmark, H., Sjoholm, H., Server, A., and 15 others. <strong>SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome.</strong> Am. J. Hum. Genet. 82: 1003-1010, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18342287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18342287</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18342287[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.ajhg.2008.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18342287">Gilfillan et al. (2008)</a> identified a C-to-T transition in the SLC9A6 gene, resulting in an arg468-to-ter (R468X) substitution predicted to remove the final transmembrane domain and C terminus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18342287" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated boys with MRXSCH, <a href="#14" class="mim-tip-reference" title="Pescosolido, M. F., Stein, D. M., Schmidt, M., El Achkar, C. M., Sabbagh, M., Rogg, J. M., Tantravahi, U., McLean, R. L., Liu, J. S., Poduri, A., Morrow, E. M. <strong>Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome.</strong> Ann. Neurol. 76: 581-593, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25044251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25044251</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25044251[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.24225" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25044251">Pescosolido et al. (2014)</a> identified heterozygosity for the same mutation in the SLC9A6 gene, which was designated a c.1498C-T transition resulting in an arg500-to-ter (R500X), based on a different transcript (ENST00000370695). Both boys inherited the mutation from their mother, and the 2 families shared a small haplotype around the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25044251" 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">rs730882187 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs730882187;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=rs730882187" 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=rs730882187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a U.K. family with the Christianson type of X-linked syndromic intellectual developmental disorder (MRXSCH; <a href="/entry/300243">300243</a>), <a href="#5" class="mim-tip-reference" title="Gilfillan, G. D., Selmer, K. K., Roxrud, I., Smith, R., Kyllerman, M., Eiklid, K., Kroken, M., Mattingsdal, M., Egeland, T., Stenmark, H., Sjoholm, H., Server, A., and 15 others. <strong>SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome.</strong> Am. J. Hum. Genet. 82: 1003-1010, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18342287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18342287</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18342287[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.ajhg.2008.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18342287">Gilfillan et al. (2008)</a> identified a splice site mutation (AA-to-CC) resulting in the skipping of exon 3 and removal of the entire predicted fourth transmembrane domain of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18342287" 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">rs730882188 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs730882188;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=rs730882188" 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=rs730882188" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of the original South African family with X-linked syndromic intellectual developmental disorder (MRXSCH; <a href="/entry/300243">300243</a>) reported by <a href="#1" class="mim-tip-reference" title="Christianson, A. L., Stevenson, R. E., van der Meyden, C. H., Pelser, J., Theron, F. W., van Rensburg, P. L., Chandler, M., Schwartz, C. E. <strong>X linked severe mental retardation, craniofacial dysmorphology, epilepsy, ophthalmoplegia, and cerebellar atrophy in a large South African kindred is localised to Xq24-q27.</strong> J. Med. Genet. 36: 759-766, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10528855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10528855</a>] [<a href="https://doi.org/10.1136/jmg.36.10.759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10528855">Christianson et al. (1999)</a>, <a href="#5" class="mim-tip-reference" title="Gilfillan, G. D., Selmer, K. K., Roxrud, I., Smith, R., Kyllerman, M., Eiklid, K., Kroken, M., Mattingsdal, M., Egeland, T., Stenmark, H., Sjoholm, H., Server, A., and 15 others. <strong>SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome.</strong> Am. J. Hum. Genet. 82: 1003-1010, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18342287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18342287</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18342287[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.ajhg.2008.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18342287">Gilfillan et al. (2008)</a> identified a 2-bp deletion in the SLC9A6 gene, predicted to result in a frameshift and premature protein truncation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18342287+10528855" 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 affected members of a family with the Christianson type of X-linked syndromic intellectual developmental disorder (MRXSCH; <a href="/entry/300243">300243</a>), <a href="#4" class="mim-tip-reference" title="Garbern, J. Y., Neumann, M., Trojanowski, J. Q., Lee, V. M.-Y., Feldman, G., Norris, J. W., Friez, M. J., Schwartz, C. E., Stevenson, R., Sima, A. A. F. <strong>A mutation affecting the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition.</strong> Brain 133: 1391-1402, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20395263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20395263</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20395263[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awq071" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20395263">Garbern et al. (2010)</a> identified a 9-bp deletion (1012_1020del) in exon 8 of the SLC9A6 gene, resulting in an in-frame deletion of 3 amino acids (338_340) in a conserved domain adjacent to a potential transmembrane domain. The phenotype included profoundly impaired intellectual development, autistic features, incontinence, and late-onset truncal ataxia. Variable features included small head, mutism, seizures, ophthalmoplegia, and hand-wringing. Dysmorphic features were not noted. Neuropathologic findings of 2 affected adult brothers showed generalized symmetric cerebral atrophy with atrophy of the white matter, and marked neuronal loss and gliosis of the globus pallidus, putamen, substantia nigra, and cerebellar cortex. There were numerous tau (MAPT; <a href="/entry/157140">157140</a>)-positive intracellular inclusions in the glial cells throughout the white matter and strongly tau-positive tangle-like inclusions in neurons of the substantia nigra, locus ceruleus, pontine nuclei, basal ganglia, thalami, and cranial nerve nuclei. Tau-positive neurons were also found in the cerebral cortex and hippocampus. The tau proteins were predominantly of the 4R type, were insoluble, and highly phosphorylated. The neuropathologic findings resembled those seen in tauopathies caused by MAPT mutations (<a href="/entry/600274">600274</a>), but no MAPT mutations were found in this family. <a href="#4" class="mim-tip-reference" title="Garbern, J. Y., Neumann, M., Trojanowski, J. Q., Lee, V. M.-Y., Feldman, G., Norris, J. W., Friez, M. J., Schwartz, C. E., Stevenson, R., Sima, A. A. F. <strong>A mutation affecting the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition.</strong> Brain 133: 1391-1402, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20395263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20395263</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20395263[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awq071" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20395263">Garbern et al. (2010)</a> suggested that the pathogenesis of this disorder resulted from aberrant MAPT processing, suggesting a possible interaction between the SLC9A6 function and cytoskeletal elements involved in vesicular transport. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20395263" 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 Dutch brothers, born of unrelated parents, with Christianson-type X-linked syndromic intellectual developmental disorder (MRXSCH; <a href="/entry/300243">300243</a>), <a href="#17" class="mim-tip-reference" title="Schuurs-Hoeijmakers, J. H. M., Vulto-van Silfhout, A. T., Vissers, L. E. L. M., van de Vondervoort, I. I. G. M., van Bon, B. W. M., de Ligt, J., Gilissen, C., Hehir-Kwa, J. Y., Neveling, K., del Rosario, M., Hira, G., Reitano, S., and 19 others. <strong>Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing.</strong> J. Med. Genet. 50: 802-811, 2013. Note: Erratum: J. Med. Genet. 55: 504 only, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24123876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24123876</a>] [<a href="https://doi.org/10.1136/jmedgenet-2013-101644" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24123876">Schuurs-Hoeijmakers et al. (2013)</a> identified a hemizygous c.1639G-T transversion in the SLC9A6 gene, resulting in a glu547-to-ter (E547X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected mother. The mutation was present in less than 1% of dbSNP (build 134) samples and in less than 1% of 672 in-house exomes. The boys had microcephaly, epilepsy, ataxic gait, and a happy personality. The family was 1 of 19 nonconsanguineous families with intellectual disability that underwent exome sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24123876" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, CHRISTIANSON TYPE</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">rs796053290 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs796053290;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=rs796053290" 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=rs796053290" 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=RCV000189417 OR RCV000224024 OR RCV000240849 OR RCV002327019" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000189417, RCV000224024, RCV000240849, RCV002327019" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000189417...</a>
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<p>In a boy and his maternal uncle with an attenuated form of Christianson-type X-linked syndromic intellectual developmental disorder (MRXSCH; <a href="/entry/300243">300243</a>), <a href="#7" class="mim-tip-reference" title="Masurel-Paulet, A., Piton, A., Chancenotte, S., Redin, C., Thauvin-Robinet, C., Henrenger, Y., Minot, D., Creppy, A., Ruffier-Bourdet, M., Thevenon, J., Kuentz, P., Lehalle, D., and 10 others. <strong>A new family with an SLC9A6 mutation expanding the phenotypic spectrum of Christianson syndrome.</strong> Am. J. Med. Genet. 170A: 2103-2110, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27256868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27256868</a>] [<a href="https://doi.org/10.1002/ajmg.a.37765" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27256868">Masurel-Paulet et al. (2016)</a> identified a hemizygous 5-bp deletion (c.526-9_526-5del) in intron 2 of the SLC9A6 gene. The mutation was found by targeted sequencing. Analysis of proband cells showed that the mutation led to the production of 4 different transcripts, with 90% of the transcripts resulting in the skipping of exon 3 and an in-frame deletion (Val177_Arg202del) in the fourth transmembrane domain that may affect protein folding within the membrane. The mutation was also found in heterozygous state in the proband's mother and his 3 sisters, all of whom had learning difficulties. <a href="#7" class="mim-tip-reference" title="Masurel-Paulet, A., Piton, A., Chancenotte, S., Redin, C., Thauvin-Robinet, C., Henrenger, Y., Minot, D., Creppy, A., Ruffier-Bourdet, M., Thevenon, J., Kuentz, P., Lehalle, D., and 10 others. <strong>A new family with an SLC9A6 mutation expanding the phenotypic spectrum of Christianson syndrome.</strong> Am. J. Med. Genet. 170A: 2103-2110, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27256868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27256868</a>] [<a href="https://doi.org/10.1002/ajmg.a.37765" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27256868">Masurel-Paulet et al. (2016)</a> postulated that the milder phenotype in this family may be explained by the residual production of about 10% of the normal transcript. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27256868" 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><div class="mim-changed mim-change">.0008 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, CHRISTIANSON TYPE</div></strong>
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<div class="mim-changed mim-change"><p>In 3 male patients (a boy and his 2 maternal uncles) from a German family (family 1) with Christianson-type X-linked syndromic intellectual developmental disorder (MRXSCH; <a href="/entry/300243">300243</a>), <a href="#15" class="mim-tip-reference" title="Riess, A., Rossier, E., Kruger, R., Dufke, A., Beck-Woedl, S., Horber, V., Alber, M., Glaser, D., Riess, O., Tzschach, A. <strong>Novel SLC9A6 mutations in two families with Christianson syndrome.</strong> Clin. Genet. 83: 596-597, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22931061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22931061</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2012.01948.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22931061">Riess et al. (2013)</a> identified a hemizygous 1-bp insertion (c.1464_1465insT, ENST00000370698) in exon 12 of the SLC9A6 gene, predicted to result in a frameshift and premature termination (Thr489TyrfsTer23). The mutation in the boy was inherited from his unaffected mother who showed non-skewed X-inactivation (54:46). Two obligate female carriers in previous generations had onset of parkinsonism at age 55 and in her seventies, respectively. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22931061" 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></div>
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<strong><div class="mim-changed mim-change">.0009 NEURODEGENERATIVE DISORDER, X-LINKED, FEMALE-RESTRICTED, WITH PARKINSONISM AND COGNITIVE IMPAIRMENT</div></strong>
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<div class="mim-changed mim-change"><p>In 3 females spanning 2 generations of a Japanese family with X-linked female-restricted neurodegenerative disorder with parkinsonism and cognitive impairment (NDPACX; <a href="/entry/301142">301142</a>), <a href="#9" class="mim-tip-reference" title="Nan, H., Kim, Y.-J., Tsuchiya, M., Ishida, A., Haro, H., Hiraide, M., Ohtsuka, T., Takiyama, Y. <strong>Novel SLC9A6 variation in female carriers with intellectual disability and atypical parkinsonism.</strong> Neurol. Genet. 8: e651, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35198730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35198730</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35198730[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/NXG.0000000000000651" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35198730">Nan et al. (2022)</a> identified a heterozygous c.265T-C transition (c.265T-C, NM_001042537) in exon 1 of the SLC9A6 gene, resulting in a trp89-to-arg (W89R) substitution at a highly conserved residue in the second transmembrane domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in public databases, including dbSNP, 1000 Genomes, and gnomAD. The variant was classified as likely pathogenic according to ACMG standards. Expression of the mutation in HEK293 cells showed that the mutant protein was expressed normally, but showed increased localization to the early endosome and recycling endosome compared to wildtype, suggesting that it may affect membrane trafficking processes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35198730" 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></div>
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<strong><div class="mim-changed mim-change">.0010 NEURODEGENERATIVE DISORDER, X-LINKED, FEMALE-RESTRICTED, WITH PARKINSONISM AND COGNITIVE IMPAIRMENT</div></strong>
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<div class="mim-changed mim-change"><p>In a Japanese woman in her mid-fifties with X-linked female-restricted neurodegenerative disorder with parkinsonism and cognitive impairment (NDPACX; <a href="/entry/301142">301142</a>), <a href="#20" class="mim-tip-reference" title="Yamamoto, Y., Takahata, K., Seki, M., Okusa, S., Tatebe, H., Ueda, R., Endo, H., Tagai, K., Moriguchi, S., Kurose, S., Ichihashi, M., Matsuura, S., Kawamura, K., Zhang, M.-R., Ueno, Y., Takiyama, Y., Tokuda, T., Higuchi, M., Ito, D. <strong>SLC9A6-linked parkinson syndrome in female heterozygotes is associated with PET-detectable tau pathology.</strong> Neurol. Genet. 11: e200235, 2025.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/39810750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">39810750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=39810750[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/NXG.0000000000200235" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="39810750">Yamamoto et al. (2025)</a> identified a heterozygous 3-bp in-frame deletion (c.1357_1359del, NM_006359) in exon 11 of the SLC9A6 gene, resulting in the deletion of conserved residue met453 (M453del). Her son, who inherited it as a hemizygous mutation, had Christianson-type X-linked syndromic intellectual developmental disorder (MRXSCH; <a href="/entry/300243">300243</a>). The mutation, which was found by whole-exome sequencing, was not present in public databases, including dbSNP, ClinVar, and the Human Gene Mutation Database. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=39810750" 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></div>
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Christianson, A. L., Stevenson, R. E., van der Meyden, C. H., Pelser, J., Theron, F. W., van Rensburg, P. L., Chandler, M., Schwartz, C. E.
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<strong>X linked severe mental retardation, craniofacial dysmorphology, epilepsy, ophthalmoplegia, and cerebellar atrophy in a large South African kindred is localised to Xq24-q27.</strong>
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J. Med. Genet. 36: 759-766, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10528855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10528855</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10528855" 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/10.1136/jmg.36.10.759" target="_blank">Full Text</a>]
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Fichou, Y., Bahi-Buisson, N., Nectoux, J., Chelly, J., Heron, D., Cuisset, L., Bienvenu, T.
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<strong>Mutation in the SLC9A6 gene is not a frequent cause of sporadic Angelman-like syndrome. (Letter)</strong>
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Europ. J. Hum. Genet. 17: 1378-1380, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19471312/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19471312</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19471312" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ejhg.2009.82" target="_blank">Full Text</a>]
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Fukura, N., Ohgaki, R., Matsushita, M., Nakamura, N., Mitsui, K., Kanazawa, H.
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<strong>A membrane-proximal region in the C-terminal tail of NHE7 is required for its distribution in the trans-Golgi network, distinct from NHE6 localization at endosomes.</strong>
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J. Membr. Biol. 234: 149-158, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20364249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20364249</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20364249" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00232-010-9242-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/brain/awq071" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2008.01.013" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1523/JNEUROSCI.2990-06.2006" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.37765" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/dnares/3.5.321" target="_blank">Full Text</a>]
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<strong>Novel SLC9A6 variation in female carriers with intellectual disability and atypical parkinsonism.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35198730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35198730</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35198730[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=35198730" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/NXG.0000000000000651" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.273.12.6951" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M705146200" target="_blank">Full Text</a>]
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<strong>The Na+/H+ exchanger NHE6 in the endosomal recycling system is involved in the development of apical bile canalicular surface domains in HepG2 cells.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20130086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20130086</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20130086[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=20130086" 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/10.1091/mbc.e09-09-0767" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.neuron.2013.07.043" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.24225" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2012.01948.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.yexcr.2009.07.012" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2013-101644" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/brain/awr250" target="_blank">Full Text</a>]
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<a id="19" class="mim-anchor"></a>
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<a id="Tarpey2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tarpey, P. S., Smith, R., Pleasance, E., Whibley, A., Edkins, S., Hardy, C., O'Meara, S., Latimer, C., Dicks, E., Menzies, A., Stephens, P., Blow, M., and 67 others.
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<strong>A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation.</strong>
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Nature Genet. 41: 535-543, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19377476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19377476</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19377476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.367" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="20" class="mim-anchor"></a>
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<a id="Yamamoto2025" class="mim-anchor"></a>
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<div class="mim-changed mim-change">
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<p class="mim-text-font">
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Yamamoto, Y., Takahata, K., Seki, M., Okusa, S., Tatebe, H., Ueda, R., Endo, H., Tagai, K., Moriguchi, S., Kurose, S., Ichihashi, M., Matsuura, S., Kawamura, K., Zhang, M.-R., Ueno, Y., Takiyama, Y., Tokuda, T., Higuchi, M., Ito, D.
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<strong>SLC9A6-linked parkinson syndrome in female heterozygotes is associated with PET-detectable tau pathology.</strong>
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Neurol. Genet. 11: e200235, 2025.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/39810750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">39810750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=39810750[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=39810750" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/NXG.0000000000200235" target="_blank">Full Text</a>]
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</ol>
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<div class="row">
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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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Cassandra L. Kniffin - updated : 03/03/2025
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</span>
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</div>
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</div>
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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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Cassandra L. Kniffin - updated : 09/07/2016<br>Cassandra L. Kniffin - updated : 2/24/2015<br>Patricia A. Hartz - updated : 9/23/2014<br>Cassandra L. Kniffin - updated : 1/6/2014<br>Cassandra L. Kniffin - updated : 4/22/2011<br>Cassandra L. Kniffin - updated : 12/10/2010<br>Patricia A. Hartz - updated : 11/12/2010<br>Anne M. Stumpf - updated : 8/31/2010<br>Ada Hamosh - updated : 10/1/2009<br>Cassandra L. Kniffin - updated : 5/5/2008
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patti M. Sherman : 3/9/2000
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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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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alopez : 03/04/2025
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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ckniffin : 03/03/2025<br>carol : 08/20/2021<br>carol : 08/19/2021<br>carol : 09/19/2018<br>carol : 09/15/2016<br>ckniffin : 09/07/2016<br>alopez : 02/29/2016<br>carol : 3/3/2015<br>mcolton : 2/25/2015<br>ckniffin : 2/24/2015<br>mgross : 10/10/2014<br>mcolton : 9/23/2014<br>carol : 1/7/2014<br>ckniffin : 1/6/2014<br>terry : 11/29/2012<br>carol : 10/26/2011<br>terry : 5/27/2011<br>wwang : 5/11/2011<br>ckniffin : 4/22/2011<br>wwang : 1/7/2011<br>ckniffin : 12/10/2010<br>wwang : 11/12/2010<br>terry : 11/12/2010<br>terry : 9/8/2010<br>alopez : 8/31/2010<br>alopez : 10/7/2009<br>terry : 10/1/2009<br>wwang : 4/21/2009<br>carol : 5/5/2008<br>ckniffin : 5/5/2008<br>alopez : 2/7/2005<br>mgross : 3/15/2000<br>mgross : 3/14/2000<br>psherman : 3/13/2000
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</span>
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<div class="container visible-print-block">
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<h3>
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<span class="mim-font">
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<strong>*</strong> 300231
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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SOLUTE CARRIER FAMILY 9, MEMBER 6; SLC9A6
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<div>
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<h4>
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<span class="mim-font">
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SODIUM/HYDROGEN EXCHANGER 6; NHE6
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</span>
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</h4>
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<br />
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SLC9A6</em></strong>
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</span>
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</p>
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</div>
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<div>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 702354007;
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<strong>
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<em>
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Cytogenetic location: Xq26.3
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Genomic coordinates <span class="small">(GRCh38)</span> : X:135,973,837-136,047,269 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="2">
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<span class="mim-font">
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Xq26.3
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<td>
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<span class="mim-font">
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Intellectual developmental disorder, X-linked syndromic, Christianson type
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</span>
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</td>
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<td>
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<span class="mim-font">
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300243
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</span>
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</td>
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<td>
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<span class="mim-font">
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X-linked
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Neurodegenerative disorder, X-linked, female-restricted, with parkinsonism and cognitive impairement
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</span>
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</td>
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<td>
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<span class="mim-font">
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301142
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</span>
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</td>
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<td>
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<span class="mim-font">
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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<br />
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The SLC9A6 gene encodes a monovalent sodium-selective sodium/hydrogen exchanger (NHE) that is found in the membranes of intracellular organelles such as mitochondria and endosomes. NHEs participate in a wide array of essential cellular processes, including control of intracellular pH, maintenance of cellular volume, and reabsorption of sodium across renal, intestinal, and other epithelia (summary by Numata et al., 1998). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By sequencing random cDNAs corresponding to relatively long transcripts from the human immature myeloid cell line KG-1, Nagase et al. (1996) identified a cDNA, which they called KIAA0267, that encodes SLC9A6. The cDNA represents at least 90% of the full-length SLC9A6 transcript; however, since it lacks an in-frame stop codon upstream of the first ATG, it may be missing 5-prime coding sequence. The 666-amino acid protein deduced from the SLC9A6 cDNA sequence contains predicted transmembrane domains. SLC9A6 shares 29% amino acid sequence identity with human NHE2 (SLC9A2; 600530) across 418 amino acids. Northern blot analysis detected SLC9A6 expression in all human tissues tested, with the highest expression in brain and skeletal muscle, and lower expression in heart, lung, liver, pancreas, small intestine, colon, kidney, spleen, thymus, peripheral blood leukocytes, prostate, testis, ovary, and placenta. </p><p>By searching sequence databases for proteins with sequence similarity to the S. cerevisiae mitochondrial sodium/hydrogen exchanger Nha2, Numata et al. (1998) identified the deduced protein product of the KIAA0267 cDNA (Nagase et al., 1996), SLC9A6. The KIAA0267-encoded protein shares 30% amino acid sequence identity with S. cerevisiae Nha2, and approximately 20 to 24% identity with the mammalian NHE isoforms NHE1 to NHE5 (see SLC9A5; 600477). Numata et al. (1998), who concluded that the KIAA0267 cDNA lacks 5-prime coding sequence, isolated a human cDNA containing the complete coding sequence of SLC9A6, which they called NHE6. The deduced 669-amino acid SLC9A6 protein has 12 putative membrane-spanning segments within the N-terminal region, and a hydrophilic C terminus, similar to the topologies predicted for other NHEs. In addition, SLC9A6 has a putative mitochondrial inner membrane targeting signal at its N terminus. Northern blot analysis detected an approximately 5.5-kb SLC9A6 transcript that was ubiquitously expressed, with the most abundant expression in mitochondrion-rich tissues such as brain, skeletal muscle, and heart. Fluorescence microscopy suggested that SLC9A6 localizes to mitochondria. Numata et al. (1998) deleted the S. cerevisiae NHA2 gene by homologous disruption and found that benzamil-inhibitable, acid-activated sodium uptake into mitochondria was abolished in the mutant strain. The mutant strain also showed retarded growth on nonfermentable carbon sources and severely reduced survival during the stationary phase of the cell cycle compared with the parental strain, consistent with a defect in aerobic metabolism. The authors suggested that Nha2 and SLC9A6 are homologous sodium/hydrogen exchangers that are important for mitochondrial function. </p><p>Ohgaki et al. (2010) reported that SLC9A6 is expressed as 2 splice variants, which they called NHE6.0 and NHE6.1. Western blot analysis and N-glycosidase treatment of HepG2 polarized human hepatoma cells revealed that mature NHE6 is a highly glycosylated protein with an apparent molecular mass of 86 kD; it also appeared as oligomers of over 200 kD. NHE6.1 localized to all compartments of the endosomal recycling system in HepG2 cells: early sorting endosomes, common recycling endosomes, and apical recycling endosomes. </p><p>Ouyang et al. (2013) found that Nhe6 was expressed in the perinuclear region, as well as in axons and dendrites and their branch points, during mouse embryonic development. Nhe6 showed a similar pattern of expression in cultured hippocampal neurons, with localization in the perinuclear region, in axons and dendrites and their branch points, and within growing neurite tips. Nhe6 colocalized with markers of early, recycling, and late endosomes. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Mapping</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Nagase et al. (1996) mapped the SLC9A6 gene to chromosome X using a radiation hybrid mapping panel. </p><p>Gilfillan et al. (2008) reported that the SLC9A6 gene maps to chromosome Xq26.3. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Hill et al. (2006) demonstrated that bullfrog saccular hair bundles regulate pH independently of the cell body using a mechanism that operates in the presence of K+, and identified NHE6 and NHE9 (SLC9A9; 608396) as strong candidates for the bundle H+ extrusion mechanism. NHE6 was identified in a subset of hair bundles, and NHE9 in all bundles. RT-PCR detected NHE6, NHE7 (SLC9A7; 300368), NHE8 (SLC9A8; 612730), and NHE9 in mouse brain, kidney, and inner ear. Hill et al. (2006) found that heterologous expression of NHE6 and NHE9 in yeast strains lacking endogenous cation/proton exchangers conferred pH-dependent tolerance to high levels of KCl and NaCl. Cation tolerance growth assays in yeast suggested that K+ and Na+ were good substrates for NHE6 and NHE9, consistent with the efficacy of these ions in promoting pH recovery in hair bundles, and that both NHE6 and NHE9 function as K+ (Na+)/H+ exchangers. </p><p>To identify interacting proteins that may regulate intracellular NHEs, Ohgaki et al. (2008) conducted a yeast 2-hybrid screen using the C terminus of NHE9 as bait. They detected an interaction between NHE9 and receptor for activated C kinase-1 (RACK1; 176981), a cytoplasmic scaffold protein, and localized the NHE9 binding region to the central C terminus. Pull-down assays detected interaction of NHE6 and NHE7, but not NHE8, with RACK1. Endogenous association of RACK1 and NHE6 was confirmed by coimmunoprecipitation and colocalization in HeLa cells. The luminal pH of the recycling endosome was elevated in RACK1 knockdown cells, accompanied by a decrease in the amount of NHE6 on the cell surface, although the total level of NHE6 was not decreased. These results indicated that RACK1 plays a role in regulating the distribution of NHE6 between endosomes and the plasma membrane and contributes to maintaining luminal pH of the endocytic recycling compartment. </p><p>In HeLa cells, Roxrud et al. (2009) found that NHE6 localized to early endosomes, recycling endosomes, and the plasma membrane. Knockdown of both NHE6 and NHE9 using siRNA resulted in more acidified early endosomes, although this did not appear to alter endosomal function. Knockdown of NHE6 alone had no detectable effect on endosomal pH. The findings suggested that these proteins release H(+) out of the endosomal lumen, thus regulating endosomal pH, and likely have redundant actions. </p><p>Ohgaki et al. (2010) found that knockdown and overexpression of NHE6.1 reduced and elevated endosomal pH, respectively. Both knockdown and overexpression of NHE6.1 inhibited the maintenance, but not formation, of apical, bile canalicular plasma membranes. Knockdown of NHE6.1 did not inhibit basolateral-to-apical transcytosis of bulk membrane lipids, but permitted their progressive loss from the apical surface, leaving cells unable to efficiently retain bulk membrane and bile canalicular proteins at the apical surface. Ohgaki et al. (2010) concluded that NHE6.1 secures the polarized distribution of membrane lipids at the apical surface of HepG2 cells and maintains cell polarity. </p><p>Using transfected COS-7 cells, Fukura et al. (2010) independently showed that epitope-tagged human NHE6 colocalized with fluorescent-labeled transferrin (190000), a marker of early and recycling endosomes. NHE7 (SLC9A7; 300368) localizes to the trans-Golgi network (TGN) and mid-trans-Golgi stacks. Using chimeric NHE6 and NHE7 constructs, they showed that 2 short sequences in the most membrane-proximal region of the C-terminal domain of NHE7 was responsible for TGN localization, whereas the membrane-proximal region of NHE6 did not contribute to endosomal localization. </p>
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</span>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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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>X-linked Syndromic Christianson-type Intellectual Developmental Disorder</em></strong></p><p>
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In affected males from 4 unrelated families with X-linked syndromic Christianson-type intellectual developmental disorder (MRXSCH; 300243), Gilfillan et al. (2008) identified 4 different hemizygous mutations in the SLC9A6 gene (300231.0001-300231.0004). Variants included an in-frame deletion, a nonsense mutation, a splice site mutation, and a frameshift. The phenotype was characterized by profoundly impaired intellectual development, epilepsy, ataxia, and microcephaly, and showed phenotypic overlap with Angelman syndrome (AS; 105830). </p><p>Fichou et al. (2009) did not find any unambiguous pathogenic mutations in the SLC9A6 gene among 59 unrelated boys with a diagnosis consistent with Angelman syndrome who did not have known molecular anomalies, suggesting that mutations in this gene are not a common cause of Angelman syndrome. </p><p>Tarpey et al. (2009) sequenced the coding exons of the X chromosome in 208 families with X-linked intellectual developmental disorder. They identified 2 independent nonrecurring truncating mutations in SLC9A6 that segregated precisely with the phenotype. In addition to X-linked impaired intellectual development, affected individuals had epilepsy and ataxia. </p><p>In affected members of a family with MRXSCH, Garbern et al. (2010) identified a mutation in the SLC9A6 gene (300231.0005). Neuropathologic findings of 2 affected adult brothers showed numerous tau (MAPT; 157140)-positive intracellular inclusions in the glial cells throughout the white matter and strongly tau-positive tangle-like inclusions in neurons of the substantia nigra, locus ceruleus, pontine nuclei, basal ganglia, thalami, and cranial nerve nuclei. Tau-positive neurons were also found in the cerebral cortex and hippocampus. The tau proteins were predominantly of the 4R type, were insoluble, and highly phosphorylated. Garbern et al. (2010) suggested that the pathogenesis of this disorder resulted from aberrant MAPT processing, suggesting a possible interaction between the SLC9A6 function and cytoskeletal elements involved in vesicular transport. </p><p>In 3 affected males of a German family (family 1) with MRXSCH, Riess et al. (2013) identified a hemizygous frameshift mutation in the SLC9A6 gene (300231.0008). The mutation was present in the unaffected mother of the proband who had random X-inactivation (54:46). The grandmother of the proband and her mother, who were thought to be obligate carriers, developed late-onset parkinsonism. The male proband of a second German family (family 2) carried a hemizygous splice site mutation in the SLC9A6 gene that was inherited from his unaffected mother, who had non-skewed X-inactivation (58:42). Functional studies of the variants were not performed. </p><p><strong><em>X-Linked Female-Restricted Neurodegenerative Disorder With Parkinsonism And Cognitive Impairment</em></strong></p><p>
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In 3 females spanning 2 generations of a Japanese family with X-linked female-restricted neurodegenerative disorder with parkinsonism and cognitive impairment (NDPACX; 301142), Nan et al. (2022) identified a heterozygous missense mutation in the SLC9A6 gene (W89R; 300231.0009). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in public databases, including dbSNP, 1000 Genomes, and gnomAD. The variant was classified as likely pathogenic according to ACMG standards. Expression of the mutation in HEK293 cells showed that the mutant protein was expressed normally, but showed increased localization to the early endosome and recycling endosome compared to wildtype, suggesting that it may affect membrane trafficking processes. </p><p>In a Japanese woman (P1) with onset of Parkinson disease in her mid-forties, Yamamoto et al. (2025) identified a heterozygous 3-bp in-frame deletion in the SLC9A6 gene (Met453del; 300231.0010). Her son, who inherited it as a hemizygous mutation, had Christianson-type X-linked syndromic intellectual developmental disorder (MRXSCH; 300243). The mutation, which was found by whole-exome sequencing, was not present in public databases, including dbSNP, ClinVar, and the Human Gene Mutation Database. Functional studies of the variant and studies of patient cells were not performed. Tau-tagged PET imaging of their patient and the 2 sisters reported by Nan et al. (2022) showed evidence of focal tau accumulation primarily in the striatum. Noting that some affected females have cognitive impairment since birth, Yamamoto et al. (2025) hypothesized that such a developmental defect could be a result of disrupted endosomal/lysosomal trafficking caused by SLC9A6 mutations rather than the tau pathology. Adult-onset neurodegenerative features could result from pathologic tau accumulation, which also may be a result of dysfunctional SLC9A6. </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>Ouyang et al. (2013) found that, although Nhe6 -/- mice appeared normal, 10 to 20% died within the first month of life. Hippocampal slices of Nhe6 -/- mice showed reduced numbers of synapses and mature synaptic spines and reduced complexity of neuronal arborization. Extracellular recordings revealed reduced extracellular synaptic potential compared with wildtype. Cultured Nhe6 -/- hippocampal pyramidal neurons showed significantly reduced axon and dendrite complexity and fewer numbers of dendrites. Defects were rescued by wildtype human NHE6, but not by a cation exchange-defective mutant protein. Neuronal endosomes normally show a gradient of pH, with more proximal endosomes having low pH, and distal endosomes in axons and dendrites having a higher pH. Ouyang et al. (2013) found that endosomes of Nhe6 -/- neurons were overacidified, with low-pH endosomes along axons and dendrites at distances about twice that of wildtype. Abnormal acidification of endosomes resulted in activation of lysosomal enzymes and degradation of endocytosed Trkb (NTRK2; 600456), a receptor for brain-derived neurotrophic factor (BDNF; 113505). Consequently, reduced Trkb availability impaired Bdnf signaling in Nhe6 -/- neurons. Inhibition of lysosomal enzymes prior to treatment of Nhe6 -/- cultures with Bdnf partially rescued Trkb expression. Treatment of Nhe6 -/- cultures with exogenous Bdnf rescued neuronal arborization. Ouyang et al. (2013) concluded that NHE6 has a role in neurotrophic BDNF-TRKB signaling by supporting a leak current that causes alkalization of endosomes, resulting in uptake, but not degradation, of ligand-bound TRKB at axons and dendrites. </p><p>Stromme et al. (2011) found that homozygous loss of Slc9a6 in female mice and hemizygous loss of Slc9A6 in male mice caused progressive accumulation of GM2 ganglioside and unesterified cholesterol in late endosome and lysosomes within neurons in selective brain regions. The amygdala was particularly affected, followed by the CA3 and CA4 regions of the hippocampus and the hypothalamus. This abnormalities were associated with little or undetectable activity of the GM2-degradative lysosomal hydrolase beta-hexosaminidase (HEXB; 606873), indicating disturbed endosomal/lysosomal function. Cerebellar Purkinje cells showed extensive degeneration in the absence of GM2 ganglioside accumulation. Soluble brain fractions from both hemizygous male and homozygous-null female mice showed small elevations of hyperphosphorylated tau compared to controls. Mutant mice were hyperactive and showed coordination deficits. Stromme et al. (2011) concluded that this disorder is similar to a lysosomal storage disease. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>10 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, CHRISTIANSON TYPE</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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SLC9A6, 6-BP DEL, NT764
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<br />
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SNP: rs886037619,
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ClinVar: RCV000012231
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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 3 affected males from a Norwegian family with the Christianson type of X-linked syndromic intellectual developmental disorder (MRXSCH; 300243), Gilfillan et al. (2008) identified a 6-bp deletion in the SLC9A6 gene, resulting in the loss of 2 highly conserved residues from the Na+/H+ exchanger domain of the protein. Unaffected carrier females also carried the deletion. </p><p>The 6-bp deletion (764_769del) results in the deletion of glu255 and ser256 in a highly conserved region of transmembrane domain-7 of the SLC9A6 protein. In HeLa cells, Roxrud et al. (2009) found that the 6-bp deletion mutant protein was unstable and rapidly degraded. The mutant protein accumulated in the ER after synthesis and did not localize to recycling endosomes, as did the wildtype protein. However, some mutant protein was found in early endosomes via a dynamin (DNM1; 602377)-dependent mechanism. Degradation of the mutant protein occurred by 2 mechanisms: the ER-associated proteosomal pathway and, for those mutant proteins that escape the ER, ubiquitination and targeting to lysosomes. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, CHRISTIANSON TYPE</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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SLC9A6, ARG468TER
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<br />
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SNP: rs122461162,
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ClinVar: RCV000012232, RCV000627211
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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 affected males from a Swedish family with the Christianson type of X-linked syndromic intellectual developmental disorder (MRXSCH; 300243), Gilfillan et al. (2008) identified a C-to-T transition in the SLC9A6 gene, resulting in an arg468-to-ter (R468X) substitution predicted to remove the final transmembrane domain and C terminus. </p><p>In 2 unrelated boys with MRXSCH, Pescosolido et al. (2014) identified heterozygosity for the same mutation in the SLC9A6 gene, which was designated a c.1498C-T transition resulting in an arg500-to-ter (R500X), based on a different transcript (ENST00000370695). Both boys inherited the mutation from their mother, and the 2 families shared a small haplotype around the mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, CHRISTIANSON TYPE</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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SLC9A6, IVS3, AA-CC
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<br />
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SNP: rs730882187,
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ClinVar: RCV000012233
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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 affected members of a U.K. family with the Christianson type of X-linked syndromic intellectual developmental disorder (MRXSCH; 300243), Gilfillan et al. (2008) identified a splice site mutation (AA-to-CC) resulting in the skipping of exon 3 and removal of the entire predicted fourth transmembrane domain of 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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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0004 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, CHRISTIANSON TYPE</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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SLC9A6, 2-BP DEL
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<br />
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SNP: rs730882188,
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ClinVar: RCV000012234
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In affected members of the original South African family with X-linked syndromic intellectual developmental disorder (MRXSCH; 300243) reported by Christianson et al. (1999), Gilfillan et al. (2008) identified a 2-bp deletion in the SLC9A6 gene, predicted to result in a frameshift and premature protein truncation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0005 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, CHRISTIANSON TYPE</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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SLC9A6, 9-BP DEL, NT1012
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<br />
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SNP: rs398122849,
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ClinVar: RCV000022841
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In affected members of a family with the Christianson type of X-linked syndromic intellectual developmental disorder (MRXSCH; 300243), Garbern et al. (2010) identified a 9-bp deletion (1012_1020del) in exon 8 of the SLC9A6 gene, resulting in an in-frame deletion of 3 amino acids (338_340) in a conserved domain adjacent to a potential transmembrane domain. The phenotype included profoundly impaired intellectual development, autistic features, incontinence, and late-onset truncal ataxia. Variable features included small head, mutism, seizures, ophthalmoplegia, and hand-wringing. Dysmorphic features were not noted. Neuropathologic findings of 2 affected adult brothers showed generalized symmetric cerebral atrophy with atrophy of the white matter, and marked neuronal loss and gliosis of the globus pallidus, putamen, substantia nigra, and cerebellar cortex. There were numerous tau (MAPT; 157140)-positive intracellular inclusions in the glial cells throughout the white matter and strongly tau-positive tangle-like inclusions in neurons of the substantia nigra, locus ceruleus, pontine nuclei, basal ganglia, thalami, and cranial nerve nuclei. Tau-positive neurons were also found in the cerebral cortex and hippocampus. The tau proteins were predominantly of the 4R type, were insoluble, and highly phosphorylated. The neuropathologic findings resembled those seen in tauopathies caused by MAPT mutations (600274), but no MAPT mutations were found in this family. Garbern et al. (2010) suggested that the pathogenesis of this disorder resulted from aberrant MAPT processing, suggesting a possible interaction between the SLC9A6 function and cytoskeletal elements involved in vesicular transport. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0006 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, CHRISTIANSON TYPE</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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SLC9A6, GLU547TER
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<br />
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SNP: rs398123003,
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ClinVar: RCV000077787
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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 Dutch brothers, born of unrelated parents, with Christianson-type X-linked syndromic intellectual developmental disorder (MRXSCH; 300243), Schuurs-Hoeijmakers et al. (2013) identified a hemizygous c.1639G-T transversion in the SLC9A6 gene, resulting in a glu547-to-ter (E547X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected mother. The mutation was present in less than 1% of dbSNP (build 134) samples and in less than 1% of 672 in-house exomes. The boys had microcephaly, epilepsy, ataxic gait, and a happy personality. The family was 1 of 19 nonconsanguineous families with intellectual disability that underwent exome sequencing. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0007 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, CHRISTIANSON TYPE</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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SLC9A6, 5-BP DEL, IVS2AS
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<br />
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SNP: rs796053290,
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ClinVar: RCV000189417, RCV000224024, RCV000240849, RCV002327019
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In a boy and his maternal uncle with an attenuated form of Christianson-type X-linked syndromic intellectual developmental disorder (MRXSCH; 300243), Masurel-Paulet et al. (2016) identified a hemizygous 5-bp deletion (c.526-9_526-5del) in intron 2 of the SLC9A6 gene. The mutation was found by targeted sequencing. Analysis of proband cells showed that the mutation led to the production of 4 different transcripts, with 90% of the transcripts resulting in the skipping of exon 3 and an in-frame deletion (Val177_Arg202del) in the fourth transmembrane domain that may affect protein folding within the membrane. The mutation was also found in heterozygous state in the proband's mother and his 3 sisters, all of whom had learning difficulties. Masurel-Paulet et al. (2016) postulated that the milder phenotype in this family may be explained by the residual production of about 10% of the normal transcript. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0008 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, CHRISTIANSON TYPE</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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SLC9A6, 1-BP INS, NT1464
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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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<div class="mim-changed mim-change"><p>In 3 male patients (a boy and his 2 maternal uncles) from a German family (family 1) with Christianson-type X-linked syndromic intellectual developmental disorder (MRXSCH; 300243), Riess et al. (2013) identified a hemizygous 1-bp insertion (c.1464_1465insT, ENST00000370698) in exon 12 of the SLC9A6 gene, predicted to result in a frameshift and premature termination (Thr489TyrfsTer23). The mutation in the boy was inherited from his unaffected mother who showed non-skewed X-inactivation (54:46). Two obligate female carriers in previous generations had onset of parkinsonism at age 55 and in her seventies, respectively. Functional studies of the variant were not performed. </p></div>
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</span>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0009 NEURODEGENERATIVE DISORDER, X-LINKED, FEMALE-RESTRICTED, WITH PARKINSONISM AND COGNITIVE IMPAIRMENT</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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SLC9A6, TRP89ARG
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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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<div class="mim-changed mim-change"><p>In 3 females spanning 2 generations of a Japanese family with X-linked female-restricted neurodegenerative disorder with parkinsonism and cognitive impairment (NDPACX; 301142), Nan et al. (2022) identified a heterozygous c.265T-C transition (c.265T-C, NM_001042537) in exon 1 of the SLC9A6 gene, resulting in a trp89-to-arg (W89R) substitution at a highly conserved residue in the second transmembrane domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in public databases, including dbSNP, 1000 Genomes, and gnomAD. The variant was classified as likely pathogenic according to ACMG standards. Expression of the mutation in HEK293 cells showed that the mutant protein was expressed normally, but showed increased localization to the early endosome and recycling endosome compared to wildtype, suggesting that it may affect membrane trafficking processes. </p></div>
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</span>
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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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<h4>
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<span class="mim-font">
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<strong>.0010 NEURODEGENERATIVE DISORDER, X-LINKED, FEMALE-RESTRICTED, WITH PARKINSONISM AND COGNITIVE IMPAIRMENT</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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INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, CHRISTIANSON TYPE, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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SLC9A6, 3-BP DEL, NT1357
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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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<div class="mim-changed mim-change"><p>In a Japanese woman in her mid-fifties with X-linked female-restricted neurodegenerative disorder with parkinsonism and cognitive impairment (NDPACX; 301142), Yamamoto et al. (2025) identified a heterozygous 3-bp in-frame deletion (c.1357_1359del, NM_006359) in exon 11 of the SLC9A6 gene, resulting in the deletion of conserved residue met453 (M453del). Her son, who inherited it as a hemizygous mutation, had Christianson-type X-linked syndromic intellectual developmental disorder (MRXSCH; 300243). The mutation, which was found by whole-exome sequencing, was not present in public databases, including dbSNP, ClinVar, and the Human Gene Mutation Database. Functional studies of the variant and studies of patient cells were not performed. </p></div>
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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>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Christianson, A. L., Stevenson, R. E., van der Meyden, C. H., Pelser, J., Theron, F. W., van Rensburg, P. L., Chandler, M., Schwartz, C. E.
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<strong>X linked severe mental retardation, craniofacial dysmorphology, epilepsy, ophthalmoplegia, and cerebellar atrophy in a large South African kindred is localised to Xq24-q27.</strong>
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J. Med. Genet. 36: 759-766, 1999.
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[PubMed: 10528855]
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[Full Text: https://doi.org/10.1136/jmg.36.10.759]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Fichou, Y., Bahi-Buisson, N., Nectoux, J., Chelly, J., Heron, D., Cuisset, L., Bienvenu, T.
|
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<strong>Mutation in the SLC9A6 gene is not a frequent cause of sporadic Angelman-like syndrome. (Letter)</strong>
|
|
Europ. J. Hum. Genet. 17: 1378-1380, 2009.
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[PubMed: 19471312]
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<p class="mim-text-font">
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Fukura, N., Ohgaki, R., Matsushita, M., Nakamura, N., Mitsui, K., Kanazawa, H.
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<strong>A membrane-proximal region in the C-terminal tail of NHE7 is required for its distribution in the trans-Golgi network, distinct from NHE6 localization at endosomes.</strong>
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J. Membr. Biol. 234: 149-158, 2010.
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<li>
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<p class="mim-text-font">
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Garbern, J. Y., Neumann, M., Trojanowski, J. Q., Lee, V. M.-Y., Feldman, G., Norris, J. W., Friez, M. J., Schwartz, C. E., Stevenson, R., Sima, A. A. F.
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<strong>A mutation affecting the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition.</strong>
|
|
Brain 133: 1391-1402, 2010.
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[PubMed: 20395263]
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[Full Text: https://doi.org/10.1093/brain/awq071]
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</p>
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<li>
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<p class="mim-text-font">
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Gilfillan, G. D., Selmer, K. K., Roxrud, I., Smith, R., Kyllerman, M., Eiklid, K., Kroken, M., Mattingsdal, M., Egeland, T., Stenmark, H., Sjoholm, H., Server, A., and 15 others.
|
|
<strong>SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome.</strong>
|
|
Am. J. Hum. Genet. 82: 1003-1010, 2008.
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[PubMed: 18342287]
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[Full Text: https://doi.org/10.1016/j.ajhg.2008.01.013]
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<p class="mim-text-font">
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Hill, J. K., Brett, C. L., Chyou, A., Kallay, L. M., Sakaguchi, M., Rao, R., Gillespie, P. G.
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<strong>Vestibular hair bundles control pH with (Na+, K+)/H+ exchangers NHE6 and NHE9.</strong>
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J. Neurosci. 26: 9944-9955, 2006.
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[PubMed: 17005858]
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[Full Text: https://doi.org/10.1523/JNEUROSCI.2990-06.2006]
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<p class="mim-text-font">
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Masurel-Paulet, A., Piton, A., Chancenotte, S., Redin, C., Thauvin-Robinet, C., Henrenger, Y., Minot, D., Creppy, A., Ruffier-Bourdet, M., Thevenon, J., Kuentz, P., Lehalle, D., and 10 others.
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|
<strong>A new family with an SLC9A6 mutation expanding the phenotypic spectrum of Christianson syndrome.</strong>
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Am. J. Med. Genet. 170A: 2103-2110, 2016.
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[PubMed: 27256868]
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[Full Text: https://doi.org/10.1002/ajmg.a.37765]
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</p>
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<li>
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<p class="mim-text-font">
|
|
Nagase, T., Seki, N., Ishikawa, K., Ohira, M., Kawarabayasi, Y., Ohara, O., Tanaka, A., Kotani, H., Miyajima, N., Nomura, N.
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<strong>Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain.</strong>
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DNA Res. 3: 321-329, 1996. Note: Supplement: DNA Res. 3: 341-354, 1996.
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[PubMed: 9039502]
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[Full Text: https://doi.org/10.1093/dnares/3.5.321]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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|
Nan, H., Kim, Y.-J., Tsuchiya, M., Ishida, A., Haro, H., Hiraide, M., Ohtsuka, T., Takiyama, Y.
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<strong>Novel SLC9A6 variation in female carriers with intellectual disability and atypical parkinsonism.</strong>
|
|
Neurol. Genet. 8: e651, 2022.
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[PubMed: 35198730]
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[Full Text: https://doi.org/10.1212/NXG.0000000000000651]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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|
Numata, M., Petrecca, K., Lake, N., Orlowski, J.
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<strong>Identification of a mitochondrial Na+/H+ exchanger.</strong>
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J. Biol. Chem. 273: 6951-6959, 1998.
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[PubMed: 9507001]
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[Full Text: https://doi.org/10.1074/jbc.273.12.6951]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Ohgaki, R., Fukura, N., Matsushita, M., Mitsui, K., Kanazawa, H.
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<strong>Cell surface levels of organellar Na+/H+ exchanger isoform 6 are regulated by interaction with RACK1.</strong>
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J. Biol. Chem. 283: 4417-4429, 2008.
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[PubMed: 18057008]
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[Full Text: https://doi.org/10.1074/jbc.M705146200]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Ohgaki, R., Matsushita, M., Kanazawa, H., Ogihara, S., Hoekstra, D., van IJzendoorn, S. C. D.
|
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<strong>The Na+/H+ exchanger NHE6 in the endosomal recycling system is involved in the development of apical bile canalicular surface domains in HepG2 cells.</strong>
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Molec. Biol. Cell 21: 1293-1304, 2010.
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[PubMed: 20130086]
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[Full Text: https://doi.org/10.1091/mbc.e09-09-0767]
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</p>
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<li>
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<p class="mim-text-font">
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Ouyang, Q., Lizarraga, S. B., Schmidt, M., Yang, U., Gong, J., Ellisor, D., Kauer, J. A., Morrow, E. M.
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|
<strong>Christianson syndrome protein NHE6 modulates TrkB endosomal signaling required for neuronal circuit development.</strong>
|
|
Neuron 80: 97-112, 2013.
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[PubMed: 24035762]
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[Full Text: https://doi.org/10.1016/j.neuron.2013.07.043]
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<li>
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<p class="mim-text-font">
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Pescosolido, M. F., Stein, D. M., Schmidt, M., El Achkar, C. M., Sabbagh, M., Rogg, J. M., Tantravahi, U., McLean, R. L., Liu, J. S., Poduri, A., Morrow, E. M.
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<strong>Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome.</strong>
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Ann. Neurol. 76: 581-593, 2014.
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[PubMed: 25044251]
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[Full Text: https://doi.org/10.1002/ana.24225]
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</p>
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<li>
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<p class="mim-text-font">
|
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Riess, A., Rossier, E., Kruger, R., Dufke, A., Beck-Woedl, S., Horber, V., Alber, M., Glaser, D., Riess, O., Tzschach, A.
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|
<strong>Novel SLC9A6 mutations in two families with Christianson syndrome.</strong>
|
|
Clin. Genet. 83: 596-597, 2013.
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[PubMed: 22931061]
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[Full Text: https://doi.org/10.1111/j.1399-0004.2012.01948.x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Roxrud, I., Raiborg, C., Gilfillan, G. D., Stromme, P., Stenmark, H.
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<strong>Dual degradation mechanisms ensure disposal of NHE6 mutant protein associated with neurological disease.</strong>
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Exp. Cell Res. 315: 3014-3027, 2009.
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[PubMed: 19619532]
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[Full Text: https://doi.org/10.1016/j.yexcr.2009.07.012]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Schuurs-Hoeijmakers, J. H. M., Vulto-van Silfhout, A. T., Vissers, L. E. L. M., van de Vondervoort, I. I. G. M., van Bon, B. W. M., de Ligt, J., Gilissen, C., Hehir-Kwa, J. Y., Neveling, K., del Rosario, M., Hira, G., Reitano, S., and 19 others.
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<strong>Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing.</strong>
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J. Med. Genet. 50: 802-811, 2013. Note: Erratum: J. Med. Genet. 55: 504 only, 2018.
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[PubMed: 24123876]
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[Full Text: https://doi.org/10.1136/jmedgenet-2013-101644]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Stromme, P., Dobrenis, K., Sillitoe, R. V., Gulinello, M., Ali, N. F., Davidson, C., Micsenyi, M. C., Stephney, G., Ellevog, L., Klungland, A., Walkley, S. U.
|
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<strong>X-linked Angelman-like syndrome caused by Slc9a6 knockout in mice exhibits evidence of endosomal-lysosomal dysfunction.</strong>
|
|
Brain 134: 3369-3383, 2011.
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[PubMed: 21964919]
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[Full Text: https://doi.org/10.1093/brain/awr250]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Tarpey, P. S., Smith, R., Pleasance, E., Whibley, A., Edkins, S., Hardy, C., O'Meara, S., Latimer, C., Dicks, E., Menzies, A., Stephens, P., Blow, M., and 67 others.
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<strong>A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation.</strong>
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Nature Genet. 41: 535-543, 2009.
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[PubMed: 19377476]
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[Full Text: https://doi.org/10.1038/ng.367]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Yamamoto, Y., Takahata, K., Seki, M., Okusa, S., Tatebe, H., Ueda, R., Endo, H., Tagai, K., Moriguchi, S., Kurose, S., Ichihashi, M., Matsuura, S., Kawamura, K., Zhang, M.-R., Ueno, Y., Takiyama, Y., Tokuda, T., Higuchi, M., Ito, D.
|
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<strong>SLC9A6-linked parkinson syndrome in female heterozygotes is associated with PET-detectable tau pathology.</strong>
|
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Neurol. Genet. 11: e200235, 2025.
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[PubMed: 39810750]
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[Full Text: https://doi.org/10.1212/NXG.0000000000200235]
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</p>
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</li>
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</ol>
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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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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
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<span class="text-nowrap mim-text-font">
|
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Contributors:
|
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 03/03/2025<br>Cassandra L. Kniffin - updated : 09/07/2016<br>Cassandra L. Kniffin - updated : 2/24/2015<br>Patricia A. Hartz - updated : 9/23/2014<br>Cassandra L. Kniffin - updated : 1/6/2014<br>Cassandra L. Kniffin - updated : 4/22/2011<br>Cassandra L. Kniffin - updated : 12/10/2010<br>Patricia A. Hartz - updated : 11/12/2010<br>Anne M. Stumpf - updated : 8/31/2010<br>Ada Hamosh - updated : 10/1/2009<br>Cassandra L. Kniffin - updated : 5/5/2008
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</span>
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</div>
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<div>
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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alopez : 03/04/2025<br>ckniffin : 03/03/2025<br>carol : 08/20/2021<br>carol : 08/19/2021<br>carol : 09/19/2018<br>carol : 09/15/2016<br>ckniffin : 09/07/2016<br>alopez : 02/29/2016<br>carol : 3/3/2015<br>mcolton : 2/25/2015<br>ckniffin : 2/24/2015<br>mgross : 10/10/2014<br>mcolton : 9/23/2014<br>carol : 1/7/2014<br>ckniffin : 1/6/2014<br>terry : 11/29/2012<br>carol : 10/26/2011<br>terry : 5/27/2011<br>wwang : 5/11/2011<br>ckniffin : 4/22/2011<br>wwang : 1/7/2011<br>ckniffin : 12/10/2010<br>wwang : 11/12/2010<br>terry : 11/12/2010<br>terry : 9/8/2010<br>alopez : 8/31/2010<br>alopez : 10/7/2009<br>terry : 10/1/2009<br>wwang : 4/21/2009<br>carol : 5/5/2008<br>ckniffin : 5/5/2008<br>alopez : 2/7/2005<br>mgross : 3/15/2000<br>mgross : 3/14/2000<br>psherman : 3/13/2000
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