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Entry
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- *182340 - ATPase, Na+/K+ TRANSPORTING, ALPHA-2 POLYPEPTIDE; ATP1A2
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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">*182340</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#geneStructure">Gene Structure</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#mapping">Mapping</a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/182340">Table View</a>
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div 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=ENSG00000018625;t=ENST00000361216" 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=477" 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=182340" 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 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=ENSG00000018625;t=ENST00000361216" 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_000702,XM_047421286" 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_000702" 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=182340" 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=01665&isoform_id=01665_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/ATP1A2" 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/179165,179239,297466,553194,1703467,4502271,37589105,61807527,119573124,119573125,119573126,119573127,189067241,193784902,193785194,193787187,194379094,194380834,194388820,929654363,957948969,957948972,2217267727,2462509521" 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/P50993" 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=477" 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=ENSG00000018625;t=ENST00000361216" 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=ATP1A2" 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=ATP1A2" 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+477" 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/ATP1A2" 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:477" 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/477" 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=chr1&hgg_gene=ENST00000361216.8&hgg_start=160115759&hgg_end=160143591&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:800" 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/atp1a2" 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=182340[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=182340[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/ATP1A2/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/ENSG00000018625" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=ATP1A2" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=ATP1A2" 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=ATP1A2" 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/ATP1A2" 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=ATP1A2&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/PA30796" 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:800" 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/FBgn0002921.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:88106" 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/ATP1A2#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:88106" 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/477/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=477" 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=WBGene00001137;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-001212-6" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:477" 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=ATP1A2&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> 1260330000<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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182340
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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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ATPase, Na+/K+ TRANSPORTING, ALPHA-2 POLYPEPTIDE; ATP1A2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
SODIUM-POTASSIUM-ATPase, ALPHA-2 POLYPEPTIDE<br />
|
|
Na,K-ATPase, ALPHA-A(+) CATALYTIC POLYPEPTIDE<br />
|
|
Na,K-ATPase, ALPHA-B POLYPEPTIDE
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=ATP1A2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ATP1A2</a></em></strong>
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/1/1310?start=-3&limit=10&highlight=1310">1q23.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:160115759-160143591&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'})">1:160,115,759-160,143,591</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
|
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=104290,619605,619602,602481,602481" 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="5">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/1310?start=-3&limit=10&highlight=1310">
|
|
1q23.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Alternating hemiplegia of childhood 1
|
|
|
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</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/104290"> 104290 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<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>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Developmental and epileptic encephalopathy 98
|
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|
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</span>
|
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<p>The ATP1A2 gene encodes the alpha-2 isoform of the Na(+),K(+)-ATPase (<a href="https://enzyme.expasy.org/EC/3.6.1.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 3.6.1.9</a>), an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane. The pump is composed of 2 subunits, a large catalytic subunit (alpha), encoded by several genes (see, e.g., ATP1A1, <a href="/entry/182310">182310</a>), and a smaller glycoprotein subunit (beta) (see ATP1B1, <a href="/entry/182330">182330</a>) (summary by <a href="#25" class="mim-tip-reference" title="Shull, M. M., Lingrel, J. B. <strong>Multiple genes encode the human Na+,K+-ATPase catalytic subunit.</strong> Proc. Nat. Acad. Sci. 84: 4039-4043, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3035563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3035563</a>] [<a href="https://doi.org/10.1073/pnas.84.12.4039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3035563">Shull and Lingrel, 1987</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3035563" 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="#25" class="mim-tip-reference" title="Shull, M. M., Lingrel, J. B. <strong>Multiple genes encode the human Na+,K+-ATPase catalytic subunit.</strong> Proc. Nat. Acad. Sci. 84: 4039-4043, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3035563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3035563</a>] [<a href="https://doi.org/10.1073/pnas.84.12.4039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3035563">Shull and Lingrel (1987)</a> identified separate genes encoding the alpha and alpha(+) isoforms of the catalytic subunit of the Na(+),K(+)-ATPase. These genes were called alpha-A (ATP1A1) and alpha-B (ATP1A2), respectively. In addition, they isolated 2 other genes, termed alpha-C (ATP1A3; <a href="/entry/182350">182350</a>) and alpha-D (ATP1A4; <a href="/entry/607321">607321</a>), one of which is physically linked to the alpha-B gene; these genes showed nucleotide and deduced amino acid homology to the catalytic subunit cDNA sequences, but did not correspond to any previously identified isoforms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3035563" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Shull, M. M., Pugh, D. G., Lingrel, J. B. <strong>Characterization of the human Na,K-ATPase alpha 2 gene and identification of intragenic restriction fragment length polymorphisms.</strong> J. Biol. Chem. 264: 17532-17543, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2477373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2477373</a>]" pmid="2477373">Shull et al. (1989)</a> cloned the ATP1A2 gene. The amino acid sequence deduced from the genomic sequence exhibited 99% identity to the rat alpha-2 isoform. Several transcription factor binding sites are located in the 5-prime end of the gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2477373" 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 alpha-2 subunit consists of 10 transmembrane helices M1-M10, harboring the Na(+) and K(+)-binding sites, and a cytoplasmic head made up of 3 subdomains: A (actuator), N (nucleotide binding), and P (phosphorylation) (summary by <a href="#22" class="mim-tip-reference" title="Schack, V. R., Holm, R., Vilsen, B. <strong>Inhibition of phosphorylation of Na+,K+-ATPase by mutations causing familial hemiplegic migraine.</strong> J. Biol. Chem. 287: 2191-2202, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22117059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22117059</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22117059[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M111.323022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22117059">Schack et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22117059" 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>ATP1A2 is expressed in skeletal muscle, heart, vascular smooth muscle, and brain (summary by <a href="#15" class="mim-tip-reference" title="Monteiro, F. P., Curry, C. J., Hevner, R., Elliott, S., Fisher, J. H., Turocy, J., Dobyns, W. B., Costa, L. A., Freitas, E., Kitajima, J. P., Kok, F. <strong>Biallelic loss of function variants in ATP1A2 cause hydrops fetalis, microcephaly, arthrogryposis and extensive cortical malformations.</strong> Europ. J. Med. Genet. 63: 103624, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30690204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30690204</a>] [<a href="https://doi.org/10.1016/j.ejmg.2019.01.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30690204">Monteiro et al., 2020</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30690204" 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="#26" class="mim-tip-reference" title="Shull, M. M., Pugh, D. G., Lingrel, J. B. <strong>Characterization of the human Na,K-ATPase alpha 2 gene and identification of intragenic restriction fragment length polymorphisms.</strong> J. Biol. Chem. 264: 17532-17543, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2477373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2477373</a>]" pmid="2477373">Shull et al. (1989)</a> determined that the ATP1A2 gene contains 23 exons and spans approximately 25 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2477373" 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="#13" class="mim-tip-reference" title="Katzmarzyk, P. T., Rankinen, T., Perusse, L., Deriaz, O., Tremblay, A., Borecki, I., Rao, D. C., Bouchard, C. <strong>Linkage and association of the sodium potassium-adenosine triphosphatase alpha-2 and beta-1 genes with respiratory quotient and resting metabolic rate in the Quebec Family Study.</strong> J. Clin. Endocr. Metab. 84: 2093-2097, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10372716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10372716</a>] [<a href="https://doi.org/10.1210/jcem.84.6.5774" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10372716">Katzmarzyk et al. (1999)</a> examined the relationship between the ATP1A2 (exon 1 and exon 21-22 with BglII) and ATP1B1 (<a href="/entry/182330">182330</a>) (MspI and PvuII) genes and resting metabolic rate (RMR) and respiratory quotient (RQ). RMR and RQ were adjusted for age, sex, fat mass, and fat-free mass. Sib-pair analyses indicated a significant linkage between RQ and the ATP1A2 exon 1 and exon 21-22 markers (P of 0.03 and 0.02, respectively). No linkage was detected between the ATP1B1 markers and either RMR or RQ, and RMR was not linked with the ATP1A2 markers. There was a significant interaction (p less than 0.0003) between ATP1A2 exon 1 carrier status and age group (younger adults (those less than 45 years old) vs older adults (those 45 or more years old)) for RQ. The association between carrier status and RQ was significant in younger adults (RQ of 0.76 in carriers vs 0.80 in noncarriers; p less than 0.0001) but was not in older adults (RQ of 0.81 in carriers vs 0.80 in noncarriers). The ATP1A2 exon 1 gene accounted for approximately 9.1% and 0.3% of the variance in RQ in younger and older adults, respectively. The results suggested that the ATP1A2 gene may play a role in fuel oxidation, particularly in younger individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10372716" 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 determine the functional roles of the ATP1A1 and ATP1A2 proteins, <a href="#9" class="mim-tip-reference" title="James, P. F., Grupp, I. L., Grupp, G., Woo, A. L., Askew, G. R., Croyle, M. L., Walsh, R. A., Lingrel, J. B. <strong>Identification of a specific role for the Na,K-ATPase alpha-2 isoform as a regulator of calcium in the heart.</strong> Molec. Cell 3: 555-563, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10360172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10360172</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80349-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10360172">James et al. (1999)</a> generated mice with a targeted disruption of either the Atp1a1 or the Atp1a2 gene. Hearts from heterozygous Atp1a2 mice were hypercontractile as a result of increased calcium transients during the contractile cycle. In contrast, hearts from heterozygous Atp1a1 mice were hypocontractile. The different functional roles of these 2 proteins were further demonstrated since inhibition of the Atp1a2 protein with ouabain increased the contractility of heterozygous Atp1a1 hearts. These results illustrated a specific role for the ATP1A2 protein in calcium signaling during cardiac contraction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10360172" 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 Southern analysis of DNA from panels of rodent/human somatic cell hybrid lines, <a href="#35" class="mim-tip-reference" title="Yang-Feng, T. L., Schneider, J. W., Lindgren, V., Shull, M. M., Benz, E. J., Jr., Lingrel, J. B., Francke, U. <strong>Chromosomal localization of human Na+,K+-ATPase alpha- and beta-subunit genes.</strong> Genomics 2: 128-138, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2842249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2842249</a>] [<a href="https://doi.org/10.1016/0888-7543(88)90094-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2842249">Yang-Feng et al. (1988)</a> mapped the ATP1A2 gene to 1cen-q32. Furthermore, they detected a common Pst1 RFLP with the ATP1A2 probe. In the course of creating a physical map of human 1q21-q23, <a href="#17" class="mim-tip-reference" title="Oakey, R. J., Watson, M. L., Seldin, M. F. <strong>Construction of a physical map on mouse and human chromosome 1: comparison of 13 Mb of mouse and 11 Mb of human DNA.</strong> Hum. Molec. Genet. 1: 613-620, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301170</a>] [<a href="https://doi.org/10.1093/hmg/1.8.613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1301170">Oakey et al. (1992)</a> confirmed this assignment. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1301170+2842249" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Stumpf, A. M. <strong>Personal Communication.</strong> Baltimore, Md. 11/09/2021."None>Stumpf (2021)</a> mapped the ATP1A2 gene to chromosome 1q23.2 based on an alignment of the ATP1A2 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC052271" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC052271</a>) with the genomic sequence (GRCh38).</p>
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<a href="#16" class="mim-tip-reference" title="Morth, J. P., Pedersen, B. P., Toustrup-Jensen, M. S., Sorensen, T. L.-M., Petersen, J., Andersen, J. P., Vilsen, B., Nissen, P. <strong>Crystal structure of the sodium-potassium pump.</strong> Nature 450: 1043-1049, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18075585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18075585</a>] [<a href="https://doi.org/10.1038/nature06419" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18075585">Morth et al. (2007)</a> presented the x-ray crystal structure at 3.5-angstrom resolution of the pig renal sodium-potassium-ATPase (Na+,K(+)-ATPase) with 2 rubidium ions bound (as potassium congeners) in an occluded state in the transmembrane part of the alpha subunit. Several of the residues forming the cavity for rubidium/potassium occlusion in the Na+,K(+)-ATPase are homologous to those binding calcium in the calcium-ion ATPase of sarcoendoplasmic reticulum (ATP2A1 (SERCA1); <a href="/entry/108730">108730</a>). The beta (see ATP1B1, <a href="/entry/182330">182330</a>) and gamma (see ATP1G1, <a href="/entry/601814">601814</a>) subunits specific to the Na+,K(+)-ATPase are associated with transmembrane helices alpha-M7/alpha-M10, and alpha-M9, respectively. The gamma subunit corresponds to a fragment of the V-type ATPase c subunit. The carboxy terminus of the alpha subunit is contained within a pocket between transmembrane helices and seems to be a novel regulatory element controlling sodium affinity, possibly influenced by the membrane potential. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18075585" 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>Crystal structures of the potassium-bound form of the sodium potassium ATPase pump revealed an intimate docking of the alpha-subunit carboxy terminus at the transmembrane domain (e.g., <a href="#16" class="mim-tip-reference" title="Morth, J. P., Pedersen, B. P., Toustrup-Jensen, M. S., Sorensen, T. L.-M., Petersen, J., Andersen, J. P., Vilsen, B., Nissen, P. <strong>Crystal structure of the sodium-potassium pump.</strong> Nature 450: 1043-1049, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18075585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18075585</a>] [<a href="https://doi.org/10.1038/nature06419" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18075585">Morth et al., 2007</a>). <a href="#20" class="mim-tip-reference" title="Poulsen, H., Khandelia, H., Morth, J. P., Bublitz, M., Mouritsen, O. G., Egebjerg, J., Nissen, P. <strong>Neurological disease mutations compromise a C-terminal ion pathway in the Na+/K+-ATPase.</strong> Nature 467: 99-102, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20720542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20720542</a>] [<a href="https://doi.org/10.1038/nature09309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20720542">Poulsen et al. (2010)</a> showed that this element is a key regulator of a theretofore unrecognized ion pathway. Models of P-type ATPases operated with a single ion conduit through the pump, but the data of <a href="#20" class="mim-tip-reference" title="Poulsen, H., Khandelia, H., Morth, J. P., Bublitz, M., Mouritsen, O. G., Egebjerg, J., Nissen, P. <strong>Neurological disease mutations compromise a C-terminal ion pathway in the Na+/K+-ATPase.</strong> Nature 467: 99-102, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20720542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20720542</a>] [<a href="https://doi.org/10.1038/nature09309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20720542">Poulsen et al. (2010)</a> suggested an additional pathway in the Na+/K(+)-ATPase between the ion-binding sites and the cytoplasm. The C-terminal pathway allows a cytoplasmic proton to enter and stabilize site III when empty in the potassium-bound state, and when potassium is released the proton will also return to the cytoplasm, thus allowing an overall asymmetric stoichiometry of the transported ions. The C terminus controls the gate to the pathway. Its structure is crucial for pump function, as demonstrated by at least 8 mutations in the region that cause severe neurologic diseases. This novel model for ion transport by the Na+/K(+)-ATPase was established by electrophysiologic studies of C-terminal mutations in familial hemiplegic migraine (<a href="/entry/602481">602481</a>) and was further substantiated by molecular dynamics simulations. <a href="#20" class="mim-tip-reference" title="Poulsen, H., Khandelia, H., Morth, J. P., Bublitz, M., Mouritsen, O. G., Egebjerg, J., Nissen, P. <strong>Neurological disease mutations compromise a C-terminal ion pathway in the Na+/K+-ATPase.</strong> Nature 467: 99-102, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20720542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20720542</a>] [<a href="https://doi.org/10.1038/nature09309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20720542">Poulsen et al. (2010)</a> considered a similar ion regulation likely to apply to the H+/K(+)-ATPase and the Ca(2+)-ATPase. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20720542+18075585" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Familial Hemiplegic Migraine 2</em></strong></p><p>
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In affected members of a large Italian family segregating familial hemiplegic migraine-2 (FHM2; <a href="/entry/602481">602481</a>), <a href="#6" class="mim-tip-reference" title="De Fusco, M., Marconi, R., Silvestri, L., Atorino, L., Rampoldi, L., Morgante, L., Ballabio, A., Aridon, P., Casari, G. <strong>Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha-2 subunit associated with familial hemiplegic migraine type 2.</strong> Nature Genet. 33: 192-196, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12539047/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12539047</a>] [<a href="https://doi.org/10.1038/ng1081" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12539047">De Fusco et al. (2003)</a> identified heterozygosity for mutations in the ATP1A2 gene (<a href="#0001">182340.0001</a>-<a href="#0002">182340.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12539047" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Jurkat-Rott, K., Freilinger, T., Dreier, J. P., Herzog, J., Gobel, H., Petzold, G. C., Montagna, P., Gasser, T., Lehmann-Horn, F., Dichgans, M. <strong>Variability of familial hemiplegic migraine with novel A1A2 Na(+)/K(+)-ATPase variants.</strong> Neurology 62: 1857-1861, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15159495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15159495</a>] [<a href="https://doi.org/10.1212/01.wnl.0000127310.11526.fd" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15159495">Jurkat-Rott et al. (2004)</a> identified 6 different mutations in the ATP1A2 gene (see, e.g., <a href="#0008">182340.0008</a>; <a href="#0009">182340.0009</a>) in affected members of 6 unrelated families with FHM2. Penetrance was mildly reduced at approximately 87%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15159495" 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="#33" class="mim-tip-reference" title="Vanmolkot, K. R. J., Stam, A. H., Raman, A., Koenderink, J. B., de Vries, B., van den Boogerd, E. H., van Vark, J., van den Heuvel, J. J. M. W., Bajaj, N., Terwindt, G. M., Haan, J., Frants, R. R., Ferrari, M. D., van den Maagdenberg, A. M. J. M. <strong>First case of compound heterozygosity in Na,K-ATPase gene ATP1A2 in familial hemiplegic migraine.</strong> Europ. J. Hum. Genet. 15: 884-888, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17473835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17473835</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201841" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17473835">Vanmolkot et al. (2007)</a> reported an affected family in which the proband with severe FHM2 was compound heterozygous for 2 mutations in the ATP1A2 gene (<a href="#0011">182340.0011</a>; <a href="#0012">182340.0012</a>). Family members with milder forms of the disorder were heterozygous for 1 of the mutations, suggesting reduced penetrance. The authors stated that this was the first report of compound heterozygosity in FHM2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17473835" 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 affected members of a 3-generation Korean family with FHM2, <a href="#18" class="mim-tip-reference" title="Oh, S.-K., Baek, J.-I., Weigand, K. M., Venselaar, H., Swarts, H. G. P., Park, S.-H., Raza, M. H., Jung, D. J., Choi, S.-Y., Lee, S.-H., Friedrich, T., Vriend, G., Koenderink, J. B., Kim, U.-K., Lee, K.-Y. <strong>A missense variant of the ATP1A2 gene is associated with a novel phenotype of progressive sensorineural hearing loss associated with migraine.</strong> Europ. J. Hum. Genet. 23: 639-645, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25138102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25138102</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25138102[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2014.154" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25138102">Oh et al. (2015)</a> identified a heterozygous missense mutation (V191M; <a href="#0015">182340.0015</a>) in the ATP1A2 gene. All affected members of the family also had progressive hearing loss. The mutation segregated with the phenotype in the family and was not found in the dbSNP or 1000 Genomes Project databases or in 200 Korean controls with normal audiograms. See DFNA7 (<a href="/entry/601412">601412</a>) and DFNA49 (<a href="/entry/608372">608372</a>) for 2 hearing loss loci that map to the same region as the ATP1A2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25138102" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Alternating Hemiplegia of Childhood 1</em></strong></p><p>
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In affected members of a family with alternating hemiplegia of childhood-1 (AHC1; <a href="/entry/104290">104290</a>), <a href="#29" class="mim-tip-reference" title="Swoboda, K. J., Kanavakis, E., Xaidara, A., Johnson, J. E., Leppert, M. F., Schlesinger-Massart, M. B., Ptacek, L. J., Silver, K., Youroukos, S. <strong>Alternating hemiplegia of childhood or familial hemiplegic migraine?: a novel ATP1A2 mutation.</strong> Ann. Neurol. 55: 884-887, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15174025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15174025</a>] [<a href="https://doi.org/10.1002/ana.20134" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15174025">Swoboda et al. (2004)</a> identified a mutation in the ATP1A2 gene (<a href="#0005">182340.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15174025" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a Brazilian boy with a phenotype reminiscent of AHC1, <a href="#21" class="mim-tip-reference" title="Sampedro Castaneda, M., Zanoteli, E., Scalco, R. S., Scaramuzzi, V., Marques Caldas, V., Conti Reed, U., da Silva, A. M. S., O'Callaghan, B., Phadke, R., Bugiardini, E., Sud, R., McCall, S., Hanna, M. G., Poulsen, H., Mannikko, R., Matthews, E. <strong>A novel ATP1A2 mutation in a patient with hypokalaemic periodic paralysis and CNS symptoms.</strong> Brain 141: 3308-3318, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30423015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30423015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30423015[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/awy283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30423015">Sampedro Castaneda et al. (2018)</a> identified a de novo heterozygous missense mutation in the ATP1A2 gene (S779N; <a href="#0023">182340.0023</a>). The mutation, which was found by Sanger sequencing, was not present in the gnomAD database. In vitro electrophysiologic studies in Xenopus oocytes showed that the mutation caused a 'leaky' inward current in the mutant pump in the presence of both high and low K+ concentrations, as well as altered Na+/K+ turnover activity rates of the pump. The voltage dependence of transient currents was left-shifted in mutant pumps. These changes were predicted to underlie abnormal membrane depolarization, resulting in muscle inexcitability leading to paralysis. The patient developed episodic tetraparesis at age 2 years. Laboratory studies during the episodes showed increased serum creatine kinase and low serum potassium. The symptoms improved with potassium, but worsened with acetazolamide. <a href="#21" class="mim-tip-reference" title="Sampedro Castaneda, M., Zanoteli, E., Scalco, R. S., Scaramuzzi, V., Marques Caldas, V., Conti Reed, U., da Silva, A. M. S., O'Callaghan, B., Phadke, R., Bugiardini, E., Sud, R., McCall, S., Hanna, M. G., Poulsen, H., Mannikko, R., Matthews, E. <strong>A novel ATP1A2 mutation in a patient with hypokalaemic periodic paralysis and CNS symptoms.</strong> Brain 141: 3308-3318, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30423015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30423015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30423015[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/awy283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30423015">Sampedro Castaneda et al. (2018)</a> noted the phenotypic similarities to hypokalemic periodic paralysis (see <a href="/entry/170400">170400</a>) but with additional central nervous system involvement, thus expanding the phenotypic spectrum of ATP1A2 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30423015" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Fetal Akinesia, Respiratory Insufficiency, Microcephaly, Polymicrogyria, and Dysmorphic Facies</em></strong></p><p>
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In 3 infants from 2 unrelated families with fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (FARIMPD; <a href="/entry/619602">619602</a>), <a href="#15" class="mim-tip-reference" title="Monteiro, F. P., Curry, C. J., Hevner, R., Elliott, S., Fisher, J. H., Turocy, J., Dobyns, W. B., Costa, L. A., Freitas, E., Kitajima, J. P., Kok, F. <strong>Biallelic loss of function variants in ATP1A2 cause hydrops fetalis, microcephaly, arthrogryposis and extensive cortical malformations.</strong> Europ. J. Med. Genet. 63: 103624, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30690204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30690204</a>] [<a href="https://doi.org/10.1016/j.ejmg.2019.01.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30690204">Monteiro et al. (2020)</a> identified homozygous frameshift mutations in the ATP1A2 gene (<a href="#0016">182340.0016</a> and <a href="#0017">182340.0017</a>). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Neither were present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but both were predicted to result in a complete loss of ATP1A2 function. All 3 patients died in the perinatal period. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30690204" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 sibs, conceived of consanguineous Algerian parents, and an unrelated infant, born of consanguineous Pakistani parents, with FARIMPD, <a href="#5" class="mim-tip-reference" title="Chatron, N., Cabet, S., Alix, E., Buenerd, A., Cox, P., Guibaud, L., Labalme, A., Marks, P., Osio, D., Putoux, A., Sanlaville, D., Lesca, G., Vasiljevic, A. <strong>A novel lethal recognizable polymicrogyric syndrome caused by ATP1A2 homozygous truncating variants.</strong> Brain 142: 3367-3374, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31608932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31608932</a>] [<a href="https://doi.org/10.1093/brain/awz272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31608932">Chatron et al. (2019)</a> identified a homozygous frameshift and nonsense mutation, respectively, in the ATP1A2 gene (<a href="#0018">182340.0018</a> and <a href="#0019">182340.0019</a>). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Both were absent from the gnomAD database. No ATP1A2 immunostaining was detected in brain samples from 2 patients, confirming complete absence of the protein and a loss-of-function effect. Functional studies of the variant were not performed. All patients either died in infancy or the pregnancies were terminated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31608932" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Developmental and Epileptic Encephalopathy 98</em></strong></p><p>
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In 6 unrelated patients with developmental and epileptic encephalopathy-98 (DEE98; <a href="/entry/619605">619605</a>), <a href="#34" class="mim-tip-reference" title="Vetro, A., Nielsen, H. N., Holm, R., Hevner, R. F., Parrini, E., Powis, Z., Moller, R. S., Bellan, C., Simonati, A., Lesca, G., Helbig, K. L., Palmer, E. E., and 18 others. <strong>ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria.</strong> Brain 144: 1435-1450, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33880529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33880529</a>] [<a href="https://doi.org/10.1093/brain/awab052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33880529">Vetro et al. (2021)</a> identified 5 de novo heterozygous missense mutations in the ATP1A2 gene (see, e.g., <a href="#0020">182340.0020</a>-<a href="#0022">182340.0022</a>). The mutations, which occurred at conserved residues, were not present in the gnomAD database. In vitro functional expression studies showed that all of the mutations caused variable functional defects in the Na+/(K+)ATPase. Variants with more severe functional deficits were associated with a more severe phenotype. The findings were consistent with a loss-of-function effect. <a href="#34" class="mim-tip-reference" title="Vetro, A., Nielsen, H. N., Holm, R., Hevner, R. F., Parrini, E., Powis, Z., Moller, R. S., Bellan, C., Simonati, A., Lesca, G., Helbig, K. L., Palmer, E. E., and 18 others. <strong>ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria.</strong> Brain 144: 1435-1450, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33880529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33880529</a>] [<a href="https://doi.org/10.1093/brain/awab052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33880529">Vetro et al. (2021)</a> estimated that about 5% of ATP1A2 mutations may be associated with DEE. Polymicrogyria was estimated to occur in about 1% of patients with ATP1A2 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33880529" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Variant Functional Studies</em></strong></p><p>
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<a href="#22" class="mim-tip-reference" title="Schack, V. R., Holm, R., Vilsen, B. <strong>Inhibition of phosphorylation of Na+,K+-ATPase by mutations causing familial hemiplegic migraine.</strong> J. Biol. Chem. 287: 2191-2202, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22117059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22117059</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22117059[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M111.323022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22117059">Schack et al. (2012)</a> reported functional analysis of 9 different pathogenic mutations in the ATP1A2 gene, including 4 in the P domain (M731T (<a href="#0003">182340.0003</a>), R593W, V628M, and E700K), 2 in the A domain (R202Q and T263M), 1 in the transmembrane domain M2 (V138A), 1 in transmembrane M4 domain near the P domain (T345A; <a href="#0007">182340.0007</a>), and 1 between M6 and M7 close to the P domain (R834Q). Expression of the mutations in COS-1 cells showed that all had reductions in the catalytic turnover rate of Na+ and K+. The decrease was most severe for R593W, V628M, M731T, and R834Q (less than one-third of wildtype), about 50% for T263M, T345A, E700K, and V138A, and less than 20% of control for R202Q. All mutants showed essentially normal affinity for K+ and Na+, but rapid kinetic studies of the phosphorylation from ATP showed reduced Vmax of phosphorylation as a major factor contributing to the reduction of the catalytic turnover rate of mutants V138A, T345A, R593W, V628M, M731T, and R834Q (2- to 6-fold decrease). The decreased phosphorylation rate would lead to enhanced K+ competition with Na+ at intracellular sites, which would compromise pump function. E700K, R202Q, and T263M phosphorylation rates were similar to wildtype, but E700K showed impaired rates of dephosphorylation, and R202Q and T263M were predicted to affect the turnover rate of the E1P/E2P pump conformations. Overall, the findings suggested that the disturbance of clearance of extracellular K+ by glial cells, thought to underlie FHM2, is due to low turnover rate of the pump and not to decreased affinity of the pump for external K+. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22117059" 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 Drosophila, <a href="#12" class="mim-tip-reference" title="Kaneko, M., Desai, B. S., Cook, B. <strong>Ionic leakage underlies a gain-of-function effect of dominant disease mutations affecting diverse P-type ATPases.</strong> Nature Genet. 46: 144-151, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24336169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24336169</a>] [<a href="https://doi.org/10.1038/ng.2850" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24336169">Kaneko et al. (2014)</a> identified a dominant missense mutation (A617T) in the calcium ATPase Serca gene (see SERCA2 (ATP2A2); <a href="/entry/108740">108740</a>) that conferred temperature-sensitive motor uncoordination in a gain-of-function manner. The homologous residue is conserved by different type II P-type ATPases, including ATP1A2. Introduction of an R751Q mutation in the Drosophila Serca gene also caused a temperature-sensitive uncoordination phenotype. The corresponding residue in human SERCA2, ATP1A2, and ATP1A3 (<a href="/entry/182350">182350</a>) is mutated in the human diseases Darier disease (<a href="/entry/124200">124200</a>), FHM2, and dystonia-12 (DYT12; <a href="/entry/128235">128235</a>), respectively. Cellular expression of Drosophila A617T resulted in temperature-induced decreased levels of stored calcium compared to wildtype, whereas cellular expression of R751Q elicited depletion of stored calcium even without heating. These calcium changes were due to leakage through the mutant channel pores that overwhelmed the pumping capacity of the cell. Similar results occurred after transfection of these mutations, as well as other disease-causing mutations that affected different parts of the protein, into mouse cells. <a href="#12" class="mim-tip-reference" title="Kaneko, M., Desai, B. S., Cook, B. <strong>Ionic leakage underlies a gain-of-function effect of dominant disease mutations affecting diverse P-type ATPases.</strong> Nature Genet. 46: 144-151, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24336169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24336169</a>] [<a href="https://doi.org/10.1038/ng.2850" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24336169">Kaneko et al. (2014)</a> concluded that ionic leakage is a gain-of-function mechanism that underlies a variety of dominant type II P-type ATPase-related diseases. <a href="#12" class="mim-tip-reference" title="Kaneko, M., Desai, B. S., Cook, B. <strong>Ionic leakage underlies a gain-of-function effect of dominant disease mutations affecting diverse P-type ATPases.</strong> Nature Genet. 46: 144-151, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24336169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24336169</a>] [<a href="https://doi.org/10.1038/ng.2850" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24336169">Kaneko et al. (2014)</a> concluded that ionic leakage is a gain-of-function mechanism that underlies a variety of dominant type II P-type ATPase-related diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24336169" 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="Ikeda, K., Onimaru, H., Yamada, J., Inoue, K., Ueno, S., Onaka, T., Toyoda, H., Arata, A., Ishikawa, T., Taketo, M. M., Fukuda, A., Kawakami, K. <strong>Malfunction of respiratory-related neuronal activity in Na+, K(+)-ATPase alpha-2 subunit-deficient mice is attributable to abnormal Cl- homeostasis in brainstem neurons.</strong> J. Neurosci. 24: 10693-10701, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15564586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15564586</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15564586[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.2909-04.2004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15564586">Ikeda et al. (2004)</a> found that homozygous knockout of the Atp1a2 gene in mice was embryonic lethal due to severe motor deficits that also abolished respiration by the medullary respiratory center neurons. Analysis of spinal cord motoneurons in mutant mice showed absence of normal spontaneous rhythmic discharges. This was associated with increased inhibitory GABA levels in the extracellular spaces throughout the brain, as well as increased chloride (Cl-) levels within neurons. <a href="#8" class="mim-tip-reference" title="Ikeda, K., Onimaru, H., Yamada, J., Inoue, K., Ueno, S., Onaka, T., Toyoda, H., Arata, A., Ishikawa, T., Taketo, M. M., Fukuda, A., Kawakami, K. <strong>Malfunction of respiratory-related neuronal activity in Na+, K(+)-ATPase alpha-2 subunit-deficient mice is attributable to abnormal Cl- homeostasis in brainstem neurons.</strong> J. Neurosci. 24: 10693-10701, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15564586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15564586</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15564586[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.2909-04.2004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15564586">Ikeda et al. (2004)</a> hypothesized that Atp1a2 normally generates a K+ gradient that fuels extrusion of cytosolic Cl- by KCC2 (SLC12A5; <a href="/entry/606726">606726</a>) in respiratory center neurons in the perinatal period. In the absence of this, due to loss of Atp1a2, neurons thus become persistently depolarized and cannot produce action potentials due to the inactivation of fast sodium channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15564586" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Ashmore, L. J., Hrizo, S. L., Paul, S. M., Van Voorhies, W. A., Beitel, G. J., Palladino, M. J. <strong>Novel mutations affecting the Na, K ATPase alpha model complex neurological diseases and implicate the sodium pump in increased longevity.</strong> Hum. Genet. 126: 431-447, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19455355/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19455355</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19455355[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/10.1007/s00439-009-0673-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19455355">Ashmore et al. (2009)</a> identified 6 different EMS-induced missense mutations in the Atp1a2 and Atp1a3 (<a href="/entry/182350">182350</a>) genes in Drosophila. All mutations resulted in reduced respiration activity consistent with a loss of ATPase function and a hypomorphic effect. Different mutant strains exhibited some abnormalities, including progressive temperature-dependent paralysis, progressive stress-sensitive paralysis, and decreased locomotor activity in response to startle, suggesting a decrease in maximal locomotion capacity. Neuromuscular studies showed allele-specific pathology, including brain vacuoles and myopathology, and biochemical studies showed decreased metabolic rates. An unexpected finding was the some mutant strains had increased longevity, which was not related to caloric restriction. Low doses of ouabain showed a similar effect on longevity in control groups. <a href="#2" class="mim-tip-reference" title="Ashmore, L. J., Hrizo, S. L., Paul, S. M., Van Voorhies, W. A., Beitel, G. J., Palladino, M. J. <strong>Novel mutations affecting the Na, K ATPase alpha model complex neurological diseases and implicate the sodium pump in increased longevity.</strong> Hum. Genet. 126: 431-447, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19455355/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19455355</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19455355[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/10.1007/s00439-009-0673-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19455355">Ashmore et al. (2009)</a> suggested that these findings may be relevant for studying the pathogenesis of FHM2 and DYT12 (<a href="/entry/128235">128235</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19455355" 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">rs28933398 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28933398;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=rs28933398" 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=rs28933398" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a large Italian family with familial hemiplegic migraine-2 (<a href="/entry/602481">602481</a>), <a href="#6" class="mim-tip-reference" title="De Fusco, M., Marconi, R., Silvestri, L., Atorino, L., Rampoldi, L., Morgante, L., Ballabio, A., Aridon, P., Casari, G. <strong>Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha-2 subunit associated with familial hemiplegic migraine type 2.</strong> Nature Genet. 33: 192-196, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12539047/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12539047</a>] [<a href="https://doi.org/10.1038/ng1081" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12539047">De Fusco et al. (2003)</a> identified a heterozygous 2395T-C mutation in the ATP1A2 gene, resulting in a leu764-to-pro (L764P) substitution. The mutation segregated with the disorder in all 22 affected members who were tested and was not present in 400 control chromosomes. Functional studies in HeLa cells showed that the L764P and W887R (<a href="#0002">182340.0002</a>) mutations inhibited Na+/K+ pump activity, but did not affect assembly or translocation to the cell membrane. Resultant abnormalities in intra- and extracellular ion concentrations may contribute to the pathophysiology of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12539047" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013781 OR RCV001533155" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013781, RCV001533155" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013781...</a>
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<p>In a family with familial hemiplegic migraine-2 (<a href="/entry/602481">602481</a>), <a href="#6" class="mim-tip-reference" title="De Fusco, M., Marconi, R., Silvestri, L., Atorino, L., Rampoldi, L., Morgante, L., Ballabio, A., Aridon, P., Casari, G. <strong>Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha-2 subunit associated with familial hemiplegic migraine type 2.</strong> Nature Genet. 33: 192-196, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12539047/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12539047</a>] [<a href="https://doi.org/10.1038/ng1081" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12539047">De Fusco et al. (2003)</a> identified a heterozygous 2763T-C mutation in the ATP1A2 gene, resulting in a trp887-to-arg (W887R) substitution. The mutation segregated with the disorder in all 7 affected members and was not present in 400 control chromosomes. Also see <a href="#0001">182340.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12539047" 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">rs28933400 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28933400;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=rs28933400" 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=rs28933400" 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 family with familial hemiplegic migraine-2 (<a href="/entry/602481">602481</a>), <a href="#32" class="mim-tip-reference" title="Vanmolkot, K. R. J., Kors, E. E., Hottenga, J.-J., Terwindt, G. M., Haan, J., Hoefnagels, W. A. J., Black, D. F., Sandkuijl, L. A., Frants, R. R., Ferrari, M. D., van den Maagdenberg, A. M. J. M. <strong>Novel mutations in the Na(+),K(+)-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions.</strong> Ann. Neurol. 54: 360-366, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12953268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12953268</a>] [<a href="https://doi.org/10.1002/ana.10674" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12953268">Vanmolkot et al. (2003)</a> identified a heterozygous 2296T-C transition in exon 16 of the ATP1A2 gene, resulting in a met731-to-thr (M731T) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12953268" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Segall, L., Mezzetti, A., Scanzano, R., Gargus, J. J., Purisima, E., Blostein, R. <strong>Alterations in the alpha-2 isoform of Na,K-ATPase associated with familial hemiplegic migraine type 2.</strong> Proc. Nat. Acad. Sci. 102: 11106-11111, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16037212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16037212</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16037212[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0504323102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16037212">Segall et al. (2005)</a> found that the mutant M731T and R689Q (<a href="#0004">182340.0004</a>) rat Atp1a2 proteins transfected into HeLa cells showed reduced catalytic turnover and increased apparent affinity for extracellular potassium. In addition, M731T showed an increased apparent affinity for ATP. <a href="#23" class="mim-tip-reference" title="Segall, L., Mezzetti, A., Scanzano, R., Gargus, J. J., Purisima, E., Blostein, R. <strong>Alterations in the alpha-2 isoform of Na,K-ATPase associated with familial hemiplegic migraine type 2.</strong> Proc. Nat. Acad. Sci. 102: 11106-11111, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16037212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16037212</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16037212[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0504323102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16037212">Segall et al. (2005)</a> suggested that the disease phenotype is caused by decreased activity of the Na+/K+ pump, resulting in delayed extracellular potassium clearance and/or altered localized calcium handling or signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16037212" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Castro, M.-J., Stam, A. H., Lemos, C., Barros, J., Gouveia, R. G., Martins, I. P., Koenderink, J. B., Vanmolkot, K. R. J., Mendes, A. P., Frants, R. R., Ferrari, M. D., Sequeiros, J., Pereira-Monteiro, J. M., van den Maagdenberg, A. M. J. M. <strong>Recurrent ATP1A2 mutations in Portuguese families with familial hemiplegic migraine.</strong> J. Hum. Genet. 52: 990-998, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17952365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17952365</a>] [<a href="https://doi.org/10.1007/s10038-007-0205-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17952365">Castro et al. (2007)</a> identified the M731T mutation in 3 affected members of a Portuguese family with FHM2. A fourth mutation carrier had only migraine with aura. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17952365" 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="#22" class="mim-tip-reference" title="Schack, V. R., Holm, R., Vilsen, B. <strong>Inhibition of phosphorylation of Na+,K+-ATPase by mutations causing familial hemiplegic migraine.</strong> J. Biol. Chem. 287: 2191-2202, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22117059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22117059</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22117059[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M111.323022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22117059">Schack et al. (2012)</a> noted that the M731T mutation occurs in the P domain. Expression of the mutation in COS-1 cells showed a severe reduction in the catalytic turnover rate of Na+ and K+, which was due to reduced Vmax of phosphorylation. The mutant showed essentially normal affinity for K+ and Na+. The decreased phosphorylation rate would lead to enhanced K+ competition with Na+ at intracellular sites, which would compromise pump function. The findings suggested that the disturbance of clearance of extracellular K+ by glial cells, thought to underlie FHM2, is due to low turnover rate of the pump and not to decreased affinity of the pump for external K+. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22117059" 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">rs28933401 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28933401;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=rs28933401" 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=rs28933401" 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=RCV000013783 OR RCV000761685" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013783, RCV000761685" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013783...</a>
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<p>In affected members of a family with familial hemiplegic migraine-2 (FHM2; <a href="/entry/602481">602481</a>), previously reported by <a href="#30" class="mim-tip-reference" title="Terwindt, G. M., Ophoff, R. A., Lindhout, D., Haan, J., Halley, D. J., Sandkuijl, L. A., Brouwer, O. F., Frants, R. R., Ferrari, M. D. <strong>Partial cosegregation of familial hemiplegic migraine and a benign familial infantile epileptic syndrome.</strong> Epilepsia 38: 915-921, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9579893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9579893</a>] [<a href="https://doi.org/10.1111/j.1528-1157.1997.tb01257.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9579893">Terwindt et al. (1997)</a>, <a href="#32" class="mim-tip-reference" title="Vanmolkot, K. R. J., Kors, E. E., Hottenga, J.-J., Terwindt, G. M., Haan, J., Hoefnagels, W. A. J., Black, D. F., Sandkuijl, L. A., Frants, R. R., Ferrari, M. D., van den Maagdenberg, A. M. J. M. <strong>Novel mutations in the Na(+),K(+)-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions.</strong> Ann. Neurol. 54: 360-366, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12953268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12953268</a>] [<a href="https://doi.org/10.1002/ana.10674" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12953268">Vanmolkot et al. (2003)</a> identified a 2170G-A transition in exon 15 of the ATP1A2 gene, resulting in an arg689-to-gln (R689Q) substitution. Three individuals with the mutation and FHM also had benign familial infantile convulsions (BFIC), 1 member had the mutation and only BFIC, and 2 members had the mutation and only migraine with or without aura. <a href="#19" class="mim-tip-reference" title="Pelzer, N., de Vries, B., Kamphorst, J. T., Vijfhuizen, L. S., Ferrari, M. D., Haan, J., van den Maagdenberg, A. M. J. M., Terwindt, G. M. <strong>PRRT2 and hemiplegic migraine: a complex association.</strong> Neurology 83: 288-290, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24928127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24928127</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000590" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24928127">Pelzer et al. (2014)</a> found that 4 affected members of the family reported by <a href="#32" class="mim-tip-reference" title="Vanmolkot, K. R. J., Kors, E. E., Hottenga, J.-J., Terwindt, G. M., Haan, J., Hoefnagels, W. A. J., Black, D. F., Sandkuijl, L. A., Frants, R. R., Ferrari, M. D., van den Maagdenberg, A. M. J. M. <strong>Novel mutations in the Na(+),K(+)-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions.</strong> Ann. Neurol. 54: 360-366, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12953268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12953268</a>] [<a href="https://doi.org/10.1002/ana.10674" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12953268">Vanmolkot et al. (2003)</a> who had BFIC carried a heterozygous truncating mutation in the PRRT2 gene (<a href="/entry/614386#0016">614386.0016</a>), consistent with benign familial infantile convulsions-2 (BFIC2; <a href="/entry/605751">605751</a>). Thus, 2 different neurologic disorders segregated in this family; the diagnosis was more complex as both disorders showed incomplete penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9579893+12953268+24928127" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Segall, L., Mezzetti, A., Scanzano, R., Gargus, J. J., Purisima, E., Blostein, R. <strong>Alterations in the alpha-2 isoform of Na,K-ATPase associated with familial hemiplegic migraine type 2.</strong> Proc. Nat. Acad. Sci. 102: 11106-11111, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16037212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16037212</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16037212[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0504323102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16037212">Segall et al. (2005)</a> found that the mutant R689Q and M731T (<a href="#0003">182340.0003</a>) rat Atp1a2 proteins transfected into HeLa cells showed reduced catalytic turnover and increased apparent affinity for extracellular potassium. <a href="#23" class="mim-tip-reference" title="Segall, L., Mezzetti, A., Scanzano, R., Gargus, J. J., Purisima, E., Blostein, R. <strong>Alterations in the alpha-2 isoform of Na,K-ATPase associated with familial hemiplegic migraine type 2.</strong> Proc. Nat. Acad. Sci. 102: 11106-11111, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16037212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16037212</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16037212[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0504323102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16037212">Segall et al. (2005)</a> suggested that the disease phenotype is caused by decreased activity of the Na+/K+ pump, resulting in delayed extracellular potassium clearance and/or altered localized calcium handling or signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16037212" 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>.0005 ALTERNATING HEMIPLEGIA OF CHILDHOOD 1</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">rs28934002 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28934002;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=rs28934002" 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=rs28934002" 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=RCV000013784 OR RCV001229312" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013784, RCV001229312" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013784...</a>
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<p>In affected members of a family with alternating hemiplegia of childhood-1 (AHC1; <a href="/entry/104290">104290</a>) originally reported by <a href="#11" class="mim-tip-reference" title="Kanavakis, E., Xaidara, A., Papathanasiou-Klontza, D., Papadimitriou, A., Velentza, S., Youroukos, S. <strong>Alternating hemiplegia of childhood: a syndrome inherited with an autosomal dominant trait.</strong> Dev. Med. Child Neurol. 45: 833-836, 2003. Note: Erratum: Dev. Med. Child Neurol. 46: 288 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14667076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14667076</a>] [<a href="https://doi.org/10.1017/s0012162203001543" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14667076">Kanavakis et al. (2003)</a>, <a href="#29" class="mim-tip-reference" title="Swoboda, K. J., Kanavakis, E., Xaidara, A., Johnson, J. E., Leppert, M. F., Schlesinger-Massart, M. B., Ptacek, L. J., Silver, K., Youroukos, S. <strong>Alternating hemiplegia of childhood or familial hemiplegic migraine?: a novel ATP1A2 mutation.</strong> Ann. Neurol. 55: 884-887, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15174025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15174025</a>] [<a href="https://doi.org/10.1002/ana.20134" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15174025">Swoboda et al. (2004)</a> identified a 1237C-A transversion in exon 9 of the ATP1A2 gene, resulting in a thr378-to-asn (T378N) substitution. The mutation affects a highly conserved residue in the second cytoplasmic loop of the protein and was not identified in 382 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15174025+14667076" 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 4 affected members of a Greek family with alternating hemiplegia of childhood, <a href="#3" class="mim-tip-reference" title="Bassi, M. T., Bresolin, N., Tonelli, A., Nazos, K., Crippa, F., Baschirotto, C., Zucca, C., Bersano, A., Dolcetta, D., Boneschi, F. M., Barone, V., Casari, G. <strong>A novel mutation in the ATP1A2 gene causes alternating hemiplegia of childhood.</strong> J. Med. Genet. 41: 621-628, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15286158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15286158</a>] [<a href="https://doi.org/10.1136/jmg.2003.017863" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15286158">Bassi et al. (2004)</a> identified the T378N mutation. The mutation was not present in unaffected members of the family or in 250 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15286158" 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">rs121918612 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918612;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=rs121918612" 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=rs121918612" 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=RCV000013785 OR RCV001533152" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013785, RCV001533152" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013785...</a>
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<p>In affected members of an Italian family with severe familial hemiplegic migraine-2 (FHM2; <a href="/entry/602481">602481</a>), <a href="#27" class="mim-tip-reference" title="Spadaro, M., Ursu, S., Lehmann-Horn, F., Veneziano, L., Antonini, G., Giunti, P., Frontali, M., Jurkat-Rott, K. <strong>A G301R Na+/K+-ATPase mutation causes familial hemiplegic migraine type 2 with cerebellar signs.</strong> Neurogenetics 5: 177-185, 2004. Note: Erratum: Neurogenetics 6: 169 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15459825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15459825</a>] [<a href="https://doi.org/10.1007/s10048-004-0183-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15459825">Spadaro et al. (2004)</a> identified a 901G-A transition in the ATP1A2 gene, resulting in a gly301-to-arg (G301R) substitution. The mutation occurs in a highly conserved residue within transmembrane segment M3 of the protein that is important for the dephosphorylation of homologous ATPases. The mutation was not identified in 179 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15459825" 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 MIGRAINE, FAMILIAL HEMIPLEGIC, 2</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">rs121918613 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918613;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=rs121918613" 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=rs121918613" 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=RCV000013786" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013786" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013786</a>
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<p>In affected members of a Finnish family with familial hemiplegic migraine-2 (FHM2; <a href="/entry/602481">602481</a>) with associated symptoms such as coma and showing linkage to 1q23, <a href="#14" class="mim-tip-reference" title="Kaunisto, M. A., Harno, H., Vanmolkot, K. R. J., Gargus, J. J., Sun, G., Hamalainen, E., Liukkonen, E., Kallela, M., van den Maagdenberg, A. M. J. M., Frants, R. R., Farkkila, M., Palotie, A., Wessman, M. <strong>A novel missense ATP1A2 mutation in a Finnish family with familial hemiplegic migraine type 2.</strong> Neurogenetics 5: 141-146, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15133718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15133718</a>] [<a href="https://doi.org/10.1007/s10048-004-0178-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15133718">Kaunisto et al. (2004)</a> identified a 1033A-G transition in exon 9 of the ATP1A2 gene, resulting in a thr345-to-ala (T345A) substitution. All 11 affected members in this family showed hemisensoric aura with mild to moderate hemiparesis affecting mostly the arm. Interictal neurologic examinations were normal. Migraine attacks usually started with gradually spreading hemisensoric aura which was always accompanied by hemiparesthesias, dysarthria, or dysphagia, and often by visual symptoms. Of the 11 affected family members, 10 reported onset before the age of 15 years. The frequency of attacks varied from 2 per month to once a year, and 2 individuals reported cessation of attacks during their teens. Minor head trauma triggered attacks in 5 of the 11 patients and severe vomiting could last for days in 4 patients. Confusion and mild anxiety were common features during attacks in 5 subjects. In 4 of these patients a mild head trauma had triggered coma accompanied by fever that lasted 2 days to 2 weeks. Hemiparetic symptoms could persist for as long as 2 weeks in some individuals. None of the patients had seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15133718" 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 functional expression studies, <a href="#24" class="mim-tip-reference" title="Segall, L., Scanzano, R., Kaunisto, M. A., Wessman, M., Palotie, A., Gargus, J. J., Blostein, R. <strong>Kinetic alterations due to a missense mutation in the Na,K-ATPase alpha-2 subunit cause familial hemiplegic migraine type 2.</strong> J. Biol. Chem. 279: 43692-43696, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15308625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15308625</a>] [<a href="https://doi.org/10.1074/jbc.M407471200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15308625">Segall et al. (2004)</a> found that cells transduced with the T345A mutant protein showed growth comparable to wildtype cells and no reduction in catalytic turnover of the subunit protein; however, kinetic studies showed that the T345A mutant protein had an approximately 2-fold decrease in apparent affinity for extracellular potassium. The authors concluded that the slow removal of potassium from the extracellular space slowed the recovery phase of nerve impulse transmission. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15308625" 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="#22" class="mim-tip-reference" title="Schack, V. R., Holm, R., Vilsen, B. <strong>Inhibition of phosphorylation of Na+,K+-ATPase by mutations causing familial hemiplegic migraine.</strong> J. Biol. Chem. 287: 2191-2202, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22117059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22117059</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22117059[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M111.323022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22117059">Schack et al. (2012)</a> noted that the T345A mutation occurs in the M4 transmembrane domain near the P domain. Expression of the mutation in COS-1 cells showed about a 50% reduction in the catalytic turnover rate of Na+ and K+, which was due to reduced Vmax of phosphorylation. The mutant showed essentially normal affinity for K+ and Na+. The decreased phosphorylation rate would lead to enhanced K+ competition with Na+ at intracellular sites, which would compromise pump function. The findings suggested that the disturbance of clearance of extracellular K+ by glial cells, thought to underlie FHM2, is due to low turnover rate of the pump and not to decreased affinity of the pump for external K+. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22117059" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 MIGRAINE, FAMILIAL HEMIPLEGIC, 2</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013787 OR RCV001533153 OR RCV004700227" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013787, RCV001533153, RCV004700227" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013787...</a>
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<p>In 6 affected members spanning 4 generations of a family with familial hemiplegic migraine-2 (FHM2; <a href="/entry/602481">602481</a>), <a href="#10" class="mim-tip-reference" title="Jurkat-Rott, K., Freilinger, T., Dreier, J. P., Herzog, J., Gobel, H., Petzold, G. C., Montagna, P., Gasser, T., Lehmann-Horn, F., Dichgans, M. <strong>Variability of familial hemiplegic migraine with novel A1A2 Na(+)/K(+)-ATPase variants.</strong> Neurology 62: 1857-1861, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15159495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15159495</a>] [<a href="https://doi.org/10.1212/01.wnl.0000127310.11526.fd" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15159495">Jurkat-Rott et al. (2004)</a> identified a heterozygous 2152G-A transition in the ATP1A2 gene, resulting in an asp718-to-asn (D718N) substitution. Age at onset ranged from 3 to 12 years, and hemiplegic episodes were long, lasting from 6 to 336 hours. In most patients, the frequency of attacks ranged from 1 to 2 episodes per month. Aural features included dysarthria, diplopia, and impaired hearing. One patient was mentally retarded and had epileptic seizures, and another had low IQ. The D718N mutation affects a magnesium-interaction site and is predicted to result in complete loss of ATPase function due to lack of catalytic activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15159495" 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">rs121918615 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918615;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=rs121918615" 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=rs121918615" 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=RCV000013788 OR RCV000529838 OR RCV001560539 OR RCV003313029" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013788, RCV000529838, RCV001560539, RCV003313029" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013788...</a>
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<p>In 5 affected members of a family with familial hemiplegic migraine-2 (FHM2; <a href="/entry/602481">602481</a>), <a href="#10" class="mim-tip-reference" title="Jurkat-Rott, K., Freilinger, T., Dreier, J. P., Herzog, J., Gobel, H., Petzold, G. C., Montagna, P., Gasser, T., Lehmann-Horn, F., Dichgans, M. <strong>Variability of familial hemiplegic migraine with novel A1A2 Na(+)/K(+)-ATPase variants.</strong> Neurology 62: 1857-1861, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15159495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15159495</a>] [<a href="https://doi.org/10.1212/01.wnl.0000127310.11526.fd" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15159495">Jurkat-Rott et al. (2004)</a> identified a heterozygous 2936C-T transition in the ATP1A2 gene, resulting in a pro979-to-leu (P979L) substitution. Age at onset ranged from 3 to 23 years, and hemiplegic attacks occurred several times per year. One patient had mental retardation, and another had epileptic seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15159495" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 MIGRAINE, FAMILIAL BASILAR</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918616 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918616;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121918616?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918616" 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=rs121918616" 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=RCV000013789 OR RCV000423537 OR RCV001851832 OR RCV003448245 OR RCV004555532 OR RCV004819208" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013789, RCV000423537, RCV001851832, RCV003448245, RCV004555532, RCV004819208" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013789...</a>
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<p>In a father and son (proband) with basilar migraine (see <a href="/entry/602481">602481</a>), <a href="#1" class="mim-tip-reference" title="Ambrosini, A., D'Onofrio, M., Grieco, G. S., Di Mambro, A., Montagna, G., Fortini, D., Nicoletti, F., Nappi, G., Sances, G., Schoenen, J., Buzzi, M. G., Santorelli, F. M., Pierelli, F. <strong>Familial basilar migraine associated with a new mutation in the ATP1A2 gene.</strong> Neurology 65: 1826-1828, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16344534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16344534</a>] [<a href="https://doi.org/10.1212/01.wnl.0000187072.71931.c0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16344534">Ambrosini et al. (2005)</a> identified a heterozygous 1643G-A transition in exon 12 of the ATP1A2 gene, resulting in an arg548-to-his (R548H) substitution in a highly conserved region of the protein. Residue 548 occurs in the major alpha-2 subunit cytoplasmic loop, which plays a key role in pump function. The mutation was not identified in 400 control chromosomes. The R548H mutation was also identified in the proband's paternal uncle who had basilar migraines in his youth, but at the time of the report had migraine without aura, and in the proband's first cousin, who had migraine without aura. <a href="#1" class="mim-tip-reference" title="Ambrosini, A., D'Onofrio, M., Grieco, G. S., Di Mambro, A., Montagna, G., Fortini, D., Nicoletti, F., Nappi, G., Sances, G., Schoenen, J., Buzzi, M. G., Santorelli, F. M., Pierelli, F. <strong>Familial basilar migraine associated with a new mutation in the ATP1A2 gene.</strong> Neurology 65: 1826-1828, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16344534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16344534</a>] [<a href="https://doi.org/10.1212/01.wnl.0000187072.71931.c0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16344534">Ambrosini et al. (2005)</a> concluded that basilar migraine is allelic to FHM2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16344534" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 MIGRAINE, FAMILIAL HEMIPLEGIC, 2</strong>
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ATP1A2, ILE286THR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918617 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918617;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=rs121918617" 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=rs121918617" 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=RCV000013790 OR RCV002513024" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013790, RCV002513024" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013790...</a>
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<p>In a young woman with severe hemiplegic migraine (FHM2; <a href="/entry/602481">602481</a>), <a href="#33" class="mim-tip-reference" title="Vanmolkot, K. R. J., Stam, A. H., Raman, A., Koenderink, J. B., de Vries, B., van den Boogerd, E. H., van Vark, J., van den Heuvel, J. J. M. W., Bajaj, N., Terwindt, G. M., Haan, J., Frants, R. R., Ferrari, M. D., van den Maagdenberg, A. M. J. M. <strong>First case of compound heterozygosity in Na,K-ATPase gene ATP1A2 in familial hemiplegic migraine.</strong> Europ. J. Hum. Genet. 15: 884-888, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17473835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17473835</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201841" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17473835">Vanmolkot et al. (2007)</a> identified compound heterozygosity for 2 mutations in the ATP1A2 gene: a 961T-C transition in exon 8, resulting in an ile286-to-thr (I286T) substitution, and a 1348C-T transition in exon 10, resulting in a thr415-to-met (T415M; <a href="#0012">182340.0012</a>) substitution, both of which are located in the intracellular portion of the protein. The patient had onset at age 8 years of hemiplegic migraine with visual aura and subsequent dysphasia, hemiplegia, and migraine headache. Her mother and maternal aunt, both of whom were heterozygous for the I286T mutation, had aura without headache and a milder form of hemiplegic migraine, respectively. In vitro functional expression studies showed that the I286T mutant protein was expressed but caused significantly decreased cell survival that reflected a dysfunctional pump. Her unaffected daughter was heterozygous for the T415M mutation, as were her father and son, who had nonmigrainous headaches and migraine with aura, respectively. In vitro functional expression studies showed that the T415M mutant protein was expressed, but cells with the mutant protein were unable to survive, indicating complete loss of function. <a href="#33" class="mim-tip-reference" title="Vanmolkot, K. R. J., Stam, A. H., Raman, A., Koenderink, J. B., de Vries, B., van den Boogerd, E. H., van Vark, J., van den Heuvel, J. J. M. W., Bajaj, N., Terwindt, G. M., Haan, J., Frants, R. R., Ferrari, M. D., van den Maagdenberg, A. M. J. M. <strong>First case of compound heterozygosity in Na,K-ATPase gene ATP1A2 in familial hemiplegic migraine.</strong> Europ. J. Hum. Genet. 15: 884-888, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17473835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17473835</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201841" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17473835">Vanmolkot et al. (2007)</a> noted that this was the first reported case of compound heterozygosity for mutations in the ATP1A2 gene and concluded that the mutations showed reduced penetrance in the heterozygous state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17473835" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918618 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918618;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121918618?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918618" 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=rs121918618" 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=RCV000013791 OR RCV000547097 OR RCV001097906 OR RCV003398497" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013791, RCV000547097, RCV001097906, RCV003398497" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013791...</a>
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<p>For discussion of the thr415-to-met (T415M) mutation in the ATP1A2 gene that was found in compound heterozygous state in a patient with familial hemiplegic migraine-2 (FHM2; <a href="/entry/602481">602481</a>) by <a href="#33" class="mim-tip-reference" title="Vanmolkot, K. R. J., Stam, A. H., Raman, A., Koenderink, J. B., de Vries, B., van den Boogerd, E. H., van Vark, J., van den Heuvel, J. J. M. W., Bajaj, N., Terwindt, G. M., Haan, J., Frants, R. R., Ferrari, M. D., van den Maagdenberg, A. M. J. M. <strong>First case of compound heterozygosity in Na,K-ATPase gene ATP1A2 in familial hemiplegic migraine.</strong> Europ. J. Hum. Genet. 15: 884-888, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17473835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17473835</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201841" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17473835">Vanmolkot et al. (2007)</a>, see <a href="#0011">182340.0011</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17473835" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918619 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918619;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121918619?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918619" 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=rs121918619" 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=RCV000013792 OR RCV000442150 OR RCV001221618" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013792, RCV000442150, RCV001221618" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013792...</a>
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<p>In 3 affected members of a family with familial hemiplegic migraine-2 (FHM2; <a href="/entry/602481">602481</a>), <a href="#31" class="mim-tip-reference" title="Tonelli, A., Gallanti, A., Bersano, A., Cardin, V., Ballabio, E., Airoldi, G., Redaelli, F., Candelise, L., Bresolin, N., Bassi, M. T. <strong>Amino acid changes in the amino terminus of the Na,K-adenosine triphosphatase alpha-2 subunit associated to familial and sporadic hemiplegic migraine.</strong> Clin. Genet. 72: 517-523, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17877748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17877748</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00892.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17877748">Tonelli et al. (2007)</a> identified a heterozygous 193C-T transition in exon 4 of the ATP1A2 gene, resulting in an arg65-to-trp (R65W) substitution in the cytoplasmic N-terminal portion of the protein, within the actuator domain (A domain). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17877748" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918620 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918620;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121918620?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918620" 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=rs121918620" 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=RCV000013793 OR RCV001037466 OR RCV001781261 OR RCV002444429" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013793, RCV001037466, RCV001781261, RCV002444429" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013793...</a>
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<p>In affected members of a Portuguese family with pure familial hemiplegic migraine-2 (FHM2; <a href="/entry/602481">602481</a>), <a href="#4" class="mim-tip-reference" title="Castro, M.-J., Stam, A. H., Lemos, C., Barros, J., Gouveia, R. G., Martins, I. P., Koenderink, J. B., Vanmolkot, K. R. J., Mendes, A. P., Frants, R. R., Ferrari, M. D., Sequeiros, J., Pereira-Monteiro, J. M., van den Maagdenberg, A. M. J. M. <strong>Recurrent ATP1A2 mutations in Portuguese families with familial hemiplegic migraine.</strong> J. Hum. Genet. 52: 990-998, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17952365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17952365</a>] [<a href="https://doi.org/10.1007/s10038-007-0205-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17952365">Castro et al. (2007)</a> identified a heterozygous 1231C-T transition in exon 9 of the ATP1A2 gene, resulting in a thr376-to-met (T376M) substitution in the M4 cytoplasmic loop. In vitro functional expression studies showed that the mutant protein had decreased function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17952365" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0015 MIGRAINE, FAMILIAL HEMIPLEGIC, 2</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">rs869025341 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869025341;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=rs869025341" 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=rs869025341" 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=RCV000207519" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000207519" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000207519</a>
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<p>In affected members of a 3-generation Korean family (KNUF-47) with familial hemiplegic migraine-2 (FHM2; <a href="/entry/602481">602481</a>), <a href="#18" class="mim-tip-reference" title="Oh, S.-K., Baek, J.-I., Weigand, K. M., Venselaar, H., Swarts, H. G. P., Park, S.-H., Raza, M. H., Jung, D. J., Choi, S.-Y., Lee, S.-H., Friedrich, T., Vriend, G., Koenderink, J. B., Kim, U.-K., Lee, K.-Y. <strong>A missense variant of the ATP1A2 gene is associated with a novel phenotype of progressive sensorineural hearing loss associated with migraine.</strong> Europ. J. Hum. Genet. 23: 639-645, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25138102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25138102</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25138102[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2014.154" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25138102">Oh et al. (2015)</a> identified a heterozygous c.571G-A transition (c.571G-A, NM_00702.3) in the ATP1A2 gene, predicting a val191-to-met (V191M) substitution at a highly conserved residue in the A domain. All affected members of the family also had progressive hearing loss. The mutation segregated with the phenotype in the family and was not found in the dbSNP or 1000 Genomes Project databases or in 200 Korean controls with normal audiograms. In silico studies suggested that the variant causes a change in hydrophobic interactions and thereby slightly destabilizes the A domain of Na(+)/K(+)-ATPase. However, Western blot analysis of recombinant ATPase proteins in insect cells revealed similar expression levels of wildtype and mutant Na(+)/K(+)-ATPase, and inhibitor binding studies showed that the ouabain-binding level for mutant and wildtype was also similar. (See DFNA7 (<a href="/entry/601412">601412</a>) and DFNA49 (<a href="/entry/608372">608372</a>) for 2 hearing loss loci that map to the same region as the ATP1A2 gene.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25138102" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0016 FETAL AKINESIA, RESPIRATORY INSUFFICIENCY, MICROCEPHALY, POLYMICROGYRIA, AND DYSMORPHIC FACIES</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">rs1558008455 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1558008455;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=rs1558008455" 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=rs1558008455" 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=RCV001777174 OR RCV003768048" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001777174, RCV003768048" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001777174...</a>
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<p>In an infant (patient 2), born of Brazilian parents who were not known to be related (family 1), with fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (FARIMPD; <a href="/entry/619602">619602</a>), <a href="#15" class="mim-tip-reference" title="Monteiro, F. P., Curry, C. J., Hevner, R., Elliott, S., Fisher, J. H., Turocy, J., Dobyns, W. B., Costa, L. A., Freitas, E., Kitajima, J. P., Kok, F. <strong>Biallelic loss of function variants in ATP1A2 cause hydrops fetalis, microcephaly, arthrogryposis and extensive cortical malformations.</strong> Europ. J. Med. Genet. 63: 103624, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30690204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30690204</a>] [<a href="https://doi.org/10.1016/j.ejmg.2019.01.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30690204">Monteiro et al. (2020)</a> identified a homozygous 2-bp deletion (c.2104_2105delTG, NM_000702), predicted to result in a frameshift and premature termination (Cys702SerfsTer12) in the cytoplasmic domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each parent. The variant was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a complete loss of ATP1A2 function. The patient had a similarly affected sib (patient 1), but genetic analysis of the sib was not performed. Patient 2 and the affected sib both died at 2 months of age. The patients' mother reported occasional migraines without aura. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30690204" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0017 FETAL AKINESIA, RESPIRATORY INSUFFICIENCY, MICROCEPHALY, POLYMICROGYRIA, AND DYSMORPHIC FACIES</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">rs1558005340 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1558005340;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=rs1558005340" 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=rs1558005340" 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=RCV001008258 OR RCV001777176" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001008258, RCV001777176" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001008258...</a>
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<p>In a newborn female (patient 3), born of consanguineous Hispanic parents (family 2), with fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (FARIMPD; <a href="/entry/619602">619602</a>), <a href="#15" class="mim-tip-reference" title="Monteiro, F. P., Curry, C. J., Hevner, R., Elliott, S., Fisher, J. H., Turocy, J., Dobyns, W. B., Costa, L. A., Freitas, E., Kitajima, J. P., Kok, F. <strong>Biallelic loss of function variants in ATP1A2 cause hydrops fetalis, microcephaly, arthrogryposis and extensive cortical malformations.</strong> Europ. J. Med. Genet. 63: 103624, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30690204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30690204</a>] [<a href="https://doi.org/10.1016/j.ejmg.2019.01.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30690204">Monteiro et al. (2020)</a> identified a homozygous 1-bp deletion (c.835delC, NM_000702) in the ATP1A2 gene, predicted to result in a frameshift and premature termination (Arg279GlyfsTer4) in the cytoplasmic domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each parent. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a complete loss of ATP1A2 function. The patient died of respiratory insufficiency soon after birth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30690204" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0018 FETAL AKINESIA, RESPIRATORY INSUFFICIENCY, MICROCEPHALY, POLYMICROGYRIA, AND DYSMORPHIC FACIES</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">rs1558003446 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1558003446;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=rs1558003446" 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=rs1558003446" 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=RCV000754580 OR RCV001777173" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000754580, RCV001777173" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000754580...</a>
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<p>In 3 sibs, conceived of consanguineous Algerian parents (family A), with fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (FARIMPD; <a href="/entry/619602">619602</a>), <a href="#5" class="mim-tip-reference" title="Chatron, N., Cabet, S., Alix, E., Buenerd, A., Cox, P., Guibaud, L., Labalme, A., Marks, P., Osio, D., Putoux, A., Sanlaville, D., Lesca, G., Vasiljevic, A. <strong>A novel lethal recognizable polymicrogyric syndrome caused by ATP1A2 homozygous truncating variants.</strong> Brain 142: 3367-3374, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31608932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31608932</a>] [<a href="https://doi.org/10.1093/brain/awz272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31608932">Chatron et al. (2019)</a> identified a homozygous 2-bp duplication (c.295_296dupTC, NM_000702.3) in the ATP1A2 gene, resulting in a frameshift and premature termination (Ile100ProfsTer71). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was absent from the gnomAD database. No ATP1A2 immunostaining was detected in patient brain samples, confirming complete absence of the protein and a loss-of-function effect. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31608932" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0019 FETAL AKINESIA, RESPIRATORY INSUFFICIENCY, MICROCEPHALY, POLYMICROGYRIA, AND DYSMORPHIC FACIES</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">rs1558010146 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1558010146;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=rs1558010146" 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=rs1558010146" 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=RCV000754579 OR RCV001777172 OR RCV003332220" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000754579, RCV001777172, RCV003332220" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000754579...</a>
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<p>In a 35-week-old fetus, born of consanguineous Pakistani parents (family B), with fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (FARIMPD; <a href="/entry/619602">619602</a>), <a href="#5" class="mim-tip-reference" title="Chatron, N., Cabet, S., Alix, E., Buenerd, A., Cox, P., Guibaud, L., Labalme, A., Marks, P., Osio, D., Putoux, A., Sanlaville, D., Lesca, G., Vasiljevic, A. <strong>A novel lethal recognizable polymicrogyric syndrome caused by ATP1A2 homozygous truncating variants.</strong> Brain 142: 3367-3374, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31608932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31608932</a>] [<a href="https://doi.org/10.1093/brain/awz272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31608932">Chatron et al. (2019)</a> identified a homozygous c.2869G-T transversion (c.2869G-T, NM_000702.3) in the ATP1A2 gene, resulting in a glu957-to-ter (E957X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD 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=31608932" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0020 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 98</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">rs1057521630 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057521630;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=rs1057521630" 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=rs1057521630" 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=RCV000443567 OR RCV001777162" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000443567, RCV001777162" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000443567...</a>
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<p>In a 5-year-old boy (patient 2) with developmental and epileptic encephalopathy-98 (DEE98; <a href="/entry/619605">619605</a>), <a href="#34" class="mim-tip-reference" title="Vetro, A., Nielsen, H. N., Holm, R., Hevner, R. F., Parrini, E., Powis, Z., Moller, R. S., Bellan, C., Simonati, A., Lesca, G., Helbig, K. L., Palmer, E. E., and 18 others. <strong>ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria.</strong> Brain 144: 1435-1450, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33880529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33880529</a>] [<a href="https://doi.org/10.1093/brain/awab052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33880529">Vetro et al. (2021)</a> identified a de novo heterozygous c.1022G-T transversion (c.1022G-T, NM_000702.3) in the ATP1A2 gene, resulting in a cys341-to-phe (C341F) substitution at a conserved residue. In vitro functional expression studies showed that the variant was unable to support COS1 cell survival in culture. Phosphorylation was decreased to 10 to 15% of wildtype. The patient had a severe phenotype with onset of seizures at 3 weeks of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33880529" 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">rs1057518514 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057518514;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=rs1057518514" 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=rs1057518514" 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=RCV000412726 OR RCV001777160" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000412726, RCV001777160" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000412726...</a>
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<p>In 2 unrelated patients (patients 3 and 4) with developmental and epileptic encephalopathy-98 (DEE; <a href="/entry/619605">619605</a>), <a href="#34" class="mim-tip-reference" title="Vetro, A., Nielsen, H. N., Holm, R., Hevner, R. F., Parrini, E., Powis, Z., Moller, R. S., Bellan, C., Simonati, A., Lesca, G., Helbig, K. L., Palmer, E. E., and 18 others. <strong>ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria.</strong> Brain 144: 1435-1450, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33880529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33880529</a>] [<a href="https://doi.org/10.1093/brain/awab052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33880529">Vetro et al. (2021)</a> identified a de novo heterozygous c.1097G-C transversion (c.1097G-C, NM_000702.3) in the ATP1A2 gene, resulting in a gly366-to-ala (G366A) substitution at a conserved residue. In vitro functional expression studies showed that the variant was unable to support COS1 cell survival in culture. Phosphorylation was decreased to 61% of wildtype, and there was decreased affinity for both Na+ and K+ ions, consistent with pump dysfunction. The patients had a severe phenotype with onset of seizures in the first month of life. Both died of complications of refractory status epilepticus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33880529" 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>.0022 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 98</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">rs2101996488 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2101996488;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=rs2101996488" 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=rs2101996488" 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=RCV001581019 OR RCV001777178 OR RCV001777179" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001581019, RCV001777178, RCV001777179" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001581019...</a>
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<p>In an 11-year-old boy (patient 6) with developmental and epileptic encephalopathy-98 (DEE98; <a href="/entry/619605">619605</a>), <a href="#34" class="mim-tip-reference" title="Vetro, A., Nielsen, H. N., Holm, R., Hevner, R. F., Parrini, E., Powis, Z., Moller, R. S., Bellan, C., Simonati, A., Lesca, G., Helbig, K. L., Palmer, E. E., and 18 others. <strong>ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria.</strong> Brain 144: 1435-1450, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33880529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33880529</a>] [<a href="https://doi.org/10.1093/brain/awab052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33880529">Vetro et al. (2021)</a> identified a de novo heterozygous c.2723G-A transition (c.2723G-A, NM_000702.3) in the ATP1A2 gene, resulting in an arg908-to-gln (R908Q) substitution at a conserved residue. In vitro functional expression studies showed that the variant was able to support COS1 cell survival in growth culture. However, the pump activity at the membrane was decreased to about 22% of controls due to reduced Na+/(K+)ATPase turnover rate. The patient had onset of focal seizures at 8 years of age. He had moderate developmental delay with hypotonic quadriparesis; brain imaging showed polymicrogyria with thick corpus callosum. <a href="#34" class="mim-tip-reference" title="Vetro, A., Nielsen, H. N., Holm, R., Hevner, R. F., Parrini, E., Powis, Z., Moller, R. S., Bellan, C., Simonati, A., Lesca, G., Helbig, K. L., Palmer, E. E., and 18 others. <strong>ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria.</strong> Brain 144: 1435-1450, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33880529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33880529</a>] [<a href="https://doi.org/10.1093/brain/awab052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33880529">Vetro et al. (2021)</a> noted that a heterozygous R908Q mutation had been reported in patients with familial hemiplegic migraine-2 (FHM2; <a href="/entry/602481">602481</a>) (see, e.g., <a href="#7" class="mim-tip-reference" title="De Vries, B., Freilinger, T., Vanmolkot, K. R. J., Koenderink, J. B., Stam, A. H., Terwindt, G. M., Babini, E., van den Boogerd, E.H., van den Heuvel, J. J. M. W., Frants, R. R., Haan, J., Pusch, M., van den Maagdenberg, A. M. J. M., Ferrari, M. D., Dichgans, M. <strong>Systematic analysis of three FHM genes in 39 sporadic patients with hemiplegic migraine.</strong> Neurology 69: 2170-2176, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18056581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18056581</a>] [<a href="https://doi.org/10.1212/01.wnl.0000295670.01629.5a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18056581">De Vries et al., 2007</a>), indicating that the same mutation may have different phenotypic consequences. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18056581+33880529" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0023 ALTERNATING HEMIPLEGIA OF CHILDHOOD 1</strong>
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ATP1A2, SER779ASN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2101995480 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2101995480;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=rs2101995480" 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=rs2101995480" 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=RCV001777180" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001777180" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001777180</a>
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<p>In a Brazilian boy with a phenotype reminiscent of alternating hemiplegia of childhood-1 (AHC1; <a href="/entry/104290">104290</a>), <a href="#21" class="mim-tip-reference" title="Sampedro Castaneda, M., Zanoteli, E., Scalco, R. S., Scaramuzzi, V., Marques Caldas, V., Conti Reed, U., da Silva, A. M. S., O'Callaghan, B., Phadke, R., Bugiardini, E., Sud, R., McCall, S., Hanna, M. G., Poulsen, H., Mannikko, R., Matthews, E. <strong>A novel ATP1A2 mutation in a patient with hypokalaemic periodic paralysis and CNS symptoms.</strong> Brain 141: 3308-3318, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30423015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30423015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30423015[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/awy283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30423015">Sampedro Castaneda et al. (2018)</a> identified a de novo heterozygous c.2336G-A transition in the ATP1A2 gene, resulting in a ser779-to-asn (S779N) substitution at a conserved residue in an ion-binding site. The mutation, which was found by Sanger sequencing, was not present in the gnomAD database. In vitro electrophysiologic studies in Xenopus oocytes showed that the mutation caused a 'leaky' inward current in the mutant pump in the presence of both high and low K+ concentrations, as well as altered Na+/K+ turnover activity rates of the pump. The voltage dependence of transient currents was left-shifted in mutant pumps. These changes were predicted to underlie abnormal membrane depolarization, resulting in muscle inexcitability leading to paralysis. The patient developed episodic tetraparesis at age 2 years. Laboratory studies during the episodes showed increased serum creatine kinase and low serum potassium. The symptoms improved with potassium, but worsened with acetazolamide. <a href="#21" class="mim-tip-reference" title="Sampedro Castaneda, M., Zanoteli, E., Scalco, R. S., Scaramuzzi, V., Marques Caldas, V., Conti Reed, U., da Silva, A. M. S., O'Callaghan, B., Phadke, R., Bugiardini, E., Sud, R., McCall, S., Hanna, M. G., Poulsen, H., Mannikko, R., Matthews, E. <strong>A novel ATP1A2 mutation in a patient with hypokalaemic periodic paralysis and CNS symptoms.</strong> Brain 141: 3308-3318, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30423015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30423015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30423015[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/awy283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30423015">Sampedro Castaneda et al. (2018)</a> noted the phenotypic similarities to hypokalemic periodic paralysis (see <a href="/entry/170400">170400</a>) but with additional central nervous system involvement, thus expanding the phenotypic spectrum of ATP1A2 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30423015" 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>REFERENCES</strong>
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<a id="Ambrosini2005" class="mim-anchor"></a>
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Ambrosini, A., D'Onofrio, M., Grieco, G. S., Di Mambro, A., Montagna, G., Fortini, D., Nicoletti, F., Nappi, G., Sances, G., Schoenen, J., Buzzi, M. G., Santorelli, F. M., Pierelli, F.
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<strong>Familial basilar migraine associated with a new mutation in the ATP1A2 gene.</strong>
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Neurology 65: 1826-1828, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16344534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16344534</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16344534" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000187072.71931.c0" target="_blank">Full Text</a>]
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Ashmore, L. J., Hrizo, S. L., Paul, S. M., Van Voorhies, W. A., Beitel, G. J., Palladino, M. J.
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<strong>Novel mutations affecting the Na, K ATPase alpha model complex neurological diseases and implicate the sodium pump in increased longevity.</strong>
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Hum. Genet. 126: 431-447, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19455355/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19455355</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19455355[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=19455355" 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/s00439-009-0673-2" target="_blank">Full Text</a>]
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Bassi, M. T., Bresolin, N., Tonelli, A., Nazos, K., Crippa, F., Baschirotto, C., Zucca, C., Bersano, A., Dolcetta, D., Boneschi, F. M., Barone, V., Casari, G.
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<strong>A novel mutation in the ATP1A2 gene causes alternating hemiplegia of childhood.</strong>
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J. Med. Genet. 41: 621-628, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15286158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15286158</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15286158" 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.2003.017863" target="_blank">Full Text</a>]
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Castro, M.-J., Stam, A. H., Lemos, C., Barros, J., Gouveia, R. G., Martins, I. P., Koenderink, J. B., Vanmolkot, K. R. J., Mendes, A. P., Frants, R. R., Ferrari, M. D., Sequeiros, J., Pereira-Monteiro, J. M., van den Maagdenberg, A. M. J. M.
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<strong>Recurrent ATP1A2 mutations in Portuguese families with familial hemiplegic migraine.</strong>
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J. Hum. Genet. 52: 990-998, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17952365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17952365</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17952365" 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/s10038-007-0205-7" target="_blank">Full Text</a>]
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Chatron, N., Cabet, S., Alix, E., Buenerd, A., Cox, P., Guibaud, L., Labalme, A., Marks, P., Osio, D., Putoux, A., Sanlaville, D., Lesca, G., Vasiljevic, A.
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<strong>A novel lethal recognizable polymicrogyric syndrome caused by ATP1A2 homozygous truncating variants.</strong>
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Brain 142: 3367-3374, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31608932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31608932</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31608932" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/awz272" target="_blank">Full Text</a>]
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De Fusco, M., Marconi, R., Silvestri, L., Atorino, L., Rampoldi, L., Morgante, L., Ballabio, A., Aridon, P., Casari, G.
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<strong>Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha-2 subunit associated with familial hemiplegic migraine type 2.</strong>
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Nature Genet. 33: 192-196, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12539047/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12539047</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12539047" 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/ng1081" target="_blank">Full Text</a>]
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<a id="De Vries2007" class="mim-anchor"></a>
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De Vries, B., Freilinger, T., Vanmolkot, K. R. J., Koenderink, J. B., Stam, A. H., Terwindt, G. M., Babini, E., van den Boogerd, E.H., van den Heuvel, J. J. M. W., Frants, R. R., Haan, J., Pusch, M., van den Maagdenberg, A. M. J. M., Ferrari, M. D., Dichgans, M.
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<strong>Systematic analysis of three FHM genes in 39 sporadic patients with hemiplegic migraine.</strong>
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Neurology 69: 2170-2176, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18056581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18056581</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18056581" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000295670.01629.5a" target="_blank">Full Text</a>]
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Ikeda, K., Onimaru, H., Yamada, J., Inoue, K., Ueno, S., Onaka, T., Toyoda, H., Arata, A., Ishikawa, T., Taketo, M. M., Fukuda, A., Kawakami, K.
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<strong>Malfunction of respiratory-related neuronal activity in Na+, K(+)-ATPase alpha-2 subunit-deficient mice is attributable to abnormal Cl- homeostasis in brainstem neurons.</strong>
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J. Neurosci. 24: 10693-10701, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15564586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15564586</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15564586[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=15564586" 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/10.1523/JNEUROSCI.2909-04.2004" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15308625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15308625</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15308625" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M407471200" target="_blank">Full Text</a>]
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<a id="Shull1987" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Shull, M. M., Lingrel, J. B.
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<strong>Multiple genes encode the human Na+,K+-ATPase catalytic subunit.</strong>
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Proc. Nat. Acad. Sci. 84: 4039-4043, 1987.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3035563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3035563</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3035563" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.84.12.4039" target="_blank">Full Text</a>]
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<a id="Shull1989" class="mim-anchor"></a>
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Shull, M. M., Pugh, D. G., Lingrel, J. B.
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<strong>Characterization of the human Na,K-ATPase alpha 2 gene and identification of intragenic restriction fragment length polymorphisms.</strong>
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J. Biol. Chem. 264: 17532-17543, 1989.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2477373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2477373</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2477373" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Spadaro2004" class="mim-anchor"></a>
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<p class="mim-text-font">
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Spadaro, M., Ursu, S., Lehmann-Horn, F., Veneziano, L., Antonini, G., Giunti, P., Frontali, M., Jurkat-Rott, K.
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<strong>A G301R Na+/K+-ATPase mutation causes familial hemiplegic migraine type 2 with cerebellar signs.</strong>
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Neurogenetics 5: 177-185, 2004. Note: Erratum: Neurogenetics 6: 169 only, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15459825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15459825</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15459825" 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/s10048-004-0183-2" target="_blank">Full Text</a>]
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<a id="Stumpf2021" class="mim-anchor"></a>
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<p class="mim-text-font">
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Stumpf, A. M.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 11/09/2021.
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Swoboda, K. J., Kanavakis, E., Xaidara, A., Johnson, J. E., Leppert, M. F., Schlesinger-Massart, M. B., Ptacek, L. J., Silver, K., Youroukos, S.
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<strong>Alternating hemiplegia of childhood or familial hemiplegic migraine?: a novel ATP1A2 mutation.</strong>
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Ann. Neurol. 55: 884-887, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15174025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15174025</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15174025" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.20134" target="_blank">Full Text</a>]
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Terwindt, G. M., Ophoff, R. A., Lindhout, D., Haan, J., Halley, D. J., Sandkuijl, L. A., Brouwer, O. F., Frants, R. R., Ferrari, M. D.
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<strong>Partial cosegregation of familial hemiplegic migraine and a benign familial infantile epileptic syndrome.</strong>
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Epilepsia 38: 915-921, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9579893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9579893</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9579893" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1528-1157.1997.tb01257.x" target="_blank">Full Text</a>]
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Tonelli, A., Gallanti, A., Bersano, A., Cardin, V., Ballabio, E., Airoldi, G., Redaelli, F., Candelise, L., Bresolin, N., Bassi, M. T.
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<strong>Amino acid changes in the amino terminus of the Na,K-adenosine triphosphatase alpha-2 subunit associated to familial and sporadic hemiplegic migraine.</strong>
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Clin. Genet. 72: 517-523, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17877748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17877748</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17877748" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2007.00892.x" target="_blank">Full Text</a>]
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Vanmolkot, K. R. J., Kors, E. E., Hottenga, J.-J., Terwindt, G. M., Haan, J., Hoefnagels, W. A. J., Black, D. F., Sandkuijl, L. A., Frants, R. R., Ferrari, M. D., van den Maagdenberg, A. M. J. M.
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<strong>Novel mutations in the Na(+),K(+)-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions.</strong>
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Ann. Neurol. 54: 360-366, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12953268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12953268</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12953268" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.10674" target="_blank">Full Text</a>]
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Vanmolkot, K. R. J., Stam, A. H., Raman, A., Koenderink, J. B., de Vries, B., van den Boogerd, E. H., van Vark, J., van den Heuvel, J. J. M. W., Bajaj, N., Terwindt, G. M., Haan, J., Frants, R. R., Ferrari, M. D., van den Maagdenberg, A. M. J. M.
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<strong>First case of compound heterozygosity in Na,K-ATPase gene ATP1A2 in familial hemiplegic migraine.</strong>
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Europ. J. Hum. Genet. 15: 884-888, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17473835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17473835</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17473835" 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/sj.ejhg.5201841" target="_blank">Full Text</a>]
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<a id="Vetro2021" class="mim-anchor"></a>
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Vetro, A., Nielsen, H. N., Holm, R., Hevner, R. F., Parrini, E., Powis, Z., Moller, R. S., Bellan, C., Simonati, A., Lesca, G., Helbig, K. L., Palmer, E. E., and 18 others.
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<strong>ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria.</strong>
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Brain 144: 1435-1450, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33880529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33880529</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33880529" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/awab052" target="_blank">Full Text</a>]
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Yang-Feng, T. L., Schneider, J. W., Lindgren, V., Shull, M. M., Benz, E. J., Jr., Lingrel, J. B., Francke, U.
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<strong>Chromosomal localization of human Na+,K+-ATPase alpha- and beta-subunit genes.</strong>
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Genomics 2: 128-138, 1988.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2842249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2842249</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2842249" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0888-7543(88)90094-8" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Anne M. Stumpf - updated : 11/10/2021
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Cassandra L. Kniffin - updated : 11/05/2021<br>Nara Sobreira - updated : 2/18/2016<br>Cassandra L. Kniffin - updated : 2/12/2015<br>Cassandra L. Kniffin - updated : 3/4/2014<br>Cassandra L. Kniffin - updated : 11/7/2012<br>Ada Hamosh - updated : 9/27/2010<br>Cassandra L. Kniffin - updated : 5/24/2010<br>Cassandra L. Kniffin - updated : 5/6/2008<br>Cassandra L. Kniffin - updated : 1/10/2008<br>Cassandra L. Kniffin - updated : 8/16/2007<br>Cassandra L. Kniffin - updated : 10/10/2006<br>Cassandra L. Kniffin - updated : 4/7/2006<br>Cassandra L. Kniffin - updated : 3/9/2005<br>Cassandra L. Kniffin - updated : 1/13/2005<br>Victor A. McKusick - updated : 12/29/2004<br>Marla J. F. O'Neill - updated : 11/3/2004<br>Cassandra L. Kniffin - updated : 10/25/2004<br>Cassandra L. Kniffin - updated : 8/4/2004<br>Cassandra L. Kniffin - updated : 12/30/2003<br>Cassandra L. Kniffin - updated : 1/24/2003<br>John A. Phillips, III - updated : 3/3/2000<br>Stylianos E. Antonarakis - updated : 7/20/1999
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Victor A. McKusick : 12/1/1987
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alopez : 08/01/2023<br>alopez : 11/10/2021<br>alopez : 11/10/2021<br>alopez : 11/10/2021<br>ckniffin : 11/05/2021<br>joanna : 08/04/2016<br>carol : 02/18/2016<br>carol : 2/19/2015<br>mcolton : 2/18/2015<br>ckniffin : 2/12/2015<br>carol : 3/5/2014<br>ckniffin : 3/4/2014<br>terry : 11/9/2012<br>carol : 11/9/2012<br>ckniffin : 11/7/2012<br>carol : 9/14/2012<br>ckniffin : 9/13/2012<br>alopez : 9/28/2010<br>alopez : 9/28/2010<br>terry : 9/27/2010<br>wwang : 5/25/2010<br>ckniffin : 5/24/2010<br>wwang : 5/14/2008<br>ckniffin : 5/6/2008<br>carol : 1/21/2008<br>ckniffin : 1/10/2008<br>wwang : 8/24/2007<br>ckniffin : 8/16/2007<br>wwang : 10/17/2006<br>ckniffin : 10/10/2006<br>wwang : 4/11/2006<br>ckniffin : 4/7/2006<br>wwang : 11/23/2005<br>ckniffin : 11/14/2005<br>wwang : 3/16/2005<br>wwang : 3/10/2005<br>ckniffin : 3/9/2005<br>tkritzer : 1/25/2005<br>ckniffin : 1/13/2005<br>tkritzer : 12/30/2004<br>terry : 12/29/2004<br>tkritzer : 11/4/2004<br>terry : 11/3/2004<br>tkritzer : 10/28/2004<br>ckniffin : 10/25/2004<br>ckniffin : 8/4/2004<br>tkritzer : 1/16/2004<br>ckniffin : 12/30/2003<br>alopez : 1/31/2003<br>carol : 1/30/2003<br>cwells : 1/28/2003<br>ckniffin : 1/24/2003<br>mgross : 3/3/2000<br>mgross : 7/21/1999<br>mgross : 7/20/1999<br>carol : 2/9/1993<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>ddp : 10/27/1989<br>root : 7/8/1988<br>marie : 3/25/1988
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<div>
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<h3>
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<span class="mim-font">
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ATPase, Na+/K+ TRANSPORTING, ALPHA-2 POLYPEPTIDE; ATP1A2
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</span>
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</h3>
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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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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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SODIUM-POTASSIUM-ATPase, ALPHA-2 POLYPEPTIDE<br />
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Na,K-ATPase, ALPHA-A(+) CATALYTIC POLYPEPTIDE<br />
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Na,K-ATPase, ALPHA-B POLYPEPTIDE
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</span>
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</h4>
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</div>
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<div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: ATP1A2</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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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 1260330000;
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</span>
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</p>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 1q23.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:160,115,759-160,143,591 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="5">
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<span class="mim-font">
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1q23.2
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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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Alternating hemiplegia of childhood 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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104290
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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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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Developmental and epileptic encephalopathy 98
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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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619605
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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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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Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies
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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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619602
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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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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Migraine, familial basilar
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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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602481
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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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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Migraine, familial hemiplegic, 2
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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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602481
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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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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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The ATP1A2 gene encodes the alpha-2 isoform of the Na(+),K(+)-ATPase (EC 3.6.1.9), an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane. The pump is composed of 2 subunits, a large catalytic subunit (alpha), encoded by several genes (see, e.g., ATP1A1, 182310), and a smaller glycoprotein subunit (beta) (see ATP1B1, 182330) (summary by Shull and Lingrel, 1987). </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>Shull and Lingrel (1987) identified separate genes encoding the alpha and alpha(+) isoforms of the catalytic subunit of the Na(+),K(+)-ATPase. These genes were called alpha-A (ATP1A1) and alpha-B (ATP1A2), respectively. In addition, they isolated 2 other genes, termed alpha-C (ATP1A3; 182350) and alpha-D (ATP1A4; 607321), one of which is physically linked to the alpha-B gene; these genes showed nucleotide and deduced amino acid homology to the catalytic subunit cDNA sequences, but did not correspond to any previously identified isoforms. </p><p>Shull et al. (1989) cloned the ATP1A2 gene. The amino acid sequence deduced from the genomic sequence exhibited 99% identity to the rat alpha-2 isoform. Several transcription factor binding sites are located in the 5-prime end of the gene. </p><p>The alpha-2 subunit consists of 10 transmembrane helices M1-M10, harboring the Na(+) and K(+)-binding sites, and a cytoplasmic head made up of 3 subdomains: A (actuator), N (nucleotide binding), and P (phosphorylation) (summary by Schack et al., 2012). </p><p>ATP1A2 is expressed in skeletal muscle, heart, vascular smooth muscle, and brain (summary by Monteiro et al., 2020). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Shull et al. (1989) determined that the ATP1A2 gene contains 23 exons and spans approximately 25 kb. </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>Katzmarzyk et al. (1999) examined the relationship between the ATP1A2 (exon 1 and exon 21-22 with BglII) and ATP1B1 (182330) (MspI and PvuII) genes and resting metabolic rate (RMR) and respiratory quotient (RQ). RMR and RQ were adjusted for age, sex, fat mass, and fat-free mass. Sib-pair analyses indicated a significant linkage between RQ and the ATP1A2 exon 1 and exon 21-22 markers (P of 0.03 and 0.02, respectively). No linkage was detected between the ATP1B1 markers and either RMR or RQ, and RMR was not linked with the ATP1A2 markers. There was a significant interaction (p less than 0.0003) between ATP1A2 exon 1 carrier status and age group (younger adults (those less than 45 years old) vs older adults (those 45 or more years old)) for RQ. The association between carrier status and RQ was significant in younger adults (RQ of 0.76 in carriers vs 0.80 in noncarriers; p less than 0.0001) but was not in older adults (RQ of 0.81 in carriers vs 0.80 in noncarriers). The ATP1A2 exon 1 gene accounted for approximately 9.1% and 0.3% of the variance in RQ in younger and older adults, respectively. The results suggested that the ATP1A2 gene may play a role in fuel oxidation, particularly in younger individuals. </p><p>To determine the functional roles of the ATP1A1 and ATP1A2 proteins, James et al. (1999) generated mice with a targeted disruption of either the Atp1a1 or the Atp1a2 gene. Hearts from heterozygous Atp1a2 mice were hypercontractile as a result of increased calcium transients during the contractile cycle. In contrast, hearts from heterozygous Atp1a1 mice were hypocontractile. The different functional roles of these 2 proteins were further demonstrated since inhibition of the Atp1a2 protein with ouabain increased the contractility of heterozygous Atp1a1 hearts. These results illustrated a specific role for the ATP1A2 protein in calcium signaling during cardiac contraction. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By Southern analysis of DNA from panels of rodent/human somatic cell hybrid lines, Yang-Feng et al. (1988) mapped the ATP1A2 gene to 1cen-q32. Furthermore, they detected a common Pst1 RFLP with the ATP1A2 probe. In the course of creating a physical map of human 1q21-q23, Oakey et al. (1992) confirmed this assignment. </p><p>Stumpf (2021) mapped the ATP1A2 gene to chromosome 1q23.2 based on an alignment of the ATP1A2 sequence (GenBank BC052271) with the genomic sequence (GRCh38).</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Crystal Structure</em></strong></p><p>
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Morth et al. (2007) presented the x-ray crystal structure at 3.5-angstrom resolution of the pig renal sodium-potassium-ATPase (Na+,K(+)-ATPase) with 2 rubidium ions bound (as potassium congeners) in an occluded state in the transmembrane part of the alpha subunit. Several of the residues forming the cavity for rubidium/potassium occlusion in the Na+,K(+)-ATPase are homologous to those binding calcium in the calcium-ion ATPase of sarcoendoplasmic reticulum (ATP2A1 (SERCA1); 108730). The beta (see ATP1B1, 182330) and gamma (see ATP1G1, 601814) subunits specific to the Na+,K(+)-ATPase are associated with transmembrane helices alpha-M7/alpha-M10, and alpha-M9, respectively. The gamma subunit corresponds to a fragment of the V-type ATPase c subunit. The carboxy terminus of the alpha subunit is contained within a pocket between transmembrane helices and seems to be a novel regulatory element controlling sodium affinity, possibly influenced by the membrane potential. </p><p>Crystal structures of the potassium-bound form of the sodium potassium ATPase pump revealed an intimate docking of the alpha-subunit carboxy terminus at the transmembrane domain (e.g., Morth et al., 2007). Poulsen et al. (2010) showed that this element is a key regulator of a theretofore unrecognized ion pathway. Models of P-type ATPases operated with a single ion conduit through the pump, but the data of Poulsen et al. (2010) suggested an additional pathway in the Na+/K(+)-ATPase between the ion-binding sites and the cytoplasm. The C-terminal pathway allows a cytoplasmic proton to enter and stabilize site III when empty in the potassium-bound state, and when potassium is released the proton will also return to the cytoplasm, thus allowing an overall asymmetric stoichiometry of the transported ions. The C terminus controls the gate to the pathway. Its structure is crucial for pump function, as demonstrated by at least 8 mutations in the region that cause severe neurologic diseases. This novel model for ion transport by the Na+/K(+)-ATPase was established by electrophysiologic studies of C-terminal mutations in familial hemiplegic migraine (602481) and was further substantiated by molecular dynamics simulations. Poulsen et al. (2010) considered a similar ion regulation likely to apply to the H+/K(+)-ATPase and the Ca(2+)-ATPase. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Familial Hemiplegic Migraine 2</em></strong></p><p>
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In affected members of a large Italian family segregating familial hemiplegic migraine-2 (FHM2; 602481), De Fusco et al. (2003) identified heterozygosity for mutations in the ATP1A2 gene (182340.0001-182340.0002). </p><p>Jurkat-Rott et al. (2004) identified 6 different mutations in the ATP1A2 gene (see, e.g., 182340.0008; 182340.0009) in affected members of 6 unrelated families with FHM2. Penetrance was mildly reduced at approximately 87%. </p><p>Vanmolkot et al. (2007) reported an affected family in which the proband with severe FHM2 was compound heterozygous for 2 mutations in the ATP1A2 gene (182340.0011; 182340.0012). Family members with milder forms of the disorder were heterozygous for 1 of the mutations, suggesting reduced penetrance. The authors stated that this was the first report of compound heterozygosity in FHM2. </p><p>In affected members of a 3-generation Korean family with FHM2, Oh et al. (2015) identified a heterozygous missense mutation (V191M; 182340.0015) in the ATP1A2 gene. All affected members of the family also had progressive hearing loss. The mutation segregated with the phenotype in the family and was not found in the dbSNP or 1000 Genomes Project databases or in 200 Korean controls with normal audiograms. See DFNA7 (601412) and DFNA49 (608372) for 2 hearing loss loci that map to the same region as the ATP1A2 gene. </p><p><strong><em>Alternating Hemiplegia of Childhood 1</em></strong></p><p>
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In affected members of a family with alternating hemiplegia of childhood-1 (AHC1; 104290), Swoboda et al. (2004) identified a mutation in the ATP1A2 gene (182340.0005). </p><p>In a Brazilian boy with a phenotype reminiscent of AHC1, Sampedro Castaneda et al. (2018) identified a de novo heterozygous missense mutation in the ATP1A2 gene (S779N; 182340.0023). The mutation, which was found by Sanger sequencing, was not present in the gnomAD database. In vitro electrophysiologic studies in Xenopus oocytes showed that the mutation caused a 'leaky' inward current in the mutant pump in the presence of both high and low K+ concentrations, as well as altered Na+/K+ turnover activity rates of the pump. The voltage dependence of transient currents was left-shifted in mutant pumps. These changes were predicted to underlie abnormal membrane depolarization, resulting in muscle inexcitability leading to paralysis. The patient developed episodic tetraparesis at age 2 years. Laboratory studies during the episodes showed increased serum creatine kinase and low serum potassium. The symptoms improved with potassium, but worsened with acetazolamide. Sampedro Castaneda et al. (2018) noted the phenotypic similarities to hypokalemic periodic paralysis (see 170400) but with additional central nervous system involvement, thus expanding the phenotypic spectrum of ATP1A2 mutations. </p><p><strong><em>Fetal Akinesia, Respiratory Insufficiency, Microcephaly, Polymicrogyria, and Dysmorphic Facies</em></strong></p><p>
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In 3 infants from 2 unrelated families with fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (FARIMPD; 619602), Monteiro et al. (2020) identified homozygous frameshift mutations in the ATP1A2 gene (182340.0016 and 182340.0017). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Neither were present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but both were predicted to result in a complete loss of ATP1A2 function. All 3 patients died in the perinatal period. </p><p>In 3 sibs, conceived of consanguineous Algerian parents, and an unrelated infant, born of consanguineous Pakistani parents, with FARIMPD, Chatron et al. (2019) identified a homozygous frameshift and nonsense mutation, respectively, in the ATP1A2 gene (182340.0018 and 182340.0019). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Both were absent from the gnomAD database. No ATP1A2 immunostaining was detected in brain samples from 2 patients, confirming complete absence of the protein and a loss-of-function effect. Functional studies of the variant were not performed. All patients either died in infancy or the pregnancies were terminated. </p><p><strong><em>Developmental and Epileptic Encephalopathy 98</em></strong></p><p>
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In 6 unrelated patients with developmental and epileptic encephalopathy-98 (DEE98; 619605), Vetro et al. (2021) identified 5 de novo heterozygous missense mutations in the ATP1A2 gene (see, e.g., 182340.0020-182340.0022). The mutations, which occurred at conserved residues, were not present in the gnomAD database. In vitro functional expression studies showed that all of the mutations caused variable functional defects in the Na+/(K+)ATPase. Variants with more severe functional deficits were associated with a more severe phenotype. The findings were consistent with a loss-of-function effect. Vetro et al. (2021) estimated that about 5% of ATP1A2 mutations may be associated with DEE. Polymicrogyria was estimated to occur in about 1% of patients with ATP1A2 mutations. </p><p><strong><em>Variant Functional Studies</em></strong></p><p>
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Schack et al. (2012) reported functional analysis of 9 different pathogenic mutations in the ATP1A2 gene, including 4 in the P domain (M731T (182340.0003), R593W, V628M, and E700K), 2 in the A domain (R202Q and T263M), 1 in the transmembrane domain M2 (V138A), 1 in transmembrane M4 domain near the P domain (T345A; 182340.0007), and 1 between M6 and M7 close to the P domain (R834Q). Expression of the mutations in COS-1 cells showed that all had reductions in the catalytic turnover rate of Na+ and K+. The decrease was most severe for R593W, V628M, M731T, and R834Q (less than one-third of wildtype), about 50% for T263M, T345A, E700K, and V138A, and less than 20% of control for R202Q. All mutants showed essentially normal affinity for K+ and Na+, but rapid kinetic studies of the phosphorylation from ATP showed reduced Vmax of phosphorylation as a major factor contributing to the reduction of the catalytic turnover rate of mutants V138A, T345A, R593W, V628M, M731T, and R834Q (2- to 6-fold decrease). The decreased phosphorylation rate would lead to enhanced K+ competition with Na+ at intracellular sites, which would compromise pump function. E700K, R202Q, and T263M phosphorylation rates were similar to wildtype, but E700K showed impaired rates of dephosphorylation, and R202Q and T263M were predicted to affect the turnover rate of the E1P/E2P pump conformations. Overall, the findings suggested that the disturbance of clearance of extracellular K+ by glial cells, thought to underlie FHM2, is due to low turnover rate of the pump and not to decreased affinity of the pump for external K+. </p><p>In Drosophila, Kaneko et al. (2014) identified a dominant missense mutation (A617T) in the calcium ATPase Serca gene (see SERCA2 (ATP2A2); 108740) that conferred temperature-sensitive motor uncoordination in a gain-of-function manner. The homologous residue is conserved by different type II P-type ATPases, including ATP1A2. Introduction of an R751Q mutation in the Drosophila Serca gene also caused a temperature-sensitive uncoordination phenotype. The corresponding residue in human SERCA2, ATP1A2, and ATP1A3 (182350) is mutated in the human diseases Darier disease (124200), FHM2, and dystonia-12 (DYT12; 128235), respectively. Cellular expression of Drosophila A617T resulted in temperature-induced decreased levels of stored calcium compared to wildtype, whereas cellular expression of R751Q elicited depletion of stored calcium even without heating. These calcium changes were due to leakage through the mutant channel pores that overwhelmed the pumping capacity of the cell. Similar results occurred after transfection of these mutations, as well as other disease-causing mutations that affected different parts of the protein, into mouse cells. Kaneko et al. (2014) concluded that ionic leakage is a gain-of-function mechanism that underlies a variety of dominant type II P-type ATPase-related diseases. Kaneko et al. (2014) concluded that ionic leakage is a gain-of-function mechanism that underlies a variety of dominant type II P-type ATPase-related diseases. </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>Ikeda et al. (2004) found that homozygous knockout of the Atp1a2 gene in mice was embryonic lethal due to severe motor deficits that also abolished respiration by the medullary respiratory center neurons. Analysis of spinal cord motoneurons in mutant mice showed absence of normal spontaneous rhythmic discharges. This was associated with increased inhibitory GABA levels in the extracellular spaces throughout the brain, as well as increased chloride (Cl-) levels within neurons. Ikeda et al. (2004) hypothesized that Atp1a2 normally generates a K+ gradient that fuels extrusion of cytosolic Cl- by KCC2 (SLC12A5; 606726) in respiratory center neurons in the perinatal period. In the absence of this, due to loss of Atp1a2, neurons thus become persistently depolarized and cannot produce action potentials due to the inactivation of fast sodium channels. </p><p>Ashmore et al. (2009) identified 6 different EMS-induced missense mutations in the Atp1a2 and Atp1a3 (182350) genes in Drosophila. All mutations resulted in reduced respiration activity consistent with a loss of ATPase function and a hypomorphic effect. Different mutant strains exhibited some abnormalities, including progressive temperature-dependent paralysis, progressive stress-sensitive paralysis, and decreased locomotor activity in response to startle, suggesting a decrease in maximal locomotion capacity. Neuromuscular studies showed allele-specific pathology, including brain vacuoles and myopathology, and biochemical studies showed decreased metabolic rates. An unexpected finding was the some mutant strains had increased longevity, which was not related to caloric restriction. Low doses of ouabain showed a similar effect on longevity in control groups. Ashmore et al. (2009) suggested that these findings may be relevant for studying the pathogenesis of FHM2 and DYT12 (128235). </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>23 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 MIGRAINE, FAMILIAL HEMIPLEGIC, 2</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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ATP1A2, LEU764PRO
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<br />
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SNP: rs28933398,
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ClinVar: RCV000013780, RCV001533154
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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 large Italian family with familial hemiplegic migraine-2 (602481), De Fusco et al. (2003) identified a heterozygous 2395T-C mutation in the ATP1A2 gene, resulting in a leu764-to-pro (L764P) substitution. The mutation segregated with the disorder in all 22 affected members who were tested and was not present in 400 control chromosomes. Functional studies in HeLa cells showed that the L764P and W887R (182340.0002) mutations inhibited Na+/K+ pump activity, but did not affect assembly or translocation to the cell membrane. Resultant abnormalities in intra- and extracellular ion concentrations may contribute to the pathophysiology of the disorder. </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 MIGRAINE, FAMILIAL HEMIPLEGIC, 2</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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ATP1A2, TRP887ARG
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<br />
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SNP: rs28933399,
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ClinVar: RCV000013781, RCV001533155
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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 family with familial hemiplegic migraine-2 (602481), De Fusco et al. (2003) identified a heterozygous 2763T-C mutation in the ATP1A2 gene, resulting in a trp887-to-arg (W887R) substitution. The mutation segregated with the disorder in all 7 affected members and was not present in 400 control chromosomes. Also see 182340.0001. </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 MIGRAINE, FAMILIAL HEMIPLEGIC, 2</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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ATP1A2, MET731THR
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<br />
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SNP: rs28933400,
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ClinVar: RCV000013782
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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 family with familial hemiplegic migraine-2 (602481), Vanmolkot et al. (2003) identified a heterozygous 2296T-C transition in exon 16 of the ATP1A2 gene, resulting in a met731-to-thr (M731T) substitution. </p><p>Segall et al. (2005) found that the mutant M731T and R689Q (182340.0004) rat Atp1a2 proteins transfected into HeLa cells showed reduced catalytic turnover and increased apparent affinity for extracellular potassium. In addition, M731T showed an increased apparent affinity for ATP. Segall et al. (2005) suggested that the disease phenotype is caused by decreased activity of the Na+/K+ pump, resulting in delayed extracellular potassium clearance and/or altered localized calcium handling or signaling. </p><p>Castro et al. (2007) identified the M731T mutation in 3 affected members of a Portuguese family with FHM2. A fourth mutation carrier had only migraine with aura. </p><p>Schack et al. (2012) noted that the M731T mutation occurs in the P domain. Expression of the mutation in COS-1 cells showed a severe reduction in the catalytic turnover rate of Na+ and K+, which was due to reduced Vmax of phosphorylation. The mutant showed essentially normal affinity for K+ and Na+. The decreased phosphorylation rate would lead to enhanced K+ competition with Na+ at intracellular sites, which would compromise pump function. The findings suggested that the disturbance of clearance of extracellular K+ by glial cells, thought to underlie FHM2, is due to low turnover rate of the pump and not to decreased affinity of the pump for external K+. </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 MIGRAINE, FAMILIAL HEMIPLEGIC, 2</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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ATP1A2, ARG689GLN
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<br />
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SNP: rs28933401,
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ClinVar: RCV000013783, RCV000761685
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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 family with familial hemiplegic migraine-2 (FHM2; 602481), previously reported by Terwindt et al. (1997), Vanmolkot et al. (2003) identified a 2170G-A transition in exon 15 of the ATP1A2 gene, resulting in an arg689-to-gln (R689Q) substitution. Three individuals with the mutation and FHM also had benign familial infantile convulsions (BFIC), 1 member had the mutation and only BFIC, and 2 members had the mutation and only migraine with or without aura. Pelzer et al. (2014) found that 4 affected members of the family reported by Vanmolkot et al. (2003) who had BFIC carried a heterozygous truncating mutation in the PRRT2 gene (614386.0016), consistent with benign familial infantile convulsions-2 (BFIC2; 605751). Thus, 2 different neurologic disorders segregated in this family; the diagnosis was more complex as both disorders showed incomplete penetrance. </p><p>Segall et al. (2005) found that the mutant R689Q and M731T (182340.0003) rat Atp1a2 proteins transfected into HeLa cells showed reduced catalytic turnover and increased apparent affinity for extracellular potassium. Segall et al. (2005) suggested that the disease phenotype is caused by decreased activity of the Na+/K+ pump, resulting in delayed extracellular potassium clearance and/or altered localized calcium handling or signaling. </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 ALTERNATING HEMIPLEGIA OF CHILDHOOD 1</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
ATP1A2, THR378ASN
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|
<br />
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|
|
SNP: rs28934002,
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|
|
ClinVar: RCV000013784, RCV001229312
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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 alternating hemiplegia of childhood-1 (AHC1; 104290) originally reported by Kanavakis et al. (2003), Swoboda et al. (2004) identified a 1237C-A transversion in exon 9 of the ATP1A2 gene, resulting in a thr378-to-asn (T378N) substitution. The mutation affects a highly conserved residue in the second cytoplasmic loop of the protein and was not identified in 382 control chromosomes. </p><p>In 4 affected members of a Greek family with alternating hemiplegia of childhood, Bassi et al. (2004) identified the T378N mutation. The mutation was not present in unaffected members of the family or in 250 control chromosomes. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 MIGRAINE, FAMILIAL HEMIPLEGIC, 2</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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ATP1A2, GLY301ARG
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|
<br />
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|
|
SNP: rs121918612,
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|
|
ClinVar: RCV000013785, RCV001533152
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</span>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of an Italian family with severe familial hemiplegic migraine-2 (FHM2; 602481), Spadaro et al. (2004) identified a 901G-A transition in the ATP1A2 gene, resulting in a gly301-to-arg (G301R) substitution. The mutation occurs in a highly conserved residue within transmembrane segment M3 of the protein that is important for the dephosphorylation of homologous ATPases. The mutation was not identified in 179 controls. </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 MIGRAINE, FAMILIAL HEMIPLEGIC, 2</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
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|
<span class="mim-text-font">
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|
ATP1A2, THR345ALA
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|
<br />
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|
|
SNP: rs121918613,
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|
ClinVar: RCV000013786
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a Finnish family with familial hemiplegic migraine-2 (FHM2; 602481) with associated symptoms such as coma and showing linkage to 1q23, Kaunisto et al. (2004) identified a 1033A-G transition in exon 9 of the ATP1A2 gene, resulting in a thr345-to-ala (T345A) substitution. All 11 affected members in this family showed hemisensoric aura with mild to moderate hemiparesis affecting mostly the arm. Interictal neurologic examinations were normal. Migraine attacks usually started with gradually spreading hemisensoric aura which was always accompanied by hemiparesthesias, dysarthria, or dysphagia, and often by visual symptoms. Of the 11 affected family members, 10 reported onset before the age of 15 years. The frequency of attacks varied from 2 per month to once a year, and 2 individuals reported cessation of attacks during their teens. Minor head trauma triggered attacks in 5 of the 11 patients and severe vomiting could last for days in 4 patients. Confusion and mild anxiety were common features during attacks in 5 subjects. In 4 of these patients a mild head trauma had triggered coma accompanied by fever that lasted 2 days to 2 weeks. Hemiparetic symptoms could persist for as long as 2 weeks in some individuals. None of the patients had seizures. </p><p>In functional expression studies, Segall et al. (2004) found that cells transduced with the T345A mutant protein showed growth comparable to wildtype cells and no reduction in catalytic turnover of the subunit protein; however, kinetic studies showed that the T345A mutant protein had an approximately 2-fold decrease in apparent affinity for extracellular potassium. The authors concluded that the slow removal of potassium from the extracellular space slowed the recovery phase of nerve impulse transmission. </p><p>Schack et al. (2012) noted that the T345A mutation occurs in the M4 transmembrane domain near the P domain. Expression of the mutation in COS-1 cells showed about a 50% reduction in the catalytic turnover rate of Na+ and K+, which was due to reduced Vmax of phosphorylation. The mutant showed essentially normal affinity for K+ and Na+. The decreased phosphorylation rate would lead to enhanced K+ competition with Na+ at intracellular sites, which would compromise pump function. The findings suggested that the disturbance of clearance of extracellular K+ by glial cells, thought to underlie FHM2, is due to low turnover rate of the pump and not to decreased affinity of the pump for external K+. </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>.0008 MIGRAINE, FAMILIAL HEMIPLEGIC, 2</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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ATP1A2, ASP718ASN
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<br />
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|
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SNP: rs121918614,
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ClinVar: RCV000013787, RCV001533153, RCV004700227
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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 6 affected members spanning 4 generations of a family with familial hemiplegic migraine-2 (FHM2; 602481), Jurkat-Rott et al. (2004) identified a heterozygous 2152G-A transition in the ATP1A2 gene, resulting in an asp718-to-asn (D718N) substitution. Age at onset ranged from 3 to 12 years, and hemiplegic episodes were long, lasting from 6 to 336 hours. In most patients, the frequency of attacks ranged from 1 to 2 episodes per month. Aural features included dysarthria, diplopia, and impaired hearing. One patient was mentally retarded and had epileptic seizures, and another had low IQ. The D718N mutation affects a magnesium-interaction site and is predicted to result in complete loss of ATPase function due to lack of catalytic activity. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0009 MIGRAINE, FAMILIAL HEMIPLEGIC, 2</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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ATP1A2, PRO979LEU
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<br />
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SNP: rs121918615,
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ClinVar: RCV000013788, RCV000529838, RCV001560539, RCV003313029
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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 5 affected members of a family with familial hemiplegic migraine-2 (FHM2; 602481), Jurkat-Rott et al. (2004) identified a heterozygous 2936C-T transition in the ATP1A2 gene, resulting in a pro979-to-leu (P979L) substitution. Age at onset ranged from 3 to 23 years, and hemiplegic attacks occurred several times per year. One patient had mental retardation, and another had epileptic seizures. </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>.0010 MIGRAINE, FAMILIAL BASILAR</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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ATP1A2, ARG548HIS
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<br />
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SNP: rs121918616,
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gnomAD: rs121918616,
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ClinVar: RCV000013789, RCV000423537, RCV001851832, RCV003448245, RCV004555532, RCV004819208
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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 father and son (proband) with basilar migraine (see 602481), Ambrosini et al. (2005) identified a heterozygous 1643G-A transition in exon 12 of the ATP1A2 gene, resulting in an arg548-to-his (R548H) substitution in a highly conserved region of the protein. Residue 548 occurs in the major alpha-2 subunit cytoplasmic loop, which plays a key role in pump function. The mutation was not identified in 400 control chromosomes. The R548H mutation was also identified in the proband's paternal uncle who had basilar migraines in his youth, but at the time of the report had migraine without aura, and in the proband's first cousin, who had migraine without aura. Ambrosini et al. (2005) concluded that basilar migraine is allelic to FHM2. </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>.0011 MIGRAINE, FAMILIAL HEMIPLEGIC, 2</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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ATP1A2, ILE286THR
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<br />
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SNP: rs121918617,
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ClinVar: RCV000013790, RCV002513024
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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 young woman with severe hemiplegic migraine (FHM2; 602481), Vanmolkot et al. (2007) identified compound heterozygosity for 2 mutations in the ATP1A2 gene: a 961T-C transition in exon 8, resulting in an ile286-to-thr (I286T) substitution, and a 1348C-T transition in exon 10, resulting in a thr415-to-met (T415M; 182340.0012) substitution, both of which are located in the intracellular portion of the protein. The patient had onset at age 8 years of hemiplegic migraine with visual aura and subsequent dysphasia, hemiplegia, and migraine headache. Her mother and maternal aunt, both of whom were heterozygous for the I286T mutation, had aura without headache and a milder form of hemiplegic migraine, respectively. In vitro functional expression studies showed that the I286T mutant protein was expressed but caused significantly decreased cell survival that reflected a dysfunctional pump. Her unaffected daughter was heterozygous for the T415M mutation, as were her father and son, who had nonmigrainous headaches and migraine with aura, respectively. In vitro functional expression studies showed that the T415M mutant protein was expressed, but cells with the mutant protein were unable to survive, indicating complete loss of function. Vanmolkot et al. (2007) noted that this was the first reported case of compound heterozygosity for mutations in the ATP1A2 gene and concluded that the mutations showed reduced penetrance in the heterozygous state. </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>.0012 MIGRAINE, FAMILIAL HEMIPLEGIC, 2</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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ATP1A2, THR415MET
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<br />
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SNP: rs121918618,
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gnomAD: rs121918618,
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ClinVar: RCV000013791, RCV000547097, RCV001097906, RCV003398497
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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>For discussion of the thr415-to-met (T415M) mutation in the ATP1A2 gene that was found in compound heterozygous state in a patient with familial hemiplegic migraine-2 (FHM2; 602481) by Vanmolkot et al. (2007), see 182340.0011. </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>.0013 MIGRAINE, FAMILIAL HEMIPLEGIC, 2</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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ATP1A2, ARG65TRP
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<br />
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SNP: rs121918619,
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gnomAD: rs121918619,
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ClinVar: RCV000013792, RCV000442150, RCV001221618
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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 members of a family with familial hemiplegic migraine-2 (FHM2; 602481), Tonelli et al. (2007) identified a heterozygous 193C-T transition in exon 4 of the ATP1A2 gene, resulting in an arg65-to-trp (R65W) substitution in the cytoplasmic N-terminal portion of the protein, within the actuator domain (A domain). </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>.0014 MIGRAINE, FAMILIAL HEMIPLEGIC, 2</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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ATP1A2, THR376MET
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<br />
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SNP: rs121918620,
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gnomAD: rs121918620,
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ClinVar: RCV000013793, RCV001037466, RCV001781261, RCV002444429
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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 Portuguese family with pure familial hemiplegic migraine-2 (FHM2; 602481), Castro et al. (2007) identified a heterozygous 1231C-T transition in exon 9 of the ATP1A2 gene, resulting in a thr376-to-met (T376M) substitution in the M4 cytoplasmic loop. In vitro functional expression studies showed that the mutant protein had decreased function. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0015 MIGRAINE, FAMILIAL HEMIPLEGIC, 2</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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ATP1A2, VAL191MET
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<br />
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SNP: rs869025341,
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ClinVar: RCV000207519
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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 3-generation Korean family (KNUF-47) with familial hemiplegic migraine-2 (FHM2; 602481), Oh et al. (2015) identified a heterozygous c.571G-A transition (c.571G-A, NM_00702.3) in the ATP1A2 gene, predicting a val191-to-met (V191M) substitution at a highly conserved residue in the A domain. All affected members of the family also had progressive hearing loss. The mutation segregated with the phenotype in the family and was not found in the dbSNP or 1000 Genomes Project databases or in 200 Korean controls with normal audiograms. In silico studies suggested that the variant causes a change in hydrophobic interactions and thereby slightly destabilizes the A domain of Na(+)/K(+)-ATPase. However, Western blot analysis of recombinant ATPase proteins in insect cells revealed similar expression levels of wildtype and mutant Na(+)/K(+)-ATPase, and inhibitor binding studies showed that the ouabain-binding level for mutant and wildtype was also similar. (See DFNA7 (601412) and DFNA49 (608372) for 2 hearing loss loci that map to the same region as the ATP1A2 gene.) </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0016 FETAL AKINESIA, RESPIRATORY INSUFFICIENCY, MICROCEPHALY, POLYMICROGYRIA, AND DYSMORPHIC FACIES</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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ATP1A2, 2-BP DEL, 2104TG
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<br />
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SNP: rs1558008455,
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ClinVar: RCV001777174, RCV003768048
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an infant (patient 2), born of Brazilian parents who were not known to be related (family 1), with fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (FARIMPD; 619602), Monteiro et al. (2020) identified a homozygous 2-bp deletion (c.2104_2105delTG, NM_000702), predicted to result in a frameshift and premature termination (Cys702SerfsTer12) in the cytoplasmic domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each parent. The variant was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a complete loss of ATP1A2 function. The patient had a similarly affected sib (patient 1), but genetic analysis of the sib was not performed. Patient 2 and the affected sib both died at 2 months of age. The patients' mother reported occasional migraines without aura. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 FETAL AKINESIA, RESPIRATORY INSUFFICIENCY, MICROCEPHALY, POLYMICROGYRIA, AND DYSMORPHIC FACIES</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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ATP1A2, 1-BP DEL, 835C
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<br />
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SNP: rs1558005340,
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ClinVar: RCV001008258, RCV001777176
|
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|
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a newborn female (patient 3), born of consanguineous Hispanic parents (family 2), with fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (FARIMPD; 619602), Monteiro et al. (2020) identified a homozygous 1-bp deletion (c.835delC, NM_000702) in the ATP1A2 gene, predicted to result in a frameshift and premature termination (Arg279GlyfsTer4) in the cytoplasmic domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each parent. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a complete loss of ATP1A2 function. The patient died of respiratory insufficiency soon after birth. </p>
|
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</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 FETAL AKINESIA, RESPIRATORY INSUFFICIENCY, MICROCEPHALY, POLYMICROGYRIA, AND DYSMORPHIC FACIES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
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|
|
ATP1A2, 2-BP DUP, 295TC
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<br />
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|
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SNP: rs1558003446,
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ClinVar: RCV000754580, RCV001777173
|
|
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|
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 sibs, conceived of consanguineous Algerian parents (family A), with fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (FARIMPD; 619602), Chatron et al. (2019) identified a homozygous 2-bp duplication (c.295_296dupTC, NM_000702.3) in the ATP1A2 gene, resulting in a frameshift and premature termination (Ile100ProfsTer71). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was absent from the gnomAD database. No ATP1A2 immunostaining was detected in patient brain samples, confirming complete absence of the protein and a loss-of-function effect. Functional studies of the variant were not performed. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 FETAL AKINESIA, RESPIRATORY INSUFFICIENCY, MICROCEPHALY, POLYMICROGYRIA, AND DYSMORPHIC FACIES</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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ATP1A2, GLU957TER
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<br />
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SNP: rs1558010146,
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ClinVar: RCV000754579, RCV001777172, RCV003332220
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 35-week-old fetus, born of consanguineous Pakistani parents (family B), with fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (FARIMPD; 619602), Chatron et al. (2019) identified a homozygous c.2869G-T transversion (c.2869G-T, NM_000702.3) in the ATP1A2 gene, resulting in a glu957-to-ter (E957X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. </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>.0020 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 98</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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ATP1A2, CYS341PHE
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<br />
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SNP: rs1057521630,
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ClinVar: RCV000443567, RCV001777162
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 5-year-old boy (patient 2) with developmental and epileptic encephalopathy-98 (DEE98; 619605), Vetro et al. (2021) identified a de novo heterozygous c.1022G-T transversion (c.1022G-T, NM_000702.3) in the ATP1A2 gene, resulting in a cys341-to-phe (C341F) substitution at a conserved residue. In vitro functional expression studies showed that the variant was unable to support COS1 cell survival in culture. Phosphorylation was decreased to 10 to 15% of wildtype. The patient had a severe phenotype with onset of seizures at 3 weeks of age. </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>.0021 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 98</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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ATP1A2, GLY366ALA
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<br />
|
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SNP: rs1057518514,
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ClinVar: RCV000412726, RCV001777160
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In 2 unrelated patients (patients 3 and 4) with developmental and epileptic encephalopathy-98 (DEE; 619605), Vetro et al. (2021) identified a de novo heterozygous c.1097G-C transversion (c.1097G-C, NM_000702.3) in the ATP1A2 gene, resulting in a gly366-to-ala (G366A) substitution at a conserved residue. In vitro functional expression studies showed that the variant was unable to support COS1 cell survival in culture. Phosphorylation was decreased to 61% of wildtype, and there was decreased affinity for both Na+ and K+ ions, consistent with pump dysfunction. The patients had a severe phenotype with onset of seizures in the first month of life. Both died of complications of refractory status epilepticus. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 98</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">
|
|
MIGRAINE, FAMILIAL HEMIPLEGIC, 2, INCLUDED
|
|
</span>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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|
ATP1A2, ARG908GLN
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<br />
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SNP: rs2101996488,
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ClinVar: RCV001581019, RCV001777178, RCV001777179
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an 11-year-old boy (patient 6) with developmental and epileptic encephalopathy-98 (DEE98; 619605), Vetro et al. (2021) identified a de novo heterozygous c.2723G-A transition (c.2723G-A, NM_000702.3) in the ATP1A2 gene, resulting in an arg908-to-gln (R908Q) substitution at a conserved residue. In vitro functional expression studies showed that the variant was able to support COS1 cell survival in growth culture. However, the pump activity at the membrane was decreased to about 22% of controls due to reduced Na+/(K+)ATPase turnover rate. The patient had onset of focal seizures at 8 years of age. He had moderate developmental delay with hypotonic quadriparesis; brain imaging showed polymicrogyria with thick corpus callosum. Vetro et al. (2021) noted that a heterozygous R908Q mutation had been reported in patients with familial hemiplegic migraine-2 (FHM2; 602481) (see, e.g., De Vries et al., 2007), indicating that the same mutation may have different phenotypic consequences. </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>.0023 ALTERNATING HEMIPLEGIA OF CHILDHOOD 1</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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ATP1A2, SER779ASN
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<br />
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SNP: rs2101995480,
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ClinVar: RCV001777180
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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 Brazilian boy with a phenotype reminiscent of alternating hemiplegia of childhood-1 (AHC1; 104290), Sampedro Castaneda et al. (2018) identified a de novo heterozygous c.2336G-A transition in the ATP1A2 gene, resulting in a ser779-to-asn (S779N) substitution at a conserved residue in an ion-binding site. The mutation, which was found by Sanger sequencing, was not present in the gnomAD database. In vitro electrophysiologic studies in Xenopus oocytes showed that the mutation caused a 'leaky' inward current in the mutant pump in the presence of both high and low K+ concentrations, as well as altered Na+/K+ turnover activity rates of the pump. The voltage dependence of transient currents was left-shifted in mutant pumps. These changes were predicted to underlie abnormal membrane depolarization, resulting in muscle inexcitability leading to paralysis. The patient developed episodic tetraparesis at age 2 years. Laboratory studies during the episodes showed increased serum creatine kinase and low serum potassium. The symptoms improved with potassium, but worsened with acetazolamide. Sampedro Castaneda et al. (2018) noted the phenotypic similarities to hypokalemic periodic paralysis (see 170400) but with additional central nervous system involvement, thus expanding the phenotypic spectrum of ATP1A2 mutations. </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>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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<strong>Familial basilar migraine associated with a new mutation in the ATP1A2 gene.</strong>
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<strong>Novel mutations affecting the Na, K ATPase alpha model complex neurological diseases and implicate the sodium pump in increased longevity.</strong>
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De Vries, B., Freilinger, T., Vanmolkot, K. R. J., Koenderink, J. B., Stam, A. H., Terwindt, G. M., Babini, E., van den Boogerd, E.H., van den Heuvel, J. J. M. W., Frants, R. R., Haan, J., Pusch, M., van den Maagdenberg, A. M. J. M., Ferrari, M. D., Dichgans, M.
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Ikeda, K., Onimaru, H., Yamada, J., Inoue, K., Ueno, S., Onaka, T., Toyoda, H., Arata, A., Ishikawa, T., Taketo, M. M., Fukuda, A., Kawakami, K.
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James, P. F., Grupp, I. L., Grupp, G., Woo, A. L., Askew, G. R., Croyle, M. L., Walsh, R. A., Lingrel, J. B.
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<strong>Identification of a specific role for the Na,K-ATPase alpha-2 isoform as a regulator of calcium in the heart.</strong>
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Molec. Cell 3: 555-563, 1999.
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<strong>A missense variant of the ATP1A2 gene is associated with a novel phenotype of progressive sensorineural hearing loss associated with migraine.</strong>
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Pelzer, N., de Vries, B., Kamphorst, J. T., Vijfhuizen, L. S., Ferrari, M. D., Haan, J., van den Maagdenberg, A. M. J. M., Terwindt, G. M.
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[PubMed: 20720542]
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<p class="mim-text-font">
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Sampedro Castaneda, M., Zanoteli, E., Scalco, R. S., Scaramuzzi, V., Marques Caldas, V., Conti Reed, U., da Silva, A. M. S., O'Callaghan, B., Phadke, R., Bugiardini, E., Sud, R., McCall, S., Hanna, M. G., Poulsen, H., Mannikko, R., Matthews, E.
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<strong>A novel ATP1A2 mutation in a patient with hypokalaemic periodic paralysis and CNS symptoms.</strong>
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Brain 141: 3308-3318, 2018.
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[PubMed: 30423015]
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[Full Text: https://doi.org/10.1093/brain/awy283]
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<strong>Inhibition of phosphorylation of Na+,K+-ATPase by mutations causing familial hemiplegic migraine.</strong>
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[PubMed: 22117059]
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<p class="mim-text-font">
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Segall, L., Mezzetti, A., Scanzano, R., Gargus, J. J., Purisima, E., Blostein, R.
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<strong>Alterations in the alpha-2 isoform of Na,K-ATPase associated with familial hemiplegic migraine type 2.</strong>
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[PubMed: 16037212]
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<p class="mim-text-font">
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<strong>Kinetic alterations due to a missense mutation in the Na,K-ATPase alpha-2 subunit cause familial hemiplegic migraine type 2.</strong>
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J. Biol. Chem. 279: 43692-43696, 2004.
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<p class="mim-text-font">
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Shull, M. M., Lingrel, J. B.
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<strong>Multiple genes encode the human Na+,K+-ATPase catalytic subunit.</strong>
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Terwindt, G. M., Ophoff, R. A., Lindhout, D., Haan, J., Halley, D. J., Sandkuijl, L. A., Brouwer, O. F., Frants, R. R., Ferrari, M. D.
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Tonelli, A., Gallanti, A., Bersano, A., Cardin, V., Ballabio, E., Airoldi, G., Redaelli, F., Candelise, L., Bresolin, N., Bassi, M. T.
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Vanmolkot, K. R. J., Kors, E. E., Hottenga, J.-J., Terwindt, G. M., Haan, J., Hoefnagels, W. A. J., Black, D. F., Sandkuijl, L. A., Frants, R. R., Ferrari, M. D., van den Maagdenberg, A. M. J. M.
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Yang-Feng, T. L., Schneider, J. W., Lindgren, V., Shull, M. M., Benz, E. J., Jr., Lingrel, J. B., Francke, U.
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Anne M. Stumpf - updated : 11/10/2021<br>Cassandra L. Kniffin - updated : 11/05/2021<br>Nara Sobreira - updated : 2/18/2016<br>Cassandra L. Kniffin - updated : 2/12/2015<br>Cassandra L. Kniffin - updated : 3/4/2014<br>Cassandra L. Kniffin - updated : 11/7/2012<br>Ada Hamosh - updated : 9/27/2010<br>Cassandra L. Kniffin - updated : 5/24/2010<br>Cassandra L. Kniffin - updated : 5/6/2008<br>Cassandra L. Kniffin - updated : 1/10/2008<br>Cassandra L. Kniffin - updated : 8/16/2007<br>Cassandra L. Kniffin - updated : 10/10/2006<br>Cassandra L. Kniffin - updated : 4/7/2006<br>Cassandra L. Kniffin - updated : 3/9/2005<br>Cassandra L. Kniffin - updated : 1/13/2005<br>Victor A. McKusick - updated : 12/29/2004<br>Marla J. F. O'Neill - updated : 11/3/2004<br>Cassandra L. Kniffin - updated : 10/25/2004<br>Cassandra L. Kniffin - updated : 8/4/2004<br>Cassandra L. Kniffin - updated : 12/30/2003<br>Cassandra L. Kniffin - updated : 1/24/2003<br>John A. Phillips, III - updated : 3/3/2000<br>Stylianos E. Antonarakis - updated : 7/20/1999
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Victor A. McKusick : 12/1/1987
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