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<title>
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Entry
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- *610513 - ATPase 13A2; ATP13A2
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- OMIM
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<p>
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<span class="h4">*610513</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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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/610513">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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</nav>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<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 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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<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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<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=ENSG00000159363;t=ENST00000326735" 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=23400" 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=610513" 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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<span class="small">
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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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<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=ENSG00000159363;t=ENST00000326735" 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_001141973,NM_001141974,NM_022089,XM_005245810,XM_005245811,XM_005245812,XM_005245815,XM_006710512,XM_006710513,XM_011541128,XM_011541129,XM_017000844,XM_017000845,XM_017000846,XM_017000847,XM_017000848,XM_017000849,XM_017000850,XM_047416537,XM_047416538,XM_047416539,XM_047416542,XM_047416544,XM_047416546,XM_047416547,XM_047416548,XM_047416549,XM_047416550,XM_047416551,XM_047416553,XM_047416554,XM_047416556,XM_047416560,XM_047416562,XM_047416563,XM_047416564,XM_047416565,XM_047416566,XM_047416567,XM_047416568,XM_047416569,XM_047416570,XM_047416571" 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_022089" 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=610513" 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=13677&isoform_id=13677_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/ATP13A2" 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/3550295,7688148,13435129,14285364,20988435,21961333,22761317,38532369,52545860,62550734,119615230,119615231,119615232,119615233,158261443,213972619,213972621,530360974,530360976,530360978,530360984,578798781,578798783,767903452,767903454,1034557175,1034557177,1034557179,1034557181,1034557183,1034557185,1034557187,2217265928,2217265931,2217265933,2217265936,2217265938,2217265942,2217265944,2217265946,2217265948,2217265950,2217265953,2217265955,2217265959,2217265961,2217265964,2217265967,2217265969,2217265972,2217265974,2217265976,2217265979,2217265981,2217265983,2217265985,2217265987,2462496133,2462496135,2462496137,2462496139,2462496141,2462496143,2462496145,2462496147,2462496149,2462496151,2462496153,2462496155,2462496157,2462496159,2462496161,2462496163,2462496165,2462496167,2462496169,2462496171,2462496173,2462496175,2462496177,2462496179,2462496181,2462496183,2462496185,2462496187,2462496189,2462496191,2462496193,2462496195,2462496197,2462496199,2462496201,2462496203,2462496205,2462496207,2462496209,2462496211,2462507154,2462507156,2462507158,2462507160,2462507162,2462507164,2462507166,2462507168,2462507170,2462507172,2462507174,2462507176,2462507178,2462507180,2462507182,2462507184,2462507186,2462507188,2462507190,2462507192,2462507194,2462507196,2462507198,2462507200,2462507202,2462507204,2462507206,2462507208,2462507210,2462507212,2462507214,2462507216,2462507218,2462507220,2462507222,2462507224,2462507226,2462507228,2462507230,2462507232" 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/Q9NQ11" 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=23400" 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=ENSG00000159363;t=ENST00000326735" 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=ATP13A2" 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=ATP13A2" 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+23400" 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/ATP13A2" 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:23400" 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/23400" 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=ENST00000617114.5&hgg_start=16985958&hgg_end=17011928&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:30213" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:30213" 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=610513[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=610513[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/ATP13A2/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/ENSG00000159363" 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=ATP13A2" 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=ATP13A2" 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=ATP13A2" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=ATP13A2&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/PA134897221" 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:30213" 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/FBgn0052000.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:1922022" 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/ATP13A2#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:1922022" 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/23400/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://omia.org/OMIA001552/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=23400" 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=WBGene00022010;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-061215-126" 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://reactome.org/content/query?q=ATP13A2&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> 1177168007, 723992000<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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610513
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</span>
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</span>
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</div>
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</div>
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ATPase 13A2; ATP13A2
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=ATP13A2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ATP13A2</a></em></strong>
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Cytogenetic location: <a href="/geneMap/1/208?start=-3&limit=10&highlight=208">1p36.13</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:16985958-17011928&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'})">1:16,985,958-17,011,928</a> </span>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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Phenotype <br /> MIM number
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Inheritance
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1p36.13
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Kufor-Rakeb syndrome
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<a href="/entry/606693"> 606693 </a>
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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Spastic paraplegia 78, autosomal recessive
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<a href="/entry/617225"> 617225 </a>
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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PheneGene Graphics <span class="caret"></span>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/610513" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/610513" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Description</strong>
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<p>ATP13A2 belongs to the P-type superfamily of ATPases that transport inorganic cations and other substrates across cell membranes (<a href="#19" class="mim-tip-reference" title="Schultheis, P. J., Hagen, T. T., O'Toole, K. K., Tachibana, A., Burke, C. R., McGill, D. L., Okunade, G. W., Shull, G. E. <strong>Characterization of the P5 subfamily of P-type transport ATPases in mice.</strong> Biochem. Biophys. Res. Commun. 323: 731-738, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15381061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15381061</a>] [<a href="https://doi.org/10.1016/j.bbrc.2004.08.156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15381061">Schultheis et al., 2004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15381061" 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>Cloning and Expression</strong>
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<p>By searching databases for homologs of the yeast ATPases Cod1 and Yor291w, <a href="#19" class="mim-tip-reference" title="Schultheis, P. J., Hagen, T. T., O'Toole, K. K., Tachibana, A., Burke, C. R., McGill, D. L., Okunade, G. W., Shull, G. E. <strong>Characterization of the P5 subfamily of P-type transport ATPases in mice.</strong> Biochem. Biophys. Res. Commun. 323: 731-738, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15381061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15381061</a>] [<a href="https://doi.org/10.1016/j.bbrc.2004.08.156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15381061">Schultheis et al. (2004)</a> identified Atp13a2 in human, mouse, rat, and dog. Atp13a2 has at least 4 transmembrane domains in its N-terminal half and 6 transmembrane domains in its C-terminal half, and the N and C termini are cytoplasmic. The central cytoplasmic region between transmembrane domains 4 and 5 contains the catalytic phosphorylation site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15381061" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Ramirez, A., Heimbach, A., Grundemann, J., Stiller, B., Hampshire, D., Cid, L. P., Goebel, I., Mubaidin, A. F., Wriekat, A.-L., Roeper, J., Al-Din, A., Hillmer, A. M., Karsak, M., Liss, B., Woods, C. G., Behrens, M. I., Kubisch, C. <strong>Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase.</strong> Nature Genet. 38: 1184-1191, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16964263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16964263</a>] [<a href="https://doi.org/10.1038/ng1884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16964263">Ramirez et al. (2006)</a> determined that the human ATP13A2 open reading frame encodes a protein of 1,180 amino acids. Northern blot analysis detected ubiquitous expression of a 3.8-kb transcript, with strongest expression in brain. Dot blot analysis confirmed predominant expression in adult human brain and demonstrated high expression in fetal brain and all tested subregions of the adult central nervous system, including substantia nigra. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16964263" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using confocal imaging, <a href="#20" class="mim-tip-reference" title="Tan, J., Zhang, T., Jiang, L., Chi, J., Hu, D., Pan, Q., Wang, D., Zhang, Z. <strong>Regulation of intracellular manganese homeostasis by Kufor-Rakeb syndrome-associated ATP13A2 protein.</strong> J. Biol. Chem. 286: 29654-29662, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21724849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21724849</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21724849[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.M111.233874" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21724849">Tan et al. (2011)</a> found that epitope-tagged ATP13A2 colocalized with lysosomal markers in transfected human. mouse, and rat cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21724849" 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="#14" class="mim-tip-reference" title="Podhajska, A., Musso, A., Trancikova, A., Stafa, K., Moser, R., Sonnay, S., Glauser, L., Moore, D. J. <strong>Common pathogenic effects of missense mutations in the P-type ATPase ATP13A2 (PARK9) associated with early-onset parkinsonism.</strong> PLoS One 7: e39942, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22768177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22768177</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22768177[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/10.1371/journal.pone.0039942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22768177">Podhajska et al. (2012)</a> found that the ATP13A2 protein localizes to intracellular vesicular compartments in neurons, including lysosomes and early and late endosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22768177" 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="#15" class="mim-tip-reference" title="Ramirez, A., Heimbach, A., Grundemann, J., Stiller, B., Hampshire, D., Cid, L. P., Goebel, I., Mubaidin, A. F., Wriekat, A.-L., Roeper, J., Al-Din, A., Hillmer, A. M., Karsak, M., Liss, B., Woods, C. G., Behrens, M. I., Kubisch, C. <strong>Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase.</strong> Nature Genet. 38: 1184-1191, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16964263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16964263</a>] [<a href="https://doi.org/10.1038/ng1884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16964263">Ramirez et al. (2006)</a> determined that the human ATP13A2 gene contains 29 coding exons and spans 26 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16964263" 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 genomic sequence analysis, <a href="#19" class="mim-tip-reference" title="Schultheis, P. J., Hagen, T. T., O'Toole, K. K., Tachibana, A., Burke, C. R., McGill, D. L., Okunade, G. W., Shull, G. E. <strong>Characterization of the P5 subfamily of P-type transport ATPases in mice.</strong> Biochem. Biophys. Res. Commun. 323: 731-738, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15381061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15381061</a>] [<a href="https://doi.org/10.1016/j.bbrc.2004.08.156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15381061">Schultheis et al. (2004)</a> mapped the ATP13A2 gene to chromosome 1. The mouse Atp13a2 gene maps to chromosome 4D3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15381061" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Ramirez, A., Heimbach, A., Grundemann, J., Stiller, B., Hampshire, D., Cid, L. P., Goebel, I., Mubaidin, A. F., Wriekat, A.-L., Roeper, J., Al-Din, A., Hillmer, A. M., Karsak, M., Liss, B., Woods, C. G., Behrens, M. I., Kubisch, C. <strong>Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase.</strong> Nature Genet. 38: 1184-1191, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16964263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16964263</a>] [<a href="https://doi.org/10.1038/ng1884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16964263">Ramirez et al. (2006)</a> identified the ATP13A2 gene within a critical interval on chromosome 1p36 linked to Kufor-Rakeb syndrome (KRS, or PARK9; <a href="/entry/606693">606693</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16964263" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#20" class="mim-tip-reference" title="Tan, J., Zhang, T., Jiang, L., Chi, J., Hu, D., Pan, Q., Wang, D., Zhang, Z. <strong>Regulation of intracellular manganese homeostasis by Kufor-Rakeb syndrome-associated ATP13A2 protein.</strong> J. Biol. Chem. 286: 29654-29662, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21724849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21724849</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21724849[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.M111.233874" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21724849">Tan et al. (2011)</a> found that human, mouse, and rat cells expressing epitope-tagged human ATP13A2 were resistant to MnCl2-induced cytotoxicity. Exposure of cells to Mn(2+) upregulated ATP13A2 expression, and upregulated ATP13A2 reduced intracellular Mn(2+) concentrations and protected cells from Mn(2+)-induced cytochrome c release and apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21724849" 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="#14" class="mim-tip-reference" title="Podhajska, A., Musso, A., Trancikova, A., Stafa, K., Moser, R., Sonnay, S., Glauser, L., Moore, D. J. <strong>Common pathogenic effects of missense mutations in the P-type ATPase ATP13A2 (PARK9) associated with early-onset parkinsonism.</strong> PLoS One 7: e39942, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22768177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22768177</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22768177[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/10.1371/journal.pone.0039942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22768177">Podhajska et al. (2012)</a> found that overexpression of ATP13A2 sensitized rat cortical neurons to neurite shortening induced by exposure to cadmium or nickel ions, supporting a functional interaction between ATP13A2 and heavy metals in postmitotic neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22768177" 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="van Veen, S., Martin, S., Van den Haute, C., Benoy, V., Lyons, J., Vanhoutte, R., Kahler, J. P., Decuypere, J.-P., Gelders, G., Lambie, E., Zielich, J., Swinnen, J. V., Annaert, W., Agostinis, P., Ghesquiere, B., Verhelst, S., Baekelandt, V., Eggermont, J., Vangheluwe, P. <strong>ATP13A2 deficiency disrupts lysosomal polyamine export.</strong> Nature 578: 419-424, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31996848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31996848</a>] [<a href="https://doi.org/10.1038/s41586-020-1968-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31996848">Van Veen et al. (2020)</a> established ATP13A2 as a lysosomal polyamine exporter that showed the highest affinity for spermine among the polyamines examined. Polyamines stimulated the activity of purified ATP13A2, whereas ATP13A2 mutants that were implicated in disease were functionally impaired to a degree that correlated with the disease phenotype. ATP13A2 promoted the cellular uptake of polyamines by endocytosis and transported them into the cytosol, highlighting a role for endolysosomes in the uptake of polyamines into cells. At high concentrations polyamines induce cell toxicity, which was exacerbated by ATP13A2 loss due to lysosomal dysfunction, lysosomal rupture, and cathepsin B (<a href="/entry/116810">116810</a>) activation. This phenotype was recapitulated in neurons and nematodes with impaired expression of ATP13A2 or its orthologs. <a href="#23" class="mim-tip-reference" title="van Veen, S., Martin, S., Van den Haute, C., Benoy, V., Lyons, J., Vanhoutte, R., Kahler, J. P., Decuypere, J.-P., Gelders, G., Lambie, E., Zielich, J., Swinnen, J. V., Annaert, W., Agostinis, P., Ghesquiere, B., Verhelst, S., Baekelandt, V., Eggermont, J., Vangheluwe, P. <strong>ATP13A2 deficiency disrupts lysosomal polyamine export.</strong> Nature 578: 419-424, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31996848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31996848</a>] [<a href="https://doi.org/10.1038/s41586-020-1968-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31996848">Van Veen et al. (2020)</a> concluded that they presented defective lysosomal polyamine export as a mechanism for lysosome-dependent cell death that may be implicated in neurodegeneration, and shed light on the molecular identity of the mammalian polyamine transport system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31996848" 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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Kufor-Rakeb syndrome (KRS; <a href="/entry/606693">606693</a>), a form of autosomal recessive hereditary parkinsonism with dementia, shows juvenile onset. <a href="#15" class="mim-tip-reference" title="Ramirez, A., Heimbach, A., Grundemann, J., Stiller, B., Hampshire, D., Cid, L. P., Goebel, I., Mubaidin, A. F., Wriekat, A.-L., Roeper, J., Al-Din, A., Hillmer, A. M., Karsak, M., Liss, B., Woods, C. G., Behrens, M. I., Kubisch, C. <strong>Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase.</strong> Nature Genet. 38: 1184-1191, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16964263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16964263</a>] [<a href="https://doi.org/10.1038/ng1884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16964263">Ramirez et al. (2006)</a> described loss-of-function mutations in the predominantly neuronal P-type ATPase gene ATP13A2 as the cause of Kufor-Rakeb syndrome. Affected members of a nonconsanguineous Chilean family were compound heterozygous for a 1-bp deletion in exon 6, inherited from the mother (<a href="#0001">610513.0001</a>), and a splice site mutation, inherited from the father (<a href="#0002">610513.0002</a>). Affected members of the original Jordanian kindred were homozygous for a 22-bp duplication (<a href="#0003">610513.0003</a>). Whereas the wildtype protein was located in the lysosome of transiently transfected cells, the unstable truncated mutants were retained in the endoplasmic reticulum and degraded by the proteasome. The findings linked ATP13A2, representing a class of proteins with unknown function and substrate specificity, to the protein networks implicated in neurodegeneration and parkinsonism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16964263" 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 man with KRS, <a href="#5" class="mim-tip-reference" title="Di Fonzo, A., Chien, H. F., Socal, M., Giraudo, S., Tassorelli, C., Iliceto, G., Fabbrini, F., Marconi, R., Fincati, E., Abbruzzese, F., Marini, P., Squitieri, F., and 14 others. <strong>ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease.</strong> Neurology 68: 1557-1562, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17485642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17485642</a>] [<a href="https://doi.org/10.1212/01.wnl.0000260963.08711.08" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17485642">Di Fonzo et al. (2007)</a> identified a homozygous mutation in the ATP13A2 gene (G504R; <a href="#0004">610513.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17485642" 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 Belgian sibs with KRS, originally reported by <a href="#2" class="mim-tip-reference" title="Carlier, G., Dubru, J. M. <strong>Familial juvenile parkinsonism.</strong> Acta Paediat. Belg. 32: 123-127, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/495089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">495089</a>]" pmid="495089">Carlier and Dubru (1979)</a>, <a href="#1" class="mim-tip-reference" title="Bras, J., Verloes, A., Schneider, S. A., Mole, S. E., Guerreiro, R. J. <strong>Mutation of the parkinsonism gene ATP13A2 causes neuronal ceroid-lipofuscinosis.</strong> Hum. Molec. Genet. 21: 2646-2650, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22388936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22388936</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22388936[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/hmg/dds089" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22388936">Bras et al. (2012)</a> identified a homozygous missense mutation in the ATP13A2 gene (M810R; <a href="#0007">610513.0007</a>). The mutation was found by exome sequencing and segregated with the disorder in the family. It was not present in the dbSNP or 1000 Genomes Project databases. Functional studies were not performed. Because some of the patients in this family had neuropathologic findings suggestive of neuronal ceroid lipofuscinosis, <a href="#1" class="mim-tip-reference" title="Bras, J., Verloes, A., Schneider, S. A., Mole, S. E., Guerreiro, R. J. <strong>Mutation of the parkinsonism gene ATP13A2 causes neuronal ceroid-lipofuscinosis.</strong> Hum. Molec. Genet. 21: 2646-2650, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22388936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22388936</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22388936[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/hmg/dds089" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22388936">Bras et al. (2012)</a> designated the disorder CLN12. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22388936+495089" 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 cellular studies, <a href="#14" class="mim-tip-reference" title="Podhajska, A., Musso, A., Trancikova, A., Stafa, K., Moser, R., Sonnay, S., Glauser, L., Moore, D. J. <strong>Common pathogenic effects of missense mutations in the P-type ATPase ATP13A2 (PARK9) associated with early-onset parkinsonism.</strong> PLoS One 7: e39942, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22768177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22768177</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22768177[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/10.1371/journal.pone.0039942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22768177">Podhajska et al. (2012)</a> found that expression of the homozygous ATP13A2 missense mutations F182L, G504R (<a href="#0004">610513.0004</a>), and G877R (<a href="#0008">610513.0008</a>) resulted in decreased steady-state levels of the mutant protein due to decreased protein stability and increased proteasomal degradation. In addition, the mutant F182L and G504R proteins showed abnormal intracellular vesicular localization to the endoplasmic reticulum, whereas G877R showed normal vesicular localization. The findings were consistent with a loss-of-function effect. Overexpression of the missense mutations did not cause cellular toxicity, although the F182L variant sensitized cortical neurons to neurite shortening induced by heavy metals, suggesting a possible gain of function. <a href="#14" class="mim-tip-reference" title="Podhajska, A., Musso, A., Trancikova, A., Stafa, K., Moser, R., Sonnay, S., Glauser, L., Moore, D. J. <strong>Common pathogenic effects of missense mutations in the P-type ATPase ATP13A2 (PARK9) associated with early-onset parkinsonism.</strong> PLoS One 7: e39942, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22768177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22768177</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22768177[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/10.1371/journal.pone.0039942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22768177">Podhajska et al. (2012)</a> noted that disease-associated missense mutations in ATP13A2 cluster in the second intracellular loop region containing the catalytic ATPase domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22768177" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using primary KRS patient dermal fibroblasts and knockdown primary mouse neurons, <a href="#21" class="mim-tip-reference" title="Tsunemi, T., Krainc, D. <strong>Zn(2+) dyshomeostasis caused by loss of ATP13A2/PARK9 leads to lysosomal dysfunction and alpha-synuclein accumulation.</strong> Hum. Molec. Genet. 23: 2791-2801, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24334770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24334770</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24334770[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/hmg/ddt572" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24334770">Tsunemi and Krainc (2014)</a> found that loss of functional ATP13A2 increased cell sensitivity to extracellular zinc. Zinc sensitivity was alleviated with Zn(2+) chelators. ATP13A2-deficient cells showed reduced lysosomal sequestration of Zn(2+) compared with wildtype, concomitant with increased expression of all cell surface and vesicular zinc transporters examined. Excess Zn(2+) elevated lysosomal pH and impaired lysosomal enzyme function and trafficking in mouse neurons in a dose-dependent manner, an effect that was exacerbated by Atp13a2 depletion. Excess Zn(2+) or Atp13a2 depletion also caused alpha-synuclein (SNCA; <a href="/entry/163890">163890</a>) oxidation and accumulation. <a href="#21" class="mim-tip-reference" title="Tsunemi, T., Krainc, D. <strong>Zn(2+) dyshomeostasis caused by loss of ATP13A2/PARK9 leads to lysosomal dysfunction and alpha-synuclein accumulation.</strong> Hum. Molec. Genet. 23: 2791-2801, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24334770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24334770</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24334770[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/hmg/ddt572" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24334770">Tsunemi and Krainc (2014)</a> concluded that ATP13A2-deficient lysosomes have a decreased capacity to store Zn(2+), resulting in Zn(2+) dyshomeostasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24334770" 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>Independently, <a href="#13" class="mim-tip-reference" title="Park, J.-S., Koentjoro, B., Veivers, D., Mackay-Sim, A., Sue, C. M. <strong>Parkinson's disease-associated human ATP13A2 (PARK9) deficiency causes zinc dyshomeostasis and mitochondrial dysfunction.</strong> Hum. Molec. Genet. 23: 2802-2815, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24399444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24399444</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24399444[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/hmg/ddt623" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24399444">Park et al. (2014)</a> detected Zn(2+) dyshomeostasis in KRS patient-derived olfactory neurospheres, with decreased capacity to sequester Zn(2+) into vesicles of the autophagy-lysosomal pathway. Loss of ATP13A2 also caused abnormal energy metabolism, with mitochondrial fragmentation and cell death as a result of ATP depletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24399444" 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="#11" class="mim-tip-reference" title="Kong, S. M. Y., Chan, B. K. K., Park, J.-S., Hill, K. J., Aitken, J. B., Cottle, L., Farghaian, H., Cole, A. R., Lay, P. A., Sue, C. M., Cooper, A. A. <strong>Parkinson's disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes alpha-synuclein externalization via exosomes.</strong> Hum. Molec. Genet. 23: 2816-2833, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24603074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24603074</a>] [<a href="https://doi.org/10.1093/hmg/ddu099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24603074">Kong et al. (2014)</a> reported findings similar to those of <a href="#21" class="mim-tip-reference" title="Tsunemi, T., Krainc, D. <strong>Zn(2+) dyshomeostasis caused by loss of ATP13A2/PARK9 leads to lysosomal dysfunction and alpha-synuclein accumulation.</strong> Hum. Molec. Genet. 23: 2791-2801, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24334770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24334770</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24334770[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/hmg/ddt572" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24334770">Tsunemi and Krainc (2014)</a> and <a href="#13" class="mim-tip-reference" title="Park, J.-S., Koentjoro, B., Veivers, D., Mackay-Sim, A., Sue, C. M. <strong>Parkinson's disease-associated human ATP13A2 (PARK9) deficiency causes zinc dyshomeostasis and mitochondrial dysfunction.</strong> Hum. Molec. Genet. 23: 2802-2815, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24399444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24399444</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24399444[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/hmg/ddt623" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24399444">Park et al. (2014)</a>. They also found that knockdown of ATP13A2 in human neuroblastoma cells resulted in sensitivity to zinc, but not to manganese. Elevated ATP13A2 expression reduced intracellular alpha-synuclein protein content by externalization via release of exosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=24603074+24334770+24399444" 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="Usenovic, M., Tresse, E., Mazzulli, J. R., Taylor, J. P., Krainc, D. <strong>Deficiency of ATP13A2 leads to lysosomal dysfunction, alpha-synuclein accumulation, and neurotoxicity.</strong> J. Neurosci. 32: 4240-4246, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22442086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22442086</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22442086[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.5575-11.2012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22442086">Usenovic et al. (2012)</a> found that knockdown of the Atp13a2 gene in cultured neurons caused accumulation and enlargement of lysosomes, decreased lysosomal degradation of accumulated proteins, accumulation of autophagosomes, and accumulation of alpha-synuclein (SNCA; <a href="/entry/163890">163890</a>), resulting in neuronal toxicity. Overexpression of Atp13a2 rescued the SNCA-mediated toxicity in cultured neurons. The findings provided a link between lysosomal dysfunction resulting from ATP13A2 mutations and neurodegeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22442086" 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 46-year-old man, born of consanguineous Pakistani parents, with autosomal recessive spastic paraplegia-78 (SPG78; <a href="/entry/617225">617225</a>), <a href="#10" class="mim-tip-reference" title="Kara, E., Tucci, A., Manzoni, C., Lynch, D. S., Elpidorou, M., Bettencourt, C., Chelban, V., Manole, A., Hamed, S. A., Haridy, N. A., Federoff, M., Preza, E., and 17 others. <strong>genetic and phenotypic characterization of complex hereditary spastic paraplegia.</strong> Brain 139: 1904-1918, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27217339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27217339</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27217339[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/aww111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27217339">Kara et al. (2016)</a> identified a homozygous mutation in the ATP13A2 gene (<a href="#0009">610513.0009</a>). Functional studies of the variant and studies of patient cells were not performed. The patient was 1 of 97 probands with complicated spastic paraplegia who underwent molecular analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27217339" 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 5 patients from 3 unrelated families with adult-onset SPG78, <a href="#6" class="mim-tip-reference" title="Estrada-Cuzcano, A., Martin, S., Chamova, T., Synofzik, M., Timmann, D., Holemans, T., Andreeva, A., Reichbauer, J., De Rycke, R., Chang, D.-I., van Veen, S., Samuel, J., and 10 others. <strong>Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78).</strong> Brain 140: 287-305, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28137957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28137957</a>] [<a href="https://doi.org/10.1093/brain/aww307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28137957">Estrada-Cuzcano et al. (2017)</a> identified homozygous or compound heterozygous mutations in the ATP13A2 gene (<a href="#0010">610513.0010</a>-<a href="#0013">610513.0013</a>). The mutation in the first family was found by whole-exome sequencing; the mutations in the 2 subsequent patients were found by direct sequencing of the ATP13A2 gene in a cohort of 795 probands with spastic paraplegia. Studies of selected patient cells and in vitro studies of some of the mutations showed abnormal intracellular localization of the mutant proteins, transcript or protein instability in some cases, and impaired lysosomal and mitochondrial function, all consistent with a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28137957" 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>Heterozygous ATP13A2 Mutations</em></strong></p><p>
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The role of heterozygous ATP13A2 variants in patients with early-onset Parkinson disease is unclear and controversial. <a href="#5" class="mim-tip-reference" title="Di Fonzo, A., Chien, H. F., Socal, M., Giraudo, S., Tassorelli, C., Iliceto, G., Fabbrini, F., Marconi, R., Fincati, E., Abbruzzese, F., Marini, P., Squitieri, F., and 14 others. <strong>ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease.</strong> Neurology 68: 1557-1562, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17485642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17485642</a>] [<a href="https://doi.org/10.1212/01.wnl.0000260963.08711.08" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17485642">Di Fonzo et al. (2007)</a> identified heterozygous ATP13A2 variants (T12M and G533R, respectively) in 2 unrelated Italian patients with early-onset parkinsonism at age 30 and 40 years, respectively, suggesting that heterozygous mutations may increase risk for development of the disease. <a href="#12" class="mim-tip-reference" title="Lin, C. H., Tan, E. K., Chen, M. L., Tan, L. C., Lim, H. Q., Chen, G. S., Wu, R. M. <strong>Novel ATP13A2 variant associated with Parkinson disease in Taiwan and Singapore.</strong> Neurology 71: 1727-1732, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19015489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19015489</a>] [<a href="https://doi.org/10.1212/01.wnl.0000335167.72412.68" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19015489">Lin et al. (2008)</a> identified a heterozygous A746T substitution in the ATP13A2 gene in 3 (1.7%) of 182 Han Chinese patients with early-onset Parkinson disease and none of 589 matched controls (relative risk of 4.3, p = 0.01). The substitution is located between the highly conserved phosphorylation region and the fifth transmembrane domain. Functional studies were not performed. <a href="#3" class="mim-tip-reference" title="Chan, A. Y. Y., Baum, L., Tang, N. L. S., Lau, C. Y. K., Ng, P. W., Hui, K. F., Mizuno, Y., Kwan, J. Y., Mok, V. C. T., Kuo, S.-H. <strong>The role of the Ala746Thr variant in the ATP13A2 gene among Chinese patients with Parkinson's disease.</strong> J. Clin. Neurosci. 20: 761-762, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23522931/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23522931</a>] [<a href="https://doi.org/10.1016/j.jocn.2012.05.052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23522931">Chan et al. (2013)</a> found a heterozygous A746T variant in 1 (1.4%) of 69 Chinese patients with early-onset PD, in 1 (0.5%) of 192 patients with late-onset PD, and in 1 (0.6%) of 180 controls. They concluded that the ATP13A2 A746T variant is not a common risk factor for PD in the Chinese population in Hong Kong. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17485642+23522931+19015489" 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 cellular studies, <a href="#14" class="mim-tip-reference" title="Podhajska, A., Musso, A., Trancikova, A., Stafa, K., Moser, R., Sonnay, S., Glauser, L., Moore, D. J. <strong>Common pathogenic effects of missense mutations in the P-type ATPase ATP13A2 (PARK9) associated with early-onset parkinsonism.</strong> PLoS One 7: e39942, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22768177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22768177</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22768177[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/10.1371/journal.pone.0039942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22768177">Podhajska et al. (2012)</a> found that the heterozygous T12M, G533R, and A746T missense variants did not obviously alter protein stability or subcellular localization, but did cause a significant decrease in the ATPase activity of ATP13A2 compared to wildtype. The findings suggested that these heterozygous variants can cause a loss of function. Overexpression of the missense mutations did not cause cellular toxicity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22768177" 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>Mutation or overexpression of the alpha-synuclein gene (SNCA; <a href="/entry/163890">163890</a>) can cause Parkinson disease (PARK1; <a href="/entry/168601">168601</a>). <a href="#8" class="mim-tip-reference" title="Gitler, A. D., Chesi, A., Geddie, M. L., Strathearn, K. E., Hamamichi, S., Hill, K. J., Caldwell, K. A., Caldwell, G. A., Cooper, A. A., Rochet, J.-C., Lindquist, S. <strong>Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity.</strong> Nature Genet. 41: 308-315, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19182805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19182805</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19182805[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/ng.300" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19182805">Gitler et al. (2009)</a> showed that the yeast homolog of human ATP13A2, termed Ypk9, could suppress overexpression-induced Snca toxicity both in yeast and in cultured rat dopaminergic neurons by decreasing intracellular Snca inclusions. Ypk9 knockdown in C. elegans enhanced misfolding of Snca. In addition, Ypk9 was found to help protect cells from manganese toxicity. These findings suggested a functional connection between Snca and the PARK9 susceptibility locus, as well as with manganese exposure as a possible environmental risk factor for PD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19182805" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Farias, F. H. G., Zeng, R., Johnson, G. S., Wininger, F. A., Taylor, J. F., Schnabel, R. D., McKay, S. D., Sanders, D. N., Lohi, H., Seppala, E. H., Wade, C. M., Lindblad-Toh, K., O'Brien, D. P., Katz, M. L. <strong>A truncating mutation in ATP13A2 is responsible for adult-onset neuronal ceroid lipofuscinosis in Tibetan terriers.</strong> Neurobiol. Dis. 42: 468-474, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21362476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21362476</a>] [<a href="https://doi.org/10.1016/j.nbd.2011.02.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21362476">Farias et al. (2011)</a> determined that a homozygous truncating mutation (1623delC) in exon 16 of the Atp13a2 gene is responsible for autosomal recessive, adult-onset neuronal ceroid lipofuscinosis (NCL) in Tibetan terriers (<a href="#16" class="mim-tip-reference" title="Riis, R. C., Cummings, J. F., Loew, E. R., de Lahunta, A. <strong>Tibetan terrier model of canine ceroid lipofuscinosis.</strong> Am. J. Med. Genet. 42: 615-621, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1609844/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1609844</a>] [<a href="https://doi.org/10.1002/ajmg.1320420437" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1609844">Riis et al., 1992</a>). Behavioral changes in these dogs were first noted between age 4 and 9 years, and brain tissue showed autofluorescent membrane-bound cytoplasmic inclusions with varied ultrastructure in neurons, consistent with a diagnosis of NCL. Although homozygous truncating mutations in human ATP13A2 cause Kufor-Rakeb syndrome (KRS; <a href="/entry/606693">606693</a>), another neurodegenerative disease, the phenotype differs between terriers and humans. Tibetan terriers with NCL develop cerebellar ataxia not reported in KRS patients, and KRS patients exhibit parkinsonism and pyramidal dysfunction not observed in affected Tibetan terriers. However, both show generalized brain atrophy, behavioral changes, and cognitive decline. The findings suggested that KRS may be a type of adult-onset NCL; however, sequencing of the ATP13A2 gene in 28 patients with adult-onset NCL (Kufs disease; CLN4A, <a href="/entry/204300">204300</a>) failed to reveal any variants likely to be disease-causing. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1609844+21362476" 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> rs765632065 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs765632065;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/rs765632065?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=rs765632065" 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=rs765632065" 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=RCV000541447 OR RCV000598921 OR RCV001201356 OR RCV001844194 OR RCV002509424 OR RCV002528398" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000541447, RCV000598921, RCV001201356, RCV001844194, RCV002509424, RCV002528398" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000541447...</a>
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<p>In a nonconsanguineous Chilean family in which 3 males and 1 female in a sibship of 11 were affected with the early-onset parkinsonism resembling that of Kufor-Rakeb syndrome (KRS; <a href="/entry/606693">606693</a>), <a href="#15" class="mim-tip-reference" title="Ramirez, A., Heimbach, A., Grundemann, J., Stiller, B., Hampshire, D., Cid, L. P., Goebel, I., Mubaidin, A. F., Wriekat, A.-L., Roeper, J., Al-Din, A., Hillmer, A. M., Karsak, M., Liss, B., Woods, C. G., Behrens, M. I., Kubisch, C. <strong>Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase.</strong> Nature Genet. 38: 1184-1191, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16964263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16964263</a>] [<a href="https://doi.org/10.1038/ng1884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16964263">Ramirez et al. (2006)</a> found 2 mutations of the ATP13A2 gene in compound heterozygosity. The mutation inherited from the mother was deletion of a cytosine at nucleotide position 3057 in exon 26, leading to a frameshift and stop codon after 2 extraneous amino acids (3057delC, 1019GlyfsTer1021). The second mutation, inherited from the father, was a guanine-to-adenine transition at position +5 of the donor splice site of exon 13 (1306+5G-A; <a href="#0002">610513.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16964263" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By confocal analysis of human, mouse, and rat cells transfected with ATP13A2 cDNA containing the 3057C deletion, <a href="#20" class="mim-tip-reference" title="Tan, J., Zhang, T., Jiang, L., Chi, J., Hu, D., Pan, Q., Wang, D., Zhang, Z. <strong>Regulation of intracellular manganese homeostasis by Kufor-Rakeb syndrome-associated ATP13A2 protein.</strong> J. Biol. Chem. 286: 29654-29662, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21724849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21724849</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21724849[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.M111.233874" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21724849">Tan et al. (2011)</a> found that the mutant protein was not targeted to lysosomes, but was retained in the endoplasmic reticulum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21724849" 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">rs786205056 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205056;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=rs786205056" 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=rs786205056" 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=RCV000001278 OR RCV001851532 OR RCV004719607" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001278, RCV001851532, RCV004719607" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001278...</a>
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<p>For discussion of the splice site mutation in the ATP13A2 gene (1306+5G-A) that was found in compound heterozygous state in patients with Kufor-Rakeb syndrome (KRS; <a href="/entry/606693">606693</a>) by <a href="#15" class="mim-tip-reference" title="Ramirez, A., Heimbach, A., Grundemann, J., Stiller, B., Hampshire, D., Cid, L. P., Goebel, I., Mubaidin, A. F., Wriekat, A.-L., Roeper, J., Al-Din, A., Hillmer, A. M., Karsak, M., Liss, B., Woods, C. G., Behrens, M. I., Kubisch, C. <strong>Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase.</strong> Nature Genet. 38: 1184-1191, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16964263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16964263</a>] [<a href="https://doi.org/10.1038/ng1884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16964263">Ramirez et al. (2006)</a>, see <a href="#0001">610513.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16964263" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By confocal analysis of human, mouse, and rat cells transfected with ATP13A2 cDNA containing this splice site mutation, <a href="#20" class="mim-tip-reference" title="Tan, J., Zhang, T., Jiang, L., Chi, J., Hu, D., Pan, Q., Wang, D., Zhang, Z. <strong>Regulation of intracellular manganese homeostasis by Kufor-Rakeb syndrome-associated ATP13A2 protein.</strong> J. Biol. Chem. 286: 29654-29662, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21724849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21724849</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21724849[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.M111.233874" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21724849">Tan et al. (2011)</a> found that the mutant protein was not targeted to lysosomes, but was retained in the endoplasmic reticulum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21724849" 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">rs2100817106 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2100817106;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=rs2100817106" 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=rs2100817106" 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=RCV000001279" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001279" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001279</a>
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<p>In the originally described Jordanian family with Kufor-Rakeb syndrome (KRS; <a href="/entry/606693">606693</a>), <a href="#15" class="mim-tip-reference" title="Ramirez, A., Heimbach, A., Grundemann, J., Stiller, B., Hampshire, D., Cid, L. P., Goebel, I., Mubaidin, A. F., Wriekat, A.-L., Roeper, J., Al-Din, A., Hillmer, A. M., Karsak, M., Liss, B., Woods, C. G., Behrens, M. I., Kubisch, C. <strong>Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase.</strong> Nature Genet. 38: 1184-1191, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16964263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16964263</a>] [<a href="https://doi.org/10.1038/ng1884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16964263">Ramirez et al. (2006)</a> demonstrated that affected individuals had a homozygous 22-bp duplication (1632_1653dup22, 552LeufsTer788), leading to a frameshift and stop codon after 236 extraneous amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16964263" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By confocal analysis of human, mouse, and rat cells transfected with ATP13A2 cDNA containing the 22-bp duplication, <a href="#20" class="mim-tip-reference" title="Tan, J., Zhang, T., Jiang, L., Chi, J., Hu, D., Pan, Q., Wang, D., Zhang, Z. <strong>Regulation of intracellular manganese homeostasis by Kufor-Rakeb syndrome-associated ATP13A2 protein.</strong> J. Biol. Chem. 286: 29654-29662, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21724849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21724849</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21724849[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.M111.233874" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21724849">Tan et al. (2011)</a> found that the mutant protein was not targeted to lysosomes, but was retained in the endoplasmic reticulum. Mutant ATP13A2 did not regulate intracellular Mn(2+) upon Mn(2+) overexposure or protect cells from Mn(2+)-induced cell death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21724849" 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">rs121918227 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918227;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=rs121918227" 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=rs121918227" 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=RCV000001280 OR RCV001851533 OR RCV002251851 OR RCV004766975" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001280, RCV001851533, RCV002251851, RCV004766975" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001280...</a>
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<p>In a Brazilian man with Kufor-Rakeb syndrome (KRS; <a href="/entry/606693">606693</a>), <a href="#5" class="mim-tip-reference" title="Di Fonzo, A., Chien, H. F., Socal, M., Giraudo, S., Tassorelli, C., Iliceto, G., Fabbrini, F., Marconi, R., Fincati, E., Abbruzzese, F., Marini, P., Squitieri, F., and 14 others. <strong>ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease.</strong> Neurology 68: 1557-1562, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17485642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17485642</a>] [<a href="https://doi.org/10.1212/01.wnl.0000260963.08711.08" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17485642">Di Fonzo et al. (2007)</a> identified a homozygous 1510G-C transversion in exon 15 of the ATP13A2 gene, resulting in a gly504-to-arg (G504R) substitution in the larger cytosolic loop close to the predicted catalytic phosphorylation site. The unaffected parents were heterozygous for the mutation, which was not found in 654 control chromosomes. The patient was diagnosed with levodopa-responsive parkinsonism at age 12 years. On examination at the age of 18, he had severe akinetic-rigid parkinsonism with episodic levodopa-induced choreic dyskinesias, visual hallucinations, and aggressive behaviors. However, his mental status remained good, and he was cognitively intact between episodes. Other features included supranuclear vertical gaze paresis, diffuse cerebral atrophy, and lip/chin tremor. He did not have myoclonus or tremor in the limbs. <a href="#5" class="mim-tip-reference" title="Di Fonzo, A., Chien, H. F., Socal, M., Giraudo, S., Tassorelli, C., Iliceto, G., Fabbrini, F., Marconi, R., Fincati, E., Abbruzzese, F., Marini, P., Squitieri, F., and 14 others. <strong>ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease.</strong> Neurology 68: 1557-1562, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17485642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17485642</a>] [<a href="https://doi.org/10.1212/01.wnl.0000260963.08711.08" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17485642">Di Fonzo et al. (2007)</a> postulated that the missense mutation may have resulted in a milder phenotype than that reported for frameshift or truncating mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17485642" 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> rs762033589 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs762033589;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/rs762033589?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=rs762033589" 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=rs762033589" 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 40-year-old man, born of consanguineous Pakistani parents, with Kufor-Rakeb syndrome (KRS; <a href="/entry/606693">606693</a>), <a href="#18" class="mim-tip-reference" title="Schneider, S. A., Paisan-Ruiz, C., Quinn, N. P., Lees, A. J., Houlden, H., Hardy, J., Bhatia, K. P. <strong>ATP13A2 mutations (PARK9) cause neurodegeneration with brain iron accumulation.</strong> Mov. Disord. 25: 979-984, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20310007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20310007</a>] [<a href="https://doi.org/10.1002/mds.22947" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20310007">Schneider et al. (2010)</a> identified a homozygous 2-bp insertion (1103insGA) in the ATP13A2 gene, resulting in a frameshift and truncation. He had mild school difficulties in childhood, but onset of major symptoms occurred at age 16, when he presented with behavioral abnormalities and extrapyramidal symptoms. The disorder was progressive, and he developed severe parkinsonism, pyramidal signs, dystonia, restricted ocular movements, and hypomimia. Brain MRI showed diffuse brain atrophy, flattening of the caudate nuclei, and iron deposition in the basal ganglia. Cognition remained relatively intact. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20310007" 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">rs587776890 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776890;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=rs587776890" 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=rs587776890" 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=RCV000023819" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023819" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023819</a>
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<p>In a boy, born of consanguineous Afghan parents, with Kufor-Rakeb syndrome (KRS; <a href="/entry/606693">606693</a>), <a href="#4" class="mim-tip-reference" title="Crosiers, D., Ceulemans, B., Meeus, B., Nuytemans, K., Pals, P., Van Broeckhoven, C., Cras, P., Theuns, J. <strong>Juvenile dystonia-parkinsonism and dementia caused by a novel ATP13A2 frameshift mutation. (Letter)</strong> Parkinsonism Relat. Disord. 17: 135-138, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21094623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21094623</a>] [<a href="https://doi.org/10.1016/j.parkreldis.2010.10.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21094623">Crosiers et al. (2011)</a> identified a homozygous 2-bp deletion (2742delTT) in exon 23 of the ATP13A2 gene, resulting in a premature stop codon and truncation of the protein at residue 324, causing a loss of function. There was no evidence of nonsense-mediated mRNA decay on RT-PCR analysis. The patient had mild mental retardation before onset of fine tremor of the hands and dystonic posturing of the neck at age 10 years. He also had slow vertical saccades, hypomimia, facial myoclonus, and dystonia. Cognitive function deteriorated rapidly, and he had dementia by age 11. Bradykinesia and rigidity were partially responsive to L-DOPA therapy, but he developed dyskinesias. The patient also had visual hallucinations and psychosis, and nuclear imaging showed decreased dopamine transporter binding in the right caudate nucleus and bilateral putamina. The heterozygous deletion was also found in the parents, as well as in a brother who had mild mental retardation, tremor, and decreased dopamine transporter binding in the putamina. <a href="#4" class="mim-tip-reference" title="Crosiers, D., Ceulemans, B., Meeus, B., Nuytemans, K., Pals, P., Van Broeckhoven, C., Cras, P., Theuns, J. <strong>Juvenile dystonia-parkinsonism and dementia caused by a novel ATP13A2 frameshift mutation. (Letter)</strong> Parkinsonism Relat. Disord. 17: 135-138, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21094623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21094623</a>] [<a href="https://doi.org/10.1016/j.parkreldis.2010.10.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21094623">Crosiers et al. (2011)</a> speculated that heterozygosity for the mutation may have contributed to the brother's phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21094623" 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">rs587777053 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777053;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=rs587777053" 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=rs587777053" 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=RCV000056335" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000056335" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000056335</a>
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<p>In 3 Belgian sibs with Kufor-Rakeb syndrome (KRS; <a href="/entry/606693">606693</a>), <a href="#1" class="mim-tip-reference" title="Bras, J., Verloes, A., Schneider, S. A., Mole, S. E., Guerreiro, R. J. <strong>Mutation of the parkinsonism gene ATP13A2 causes neuronal ceroid-lipofuscinosis.</strong> Hum. Molec. Genet. 21: 2646-2650, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22388936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22388936</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22388936[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/hmg/dds089" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22388936">Bras et al. (2012)</a> identified a homozygous c.2429T-G transversion in exon 22 of the ATP13A2 gene, resulting in a met810-to-arg (M810R) substitution at a highly conserved residue. The mutation was found by exome sequencing and segregated with the disorder in the family. It was not present in the dbSNP (build 135) or 1000 Genomes Project databases. Functional studies were not performed. The family was originally reported by <a href="#2" class="mim-tip-reference" title="Carlier, G., Dubru, J. M. <strong>Familial juvenile parkinsonism.</strong> Acta Paediat. Belg. 32: 123-127, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/495089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">495089</a>]" pmid="495089">Carlier and Dubru (1979)</a>. Because some of the patients in this family had neuropathologic findings suggestive of neuronal ceroid lipofuscinosis, <a href="#1" class="mim-tip-reference" title="Bras, J., Verloes, A., Schneider, S. A., Mole, S. E., Guerreiro, R. J. <strong>Mutation of the parkinsonism gene ATP13A2 causes neuronal ceroid-lipofuscinosis.</strong> Hum. Molec. Genet. 21: 2646-2650, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22388936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22388936</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22388936[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/hmg/dds089" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22388936">Bras et al. (2012)</a> designated the disorder CLN12. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22388936+495089" 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> rs144701072 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs144701072;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/rs144701072?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=rs144701072" 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=rs144701072" 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=RCV000056336" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000056336" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000056336</a>
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<p>In 2 Italian brothers with Kufor-Rakeb syndrome (KRS; <a href="/entry/606693">606693</a>), <a href="#17" class="mim-tip-reference" title="Santoro, L., Breedveld, G. J., Manganelli, F., Iodice, R., Pisciotta, C., Nolano, M., Punzo, F., Quarantelli, M., Pappata, S., Di Fonzo, A., Oostra, B. A., Bonifati, V. <strong>Novel ATP13A2 (PARK9) homozygous mutation in a family with marked phenotype variability.</strong> Neurogenetics 12: 33-39, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20853184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20853184</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20853184[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/s10048-010-0259-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20853184">Santoro et al. (2011)</a> identified a homozygous c.2629G-A transition in exon 24 of the ATP13A2 gene, resulting in a gly877-to-arg (G877R) substitution at a highly conserved residue in the catalytic autophosphorylation P2 domain in the large cytoplasmic loop between the M4 and M5 transmembrane domains. The unaffected parents were heterozygous for the mutation, which was not found in 336 control chromosomes. The brothers and their unaffected mother also carried a heterozygous R481C mutation in the FBXO7 gene (<a href="/entry/605648">605648</a>); biallelic mutation in the FBXO7 gene causes early-onset PARK15 (<a href="/entry/260300">260300</a>). The FBXO7 mutation occurred at a highly conserved residue and was not found in 318 control chromosomes, but the significance of this finding was unclear. The disease course in the 2 brothers showed phenotypic variability. The more severely affected brother, who had a history of perinatal asphyxia, developed slowly progressive parkinsonism at age 10 years, followed by pyramidal signs, extrapyramidal signs, and cognitive impairment. At age 41 years, he showed dysphagia, dysarthria, abnormal eye movements, hypomimia, mini-myoclonus of the facial muscles, dystonia, and spasticity. The 31-year-old brother had difficulty in school, mild gaze palsy, hyperreflexia, mildly increased axial tone, and mild rigidity, but was otherwise asymptomatic. Transcranial magnetic stimulation in both patients showed prolonged central motor conduction times, and brain imaging showed decreased dopamine transporter density in the striatum. There was also cerebral and cerebellar cortical atrophy. There was no evidence of iron accumulation in the basal ganglia. <a href="#17" class="mim-tip-reference" title="Santoro, L., Breedveld, G. J., Manganelli, F., Iodice, R., Pisciotta, C., Nolano, M., Punzo, F., Quarantelli, M., Pappata, S., Di Fonzo, A., Oostra, B. A., Bonifati, V. <strong>Novel ATP13A2 (PARK9) homozygous mutation in a family with marked phenotype variability.</strong> Neurogenetics 12: 33-39, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20853184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20853184</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20853184[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/s10048-010-0259-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20853184">Santoro et al. (2011)</a> concluded that unknown modifiers were responsible for the observed intrafamilial phenotypic variation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20853184" 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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ATP13A2, 3-BP DEL, NT3017
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1057519290 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519290;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=rs1057519290" 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=rs1057519290" 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 46-year-old man (proband 41), born of consanguineous Pakistani parents, with autosomal recessive spastic paraplegia-78 (SPG78; <a href="/entry/617225">617225</a>), <a href="#10" class="mim-tip-reference" title="Kara, E., Tucci, A., Manzoni, C., Lynch, D. S., Elpidorou, M., Bettencourt, C., Chelban, V., Manole, A., Hamed, S. A., Haridy, N. A., Federoff, M., Preza, E., and 17 others. <strong>genetic and phenotypic characterization of complex hereditary spastic paraplegia.</strong> Brain 139: 1904-1918, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27217339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27217339</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27217339[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/aww111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27217339">Kara et al. (2016)</a> identified a homozygous 3-bp deletion (c.3020_3022del, NM_001141974.2), resulting in an in-frame deletion (Phe1007del) near/in the transmembrane helix. The variant, which was found by targeted next generation sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP database and was not found in over 100,000 ExAC controls. Functional studies of the variant and studies of patients cells were not performed. (In the text of the article by <a href="#10" class="mim-tip-reference" title="Kara, E., Tucci, A., Manzoni, C., Lynch, D. S., Elpidorou, M., Bettencourt, C., Chelban, V., Manole, A., Hamed, S. A., Haridy, N. A., Federoff, M., Preza, E., and 17 others. <strong>genetic and phenotypic characterization of complex hereditary spastic paraplegia.</strong> Brain 139: 1904-1918, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27217339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27217339</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27217339[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/aww111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27217339">Kara et al. (2016)</a>, the variant is given as c.3017_3019del; p.1006_1007del.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27217339" 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 SPASTIC PARAPLEGIA 78, AUTOSOMAL RECESSIVE</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">rs1057519291 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519291;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=rs1057519291" 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=rs1057519291" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 3 brothers, born of Belgian parents (family HSP84), with autosomal recessive spastic paraplegia-78 (SPG78; <a href="/entry/617225">617225</a>), <a href="#6" class="mim-tip-reference" title="Estrada-Cuzcano, A., Martin, S., Chamova, T., Synofzik, M., Timmann, D., Holemans, T., Andreeva, A., Reichbauer, J., De Rycke, R., Chang, D.-I., van Veen, S., Samuel, J., and 10 others. <strong>Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78).</strong> Brain 140: 287-305, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28137957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28137957</a>] [<a href="https://doi.org/10.1093/brain/aww307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28137957">Estrada-Cuzcano et al. (2017)</a> identified a homozygous c.1535C-T transition (c.1535C-T, NM_001141973.1) in the ATP13A2 gene, resulting in a thr512-to-ile (T512I) substitution at a highly conserved residue in the autophosphorylation motif. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (build 135), Exome Variant Server (August 2014), and 1000 Genomes Project (2015) databases, and an in-house database. It was not found in 94 ethnically matched controls. The patients' unaffected father was heterozygous for the mutation; DNA from the unaffected mother was not available. Patient-derived fibroblasts had increased lysosomes that contained abnormal storage material, as well as increased mitochondrial mass with a reduction in mitochondrial membrane potential compared to controls. The mutant protein was mislocalized to the endoplasmic reticulum and was unable to undergo autophosphorylation. <a href="#6" class="mim-tip-reference" title="Estrada-Cuzcano, A., Martin, S., Chamova, T., Synofzik, M., Timmann, D., Holemans, T., Andreeva, A., Reichbauer, J., De Rycke, R., Chang, D.-I., van Veen, S., Samuel, J., and 10 others. <strong>Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78).</strong> Brain 140: 287-305, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28137957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28137957</a>] [<a href="https://doi.org/10.1093/brain/aww307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28137957">Estrada-Cuzcano et al. (2017)</a> noted that the same homozygous mutation had previously been identified in a Lebanese patient (L6025) who was diagnosed with Kufor-Rakeb syndrome (KRS; <a href="/entry/606693">606693</a>) based on genetic findings (<a href="#22" class="mim-tip-reference" title="Usenovic, M., Tresse, E., Mazzulli, J. R., Taylor, J. P., Krainc, D. <strong>Deficiency of ATP13A2 leads to lysosomal dysfunction, alpha-synuclein accumulation, and neurotoxicity.</strong> J. Neurosci. 32: 4240-4246, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22442086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22442086</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22442086[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.5575-11.2012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22442086">Usenovic et al., 2012</a>), but <a href="#6" class="mim-tip-reference" title="Estrada-Cuzcano, A., Martin, S., Chamova, T., Synofzik, M., Timmann, D., Holemans, T., Andreeva, A., Reichbauer, J., De Rycke, R., Chang, D.-I., van Veen, S., Samuel, J., and 10 others. <strong>Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78).</strong> Brain 140: 287-305, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28137957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28137957</a>] [<a href="https://doi.org/10.1093/brain/aww307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28137957">Estrada-Cuzcano et al. (2017)</a> noted that the Lebanese patient had onset at age 44 years of features consistent with SPG78. <a href="#6" class="mim-tip-reference" title="Estrada-Cuzcano, A., Martin, S., Chamova, T., Synofzik, M., Timmann, D., Holemans, T., Andreeva, A., Reichbauer, J., De Rycke, R., Chang, D.-I., van Veen, S., Samuel, J., and 10 others. <strong>Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78).</strong> Brain 140: 287-305, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28137957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28137957</a>] [<a href="https://doi.org/10.1093/brain/aww307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28137957">Estrada-Cuzcano et al. (2017)</a> stated that this variant was originally reported as c.1550C-T (NM_022089.2), resulting in a thr517-to-ile (T517I) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22442086+28137957" 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="Usenovic, M., Tresse, E., Mazzulli, J. R., Taylor, J. P., Krainc, D. <strong>Deficiency of ATP13A2 leads to lysosomal dysfunction, alpha-synuclein accumulation, and neurotoxicity.</strong> J. Neurosci. 32: 4240-4246, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22442086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22442086</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22442086[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.5575-11.2012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22442086">Usenovic et al. (2012)</a> found that fibroblasts derived from the Lebanese patient homozygous for the c.1550C-T mutation had accumulation of enlarged lysosomes and impaired lysosomal degradation activity compared to controls. <a href="#9" class="mim-tip-reference" title="Grunewald, A., Arns, B., Seibler, P., Rakovic, A., Munchau, A., Ramirez, A., Sue, C. M., Klein, C. <strong>ATP13A2 mutations impair mitochondrial function in fibroblasts from patients with Kufor-Rakeb syndrome.</strong> Neurobiol. Aging 33: 1843.e1-1843.e7, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22296644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22296644</a>] [<a href="https://doi.org/10.1016/j.neurobiolaging.2011.12.035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22296644">Grunewald et al. (2012)</a> found that fibroblasts derived from the Lebanese patient had mitochondrial dysfunction as manifest by decreased ATP production, increased oxygen consumption, fragmentation of the mitochondrial network, and increased mtDNA, suggesting impaired mitophagy. These cellular defects could be rescued by expression of wildtype ATP13A2. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22442086+22296644" 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">rs1057519292 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519292;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=rs1057519292" 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=rs1057519292" 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=RCV000415546 OR RCV004767251" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000415546, RCV004767251" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000415546...</a>
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<p>In a Serbian woman (family HIH21480) with autosomal recessive spastic paraplegia-78 (SPG78; <a href="/entry/617225">617225</a>), <a href="#6" class="mim-tip-reference" title="Estrada-Cuzcano, A., Martin, S., Chamova, T., Synofzik, M., Timmann, D., Holemans, T., Andreeva, A., Reichbauer, J., De Rycke, R., Chang, D.-I., van Veen, S., Samuel, J., and 10 others. <strong>Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78).</strong> Brain 140: 287-305, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28137957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28137957</a>] [<a href="https://doi.org/10.1093/brain/aww307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28137957">Estrada-Cuzcano et al. (2017)</a> identified a homozygous c.364C-T transition (c.364C-T, NM_001141973.1) in exon 5 of the ATP13A2 gene, resulting in a gln122-to-ter (Q122X) substitution. The mutation was found by direct sequencing of the ATP13A2 gene in a cohort of 795 probands with spastic paraplegia. The unaffected parents were deceased and DNA was not available for segregation studies. The mutation was predicted to result in nonsense-mediated mRNA decay and a null allele, but 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=28137957" 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> rs1057519293 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519293;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/rs1057519293?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=rs1057519293" 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=rs1057519293" 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 Bosnian man (family HIH22132) with autosomal recessive spastic paraplegia-78 (SPG78; <a href="/entry/617225">617225</a>), <a href="#6" class="mim-tip-reference" title="Estrada-Cuzcano, A., Martin, S., Chamova, T., Synofzik, M., Timmann, D., Holemans, T., Andreeva, A., Reichbauer, J., De Rycke, R., Chang, D.-I., van Veen, S., Samuel, J., and 10 others. <strong>Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78).</strong> Brain 140: 287-305, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28137957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28137957</a>] [<a href="https://doi.org/10.1093/brain/aww307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28137957">Estrada-Cuzcano et al. (2017)</a> identified compound heterozygous mutations in the ATP13A2 gene: a c.1330C-T transition (c.1330C-T, NM_001141973.1), resulting in an arg444-to-ter (R444X) substitution, and a c.3403C-T transition, resulting in a gln1135-to-ter (Q1135X; <a href="#0013">610513.0013</a>) substitution. The mutations were found by direct sequencing of the ATP13A2 gene in a cohort of 795 probands with spastic paraplegia. DNA from the unaffected parents was unavailable for segregation studies. The R444X mutation was predicted to result in nonsense-mediated mRNA decay (NMD) and a null allele, whereas the Q1135X mutation is located in the last exon and may potentially escape NMD. In vitro functional expression studies of the Q1135X mutation showed decreased expression of the mutant protein, loss of autophosphorylation, and mislocalization to the endoplasmic reticulum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28137957" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 SPASTIC PARAPLEGIA 78, AUTOSOMAL RECESSIVE</strong>
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ATP13A2, GLN1135TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1057519289 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519289;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=rs1057519289" 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=rs1057519289" 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=RCV000415542 OR RCV002502449 OR RCV004767250" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000415542, RCV002502449, RCV004767250" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000415542...</a>
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<p>For discussion of the c.3403C-T transition (c.3403C-T, NM_001141973.1) in the ATP13A2 gene, resulting in a gln1135-to-ter (Q1135X) substitution, that was found in compound heterozygous state in a patient with autosomal recessive spastic paraplegia-78 (SPG78; <a href="/entry/617225">617225</a>) by <a href="#6" class="mim-tip-reference" title="Estrada-Cuzcano, A., Martin, S., Chamova, T., Synofzik, M., Timmann, D., Holemans, T., Andreeva, A., Reichbauer, J., De Rycke, R., Chang, D.-I., van Veen, S., Samuel, J., and 10 others. <strong>Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78).</strong> Brain 140: 287-305, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28137957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28137957</a>] [<a href="https://doi.org/10.1093/brain/aww307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28137957">Estrada-Cuzcano et al. (2017)</a>, see <a href="#0012">610513.0012</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28137957" 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 href="https://doi.org/10.1093/hmg/dds089" target="_blank">Full Text</a>]
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Chan, A. Y. Y., Baum, L., Tang, N. L. S., Lau, C. Y. K., Ng, P. W., Hui, K. F., Mizuno, Y., Kwan, J. Y., Mok, V. C. T., Kuo, S.-H.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23522931/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23522931</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23522931" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.jocn.2012.05.052" target="_blank">Full Text</a>]
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Crosiers, D., Ceulemans, B., Meeus, B., Nuytemans, K., Pals, P., Van Broeckhoven, C., Cras, P., Theuns, J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21094623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21094623</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21094623" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.parkreldis.2010.10.011" target="_blank">Full Text</a>]
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Di Fonzo, A., Chien, H. F., Socal, M., Giraudo, S., Tassorelli, C., Iliceto, G., Fabbrini, F., Marconi, R., Fincati, E., Abbruzzese, F., Marini, P., Squitieri, F., and 14 others.
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Neurology 68: 1557-1562, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17485642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17485642</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17485642" 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.0000260963.08711.08" target="_blank">Full Text</a>]
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Estrada-Cuzcano, A., Martin, S., Chamova, T., Synofzik, M., Timmann, D., Holemans, T., Andreeva, A., Reichbauer, J., De Rycke, R., Chang, D.-I., van Veen, S., Samuel, J., and 10 others.
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<strong>Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78).</strong>
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Brain 140: 287-305, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28137957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28137957</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28137957" 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/aww307" target="_blank">Full Text</a>]
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Farias, F. H. G., Zeng, R., Johnson, G. S., Wininger, F. A., Taylor, J. F., Schnabel, R. D., McKay, S. D., Sanders, D. N., Lohi, H., Seppala, E. H., Wade, C. M., Lindblad-Toh, K., O'Brien, D. P., Katz, M. L.
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<strong>A truncating mutation in ATP13A2 is responsible for adult-onset neuronal ceroid lipofuscinosis in Tibetan terriers.</strong>
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Neurobiol. Dis. 42: 468-474, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21362476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21362476</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21362476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.nbd.2011.02.009" target="_blank">Full Text</a>]
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Gitler, A. D., Chesi, A., Geddie, M. L., Strathearn, K. E., Hamamichi, S., Hill, K. J., Caldwell, K. A., Caldwell, G. A., Cooper, A. A., Rochet, J.-C., Lindquist, S.
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Nature Genet. 41: 308-315, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19182805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19182805</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19182805[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=19182805" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.300" target="_blank">Full Text</a>]
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Grunewald, A., Arns, B., Seibler, P., Rakovic, A., Munchau, A., Ramirez, A., Sue, C. M., Klein, C.
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<strong>ATP13A2 mutations impair mitochondrial function in fibroblasts from patients with Kufor-Rakeb syndrome.</strong>
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Neurobiol. Aging 33: 1843.e1-1843.e7, 2012. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22296644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22296644</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22296644" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.neurobiolaging.2011.12.035" target="_blank">Full Text</a>]
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Kara, E., Tucci, A., Manzoni, C., Lynch, D. S., Elpidorou, M., Bettencourt, C., Chelban, V., Manole, A., Hamed, S. A., Haridy, N. A., Federoff, M., Preza, E., and 17 others.
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<strong>genetic and phenotypic characterization of complex hereditary spastic paraplegia.</strong>
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Brain 139: 1904-1918, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27217339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27217339</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27217339[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=27217339" 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/aww111" target="_blank">Full Text</a>]
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Kong, S. M. Y., Chan, B. K. K., Park, J.-S., Hill, K. J., Aitken, J. B., Cottle, L., Farghaian, H., Cole, A. R., Lay, P. A., Sue, C. M., Cooper, A. A.
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<strong>Parkinson's disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes alpha-synuclein externalization via exosomes.</strong>
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Hum. Molec. Genet. 23: 2816-2833, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24603074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24603074</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24603074" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddu099" target="_blank">Full Text</a>]
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<a id="Lin2008" class="mim-anchor"></a>
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Lin, C. H., Tan, E. K., Chen, M. L., Tan, L. C., Lim, H. Q., Chen, G. S., Wu, R. M.
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<strong>Novel ATP13A2 variant associated with Parkinson disease in Taiwan and Singapore.</strong>
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Neurology 71: 1727-1732, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19015489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19015489</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19015489" 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.0000335167.72412.68" target="_blank">Full Text</a>]
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<a id="Park2014" class="mim-anchor"></a>
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Park, J.-S., Koentjoro, B., Veivers, D., Mackay-Sim, A., Sue, C. M.
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<strong>Parkinson's disease-associated human ATP13A2 (PARK9) deficiency causes zinc dyshomeostasis and mitochondrial dysfunction.</strong>
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Hum. Molec. Genet. 23: 2802-2815, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24399444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24399444</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24399444[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=24399444" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddt623" target="_blank">Full Text</a>]
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<a id="Podhajska2012" class="mim-anchor"></a>
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Podhajska, A., Musso, A., Trancikova, A., Stafa, K., Moser, R., Sonnay, S., Glauser, L., Moore, D. J.
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<strong>Common pathogenic effects of missense mutations in the P-type ATPase ATP13A2 (PARK9) associated with early-onset parkinsonism.</strong>
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PLoS One 7: e39942, 2012. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22768177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22768177</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22768177[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=22768177" 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/10.1371/journal.pone.0039942" target="_blank">Full Text</a>]
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<a id="Ramirez2006" class="mim-anchor"></a>
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Ramirez, A., Heimbach, A., Grundemann, J., Stiller, B., Hampshire, D., Cid, L. P., Goebel, I., Mubaidin, A. F., Wriekat, A.-L., Roeper, J., Al-Din, A., Hillmer, A. M., Karsak, M., Liss, B., Woods, C. G., Behrens, M. I., Kubisch, C.
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<strong>Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase.</strong>
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Nature Genet. 38: 1184-1191, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16964263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16964263</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16964263" 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/ng1884" target="_blank">Full Text</a>]
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<a id="Riis1992" class="mim-anchor"></a>
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Riis, R. C., Cummings, J. F., Loew, E. R., de Lahunta, A.
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<strong>Tibetan terrier model of canine ceroid lipofuscinosis.</strong>
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Am. J. Med. Genet. 42: 615-621, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1609844/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1609844</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1609844" 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/ajmg.1320420437" target="_blank">Full Text</a>]
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<a id="Santoro2011" class="mim-anchor"></a>
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Santoro, L., Breedveld, G. J., Manganelli, F., Iodice, R., Pisciotta, C., Nolano, M., Punzo, F., Quarantelli, M., Pappata, S., Di Fonzo, A., Oostra, B. A., Bonifati, V.
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<strong>Novel ATP13A2 (PARK9) homozygous mutation in a family with marked phenotype variability.</strong>
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Neurogenetics 12: 33-39, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20853184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20853184</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20853184[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=20853184" 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/s10048-010-0259-0" target="_blank">Full Text</a>]
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<a id="Schneider2010" class="mim-anchor"></a>
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Schneider, S. A., Paisan-Ruiz, C., Quinn, N. P., Lees, A. J., Houlden, H., Hardy, J., Bhatia, K. P.
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<strong>ATP13A2 mutations (PARK9) cause neurodegeneration with brain iron accumulation.</strong>
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Mov. Disord. 25: 979-984, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20310007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20310007</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20310007" 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/mds.22947" target="_blank">Full Text</a>]
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<a id="Schultheis2004" class="mim-anchor"></a>
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Schultheis, P. J., Hagen, T. T., O'Toole, K. K., Tachibana, A., Burke, C. R., McGill, D. L., Okunade, G. W., Shull, G. E.
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<strong>Characterization of the P5 subfamily of P-type transport ATPases in mice.</strong>
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Biochem. Biophys. Res. Commun. 323: 731-738, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15381061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15381061</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15381061" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.bbrc.2004.08.156" target="_blank">Full Text</a>]
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<a id="Tan2011" class="mim-anchor"></a>
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Tan, J., Zhang, T., Jiang, L., Chi, J., Hu, D., Pan, Q., Wang, D., Zhang, Z.
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<strong>Regulation of intracellular manganese homeostasis by Kufor-Rakeb syndrome-associated ATP13A2 protein.</strong>
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J. Biol. Chem. 286: 29654-29662, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21724849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21724849</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21724849[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=21724849" 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.M111.233874" target="_blank">Full Text</a>]
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<a id="Tsunemi2014" class="mim-anchor"></a>
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Tsunemi, T., Krainc, D.
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<strong>Zn(2+) dyshomeostasis caused by loss of ATP13A2/PARK9 leads to lysosomal dysfunction and alpha-synuclein accumulation.</strong>
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Hum. Molec. Genet. 23: 2791-2801, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24334770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24334770</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24334770[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=24334770" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddt572" target="_blank">Full Text</a>]
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<a id="Usenovic2012" class="mim-anchor"></a>
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Usenovic, M., Tresse, E., Mazzulli, J. R., Taylor, J. P., Krainc, D.
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<strong>Deficiency of ATP13A2 leads to lysosomal dysfunction, alpha-synuclein accumulation, and neurotoxicity.</strong>
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J. Neurosci. 32: 4240-4246, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22442086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22442086</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22442086[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=22442086" 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.5575-11.2012" target="_blank">Full Text</a>]
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<a id="van Veen2020" class="mim-anchor"></a>
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van Veen, S., Martin, S., Van den Haute, C., Benoy, V., Lyons, J., Vanhoutte, R., Kahler, J. P., Decuypere, J.-P., Gelders, G., Lambie, E., Zielich, J., Swinnen, J. V., Annaert, W., Agostinis, P., Ghesquiere, B., Verhelst, S., Baekelandt, V., Eggermont, J., Vangheluwe, P.
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<strong>ATP13A2 deficiency disrupts lysosomal polyamine export.</strong>
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Nature 578: 419-424, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31996848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31996848</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31996848" 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/s41586-020-1968-7" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Ada Hamosh - updated : 08/27/2020
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Cassandra L. Kniffin - updated : 11/23/2016<br>Patricia A. Hartz - updated : 8/8/2014<br>Cassandra L. Kniffin - updated : 10/9/2013<br>Patricia A. Hartz - updated : 4/24/2012<br>Cassandra L. Kniffin - updated : 10/18/2011<br>Cassandra L. Kniffin - updated : 6/21/2011<br>Cassandra L. Kniffin - updated : 2/24/2011<br>Cassandra L. Kniffin - updated : 4/24/2009<br>Cassandra L. Kniffin - updated : 12/27/2007<br>Victor A. McKusick - updated : 10/26/2006
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Patricia A. Hartz : 10/20/2006
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alopez : 08/27/2020<br>carol : 07/21/2017<br>carol : 02/01/2017<br>carol : 01/11/2017<br>carol : 01/11/2017<br>carol : 01/10/2017<br>carol : 01/10/2017<br>ckniffin : 01/10/2017<br>ckniffin : 11/23/2016<br>carol : 05/27/2015<br>carol : 5/18/2015<br>mcolton : 5/8/2015<br>joanna : 9/5/2014<br>mgross : 8/8/2014<br>mcolton : 8/8/2014<br>mcolton : 2/24/2014<br>carol : 10/10/2013<br>carol : 10/10/2013<br>carol : 10/10/2013<br>ckniffin : 10/9/2013<br>mgross : 5/14/2012<br>terry : 4/24/2012<br>carol : 10/27/2011<br>ckniffin : 10/18/2011<br>wwang : 7/7/2011<br>ckniffin : 6/21/2011<br>wwang : 3/7/2011<br>ckniffin : 2/24/2011<br>carol : 6/23/2009<br>wwang : 5/4/2009<br>ckniffin : 4/24/2009<br>wwang : 1/15/2008<br>ckniffin : 12/27/2007<br>alopez : 10/30/2006<br>terry : 10/26/2006<br>mgross : 10/20/2006
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<h3>
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<span class="mim-font">
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<strong>*</strong> 610513
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</span>
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</h3>
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<h3>
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<span class="mim-font">
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ATPase 13A2; ATP13A2
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</span>
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</h3>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: ATP13A2</em></strong>
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</span>
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</p>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 1177168007, 723992000;
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<strong>
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<em>
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Cytogenetic location: 1p36.13
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:16,985,958-17,011,928 </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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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<th>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<td rowspan="2">
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<span class="mim-font">
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1p36.13
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<span class="mim-font">
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Kufor-Rakeb syndrome
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<span class="mim-font">
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606693
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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<span class="mim-font">
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Spastic paraplegia 78, autosomal recessive
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<span class="mim-font">
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617225
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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<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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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>ATP13A2 belongs to the P-type superfamily of ATPases that transport inorganic cations and other substrates across cell membranes (Schultheis et al., 2004). </p>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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<span class="mim-text-font">
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<p>By searching databases for homologs of the yeast ATPases Cod1 and Yor291w, Schultheis et al. (2004) identified Atp13a2 in human, mouse, rat, and dog. Atp13a2 has at least 4 transmembrane domains in its N-terminal half and 6 transmembrane domains in its C-terminal half, and the N and C termini are cytoplasmic. The central cytoplasmic region between transmembrane domains 4 and 5 contains the catalytic phosphorylation site. </p><p>Ramirez et al. (2006) determined that the human ATP13A2 open reading frame encodes a protein of 1,180 amino acids. Northern blot analysis detected ubiquitous expression of a 3.8-kb transcript, with strongest expression in brain. Dot blot analysis confirmed predominant expression in adult human brain and demonstrated high expression in fetal brain and all tested subregions of the adult central nervous system, including substantia nigra. </p><p>Using confocal imaging, Tan et al. (2011) found that epitope-tagged ATP13A2 colocalized with lysosomal markers in transfected human. mouse, and rat cells. </p><p>Podhajska et al. (2012) found that the ATP13A2 protein localizes to intracellular vesicular compartments in neurons, including lysosomes and early and late endosomes. </p>
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</span>
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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>Ramirez et al. (2006) determined that the human ATP13A2 gene contains 29 coding exons and spans 26 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>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 genomic sequence analysis, Schultheis et al. (2004) mapped the ATP13A2 gene to chromosome 1. The mouse Atp13a2 gene maps to chromosome 4D3. </p><p>Ramirez et al. (2006) identified the ATP13A2 gene within a critical interval on chromosome 1p36 linked to Kufor-Rakeb syndrome (KRS, or PARK9; 606693). </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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<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>Tan et al. (2011) found that human, mouse, and rat cells expressing epitope-tagged human ATP13A2 were resistant to MnCl2-induced cytotoxicity. Exposure of cells to Mn(2+) upregulated ATP13A2 expression, and upregulated ATP13A2 reduced intracellular Mn(2+) concentrations and protected cells from Mn(2+)-induced cytochrome c release and apoptosis. </p><p>Podhajska et al. (2012) found that overexpression of ATP13A2 sensitized rat cortical neurons to neurite shortening induced by exposure to cadmium or nickel ions, supporting a functional interaction between ATP13A2 and heavy metals in postmitotic neurons. </p><p>Van Veen et al. (2020) established ATP13A2 as a lysosomal polyamine exporter that showed the highest affinity for spermine among the polyamines examined. Polyamines stimulated the activity of purified ATP13A2, whereas ATP13A2 mutants that were implicated in disease were functionally impaired to a degree that correlated with the disease phenotype. ATP13A2 promoted the cellular uptake of polyamines by endocytosis and transported them into the cytosol, highlighting a role for endolysosomes in the uptake of polyamines into cells. At high concentrations polyamines induce cell toxicity, which was exacerbated by ATP13A2 loss due to lysosomal dysfunction, lysosomal rupture, and cathepsin B (116810) activation. This phenotype was recapitulated in neurons and nematodes with impaired expression of ATP13A2 or its orthologs. Van Veen et al. (2020) concluded that they presented defective lysosomal polyamine export as a mechanism for lysosome-dependent cell death that may be implicated in neurodegeneration, and shed light on the molecular identity of the mammalian polyamine transport system. </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>Biallelic ATP13A2 Mutations</em></strong></p><p>
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Kufor-Rakeb syndrome (KRS; 606693), a form of autosomal recessive hereditary parkinsonism with dementia, shows juvenile onset. Ramirez et al. (2006) described loss-of-function mutations in the predominantly neuronal P-type ATPase gene ATP13A2 as the cause of Kufor-Rakeb syndrome. Affected members of a nonconsanguineous Chilean family were compound heterozygous for a 1-bp deletion in exon 6, inherited from the mother (610513.0001), and a splice site mutation, inherited from the father (610513.0002). Affected members of the original Jordanian kindred were homozygous for a 22-bp duplication (610513.0003). Whereas the wildtype protein was located in the lysosome of transiently transfected cells, the unstable truncated mutants were retained in the endoplasmic reticulum and degraded by the proteasome. The findings linked ATP13A2, representing a class of proteins with unknown function and substrate specificity, to the protein networks implicated in neurodegeneration and parkinsonism. </p><p>In a Brazilian man with KRS, Di Fonzo et al. (2007) identified a homozygous mutation in the ATP13A2 gene (G504R; 610513.0004). </p><p>In 3 Belgian sibs with KRS, originally reported by Carlier and Dubru (1979), Bras et al. (2012) identified a homozygous missense mutation in the ATP13A2 gene (M810R; 610513.0007). The mutation was found by exome sequencing and segregated with the disorder in the family. It was not present in the dbSNP or 1000 Genomes Project databases. Functional studies were not performed. Because some of the patients in this family had neuropathologic findings suggestive of neuronal ceroid lipofuscinosis, Bras et al. (2012) designated the disorder CLN12. </p><p>In cellular studies, Podhajska et al. (2012) found that expression of the homozygous ATP13A2 missense mutations F182L, G504R (610513.0004), and G877R (610513.0008) resulted in decreased steady-state levels of the mutant protein due to decreased protein stability and increased proteasomal degradation. In addition, the mutant F182L and G504R proteins showed abnormal intracellular vesicular localization to the endoplasmic reticulum, whereas G877R showed normal vesicular localization. The findings were consistent with a loss-of-function effect. Overexpression of the missense mutations did not cause cellular toxicity, although the F182L variant sensitized cortical neurons to neurite shortening induced by heavy metals, suggesting a possible gain of function. Podhajska et al. (2012) noted that disease-associated missense mutations in ATP13A2 cluster in the second intracellular loop region containing the catalytic ATPase domain. </p><p>Using primary KRS patient dermal fibroblasts and knockdown primary mouse neurons, Tsunemi and Krainc (2014) found that loss of functional ATP13A2 increased cell sensitivity to extracellular zinc. Zinc sensitivity was alleviated with Zn(2+) chelators. ATP13A2-deficient cells showed reduced lysosomal sequestration of Zn(2+) compared with wildtype, concomitant with increased expression of all cell surface and vesicular zinc transporters examined. Excess Zn(2+) elevated lysosomal pH and impaired lysosomal enzyme function and trafficking in mouse neurons in a dose-dependent manner, an effect that was exacerbated by Atp13a2 depletion. Excess Zn(2+) or Atp13a2 depletion also caused alpha-synuclein (SNCA; 163890) oxidation and accumulation. Tsunemi and Krainc (2014) concluded that ATP13A2-deficient lysosomes have a decreased capacity to store Zn(2+), resulting in Zn(2+) dyshomeostasis. </p><p>Independently, Park et al. (2014) detected Zn(2+) dyshomeostasis in KRS patient-derived olfactory neurospheres, with decreased capacity to sequester Zn(2+) into vesicles of the autophagy-lysosomal pathway. Loss of ATP13A2 also caused abnormal energy metabolism, with mitochondrial fragmentation and cell death as a result of ATP depletion. </p><p>Kong et al. (2014) reported findings similar to those of Tsunemi and Krainc (2014) and Park et al. (2014). They also found that knockdown of ATP13A2 in human neuroblastoma cells resulted in sensitivity to zinc, but not to manganese. Elevated ATP13A2 expression reduced intracellular alpha-synuclein protein content by externalization via release of exosomes. </p><p>Usenovic et al. (2012) found that knockdown of the Atp13a2 gene in cultured neurons caused accumulation and enlargement of lysosomes, decreased lysosomal degradation of accumulated proteins, accumulation of autophagosomes, and accumulation of alpha-synuclein (SNCA; 163890), resulting in neuronal toxicity. Overexpression of Atp13a2 rescued the SNCA-mediated toxicity in cultured neurons. The findings provided a link between lysosomal dysfunction resulting from ATP13A2 mutations and neurodegeneration. </p><p>In a 46-year-old man, born of consanguineous Pakistani parents, with autosomal recessive spastic paraplegia-78 (SPG78; 617225), Kara et al. (2016) identified a homozygous mutation in the ATP13A2 gene (610513.0009). Functional studies of the variant and studies of patient cells were not performed. The patient was 1 of 97 probands with complicated spastic paraplegia who underwent molecular analysis. </p><p>In 5 patients from 3 unrelated families with adult-onset SPG78, Estrada-Cuzcano et al. (2017) identified homozygous or compound heterozygous mutations in the ATP13A2 gene (610513.0010-610513.0013). The mutation in the first family was found by whole-exome sequencing; the mutations in the 2 subsequent patients were found by direct sequencing of the ATP13A2 gene in a cohort of 795 probands with spastic paraplegia. Studies of selected patient cells and in vitro studies of some of the mutations showed abnormal intracellular localization of the mutant proteins, transcript or protein instability in some cases, and impaired lysosomal and mitochondrial function, all consistent with a loss of function. </p><p><strong><em>Heterozygous ATP13A2 Mutations</em></strong></p><p>
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The role of heterozygous ATP13A2 variants in patients with early-onset Parkinson disease is unclear and controversial. Di Fonzo et al. (2007) identified heterozygous ATP13A2 variants (T12M and G533R, respectively) in 2 unrelated Italian patients with early-onset parkinsonism at age 30 and 40 years, respectively, suggesting that heterozygous mutations may increase risk for development of the disease. Lin et al. (2008) identified a heterozygous A746T substitution in the ATP13A2 gene in 3 (1.7%) of 182 Han Chinese patients with early-onset Parkinson disease and none of 589 matched controls (relative risk of 4.3, p = 0.01). The substitution is located between the highly conserved phosphorylation region and the fifth transmembrane domain. Functional studies were not performed. Chan et al. (2013) found a heterozygous A746T variant in 1 (1.4%) of 69 Chinese patients with early-onset PD, in 1 (0.5%) of 192 patients with late-onset PD, and in 1 (0.6%) of 180 controls. They concluded that the ATP13A2 A746T variant is not a common risk factor for PD in the Chinese population in Hong Kong. </p><p>In cellular studies, Podhajska et al. (2012) found that the heterozygous T12M, G533R, and A746T missense variants did not obviously alter protein stability or subcellular localization, but did cause a significant decrease in the ATPase activity of ATP13A2 compared to wildtype. The findings suggested that these heterozygous variants can cause a loss of function. Overexpression of the missense mutations did not cause cellular toxicity. </p>
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</span>
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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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<span class="mim-text-font">
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<p>Mutation or overexpression of the alpha-synuclein gene (SNCA; 163890) can cause Parkinson disease (PARK1; 168601). Gitler et al. (2009) showed that the yeast homolog of human ATP13A2, termed Ypk9, could suppress overexpression-induced Snca toxicity both in yeast and in cultured rat dopaminergic neurons by decreasing intracellular Snca inclusions. Ypk9 knockdown in C. elegans enhanced misfolding of Snca. In addition, Ypk9 was found to help protect cells from manganese toxicity. These findings suggested a functional connection between Snca and the PARK9 susceptibility locus, as well as with manganese exposure as a possible environmental risk factor for PD. </p><p>Farias et al. (2011) determined that a homozygous truncating mutation (1623delC) in exon 16 of the Atp13a2 gene is responsible for autosomal recessive, adult-onset neuronal ceroid lipofuscinosis (NCL) in Tibetan terriers (Riis et al., 1992). Behavioral changes in these dogs were first noted between age 4 and 9 years, and brain tissue showed autofluorescent membrane-bound cytoplasmic inclusions with varied ultrastructure in neurons, consistent with a diagnosis of NCL. Although homozygous truncating mutations in human ATP13A2 cause Kufor-Rakeb syndrome (KRS; 606693), another neurodegenerative disease, the phenotype differs between terriers and humans. Tibetan terriers with NCL develop cerebellar ataxia not reported in KRS patients, and KRS patients exhibit parkinsonism and pyramidal dysfunction not observed in affected Tibetan terriers. However, both show generalized brain atrophy, behavioral changes, and cognitive decline. The findings suggested that KRS may be a type of adult-onset NCL; however, sequencing of the ATP13A2 gene in 28 patients with adult-onset NCL (Kufs disease; CLN4A, 204300) failed to reveal any variants likely to be disease-causing. </p>
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</span>
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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>13 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 KUFOR-RAKEB SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ATP13A2, 1-BP DEL, 3057C
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<br />
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SNP: rs765632065,
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gnomAD: rs765632065,
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ClinVar: RCV000541447, RCV000598921, RCV001201356, RCV001844194, RCV002509424, RCV002528398
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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 nonconsanguineous Chilean family in which 3 males and 1 female in a sibship of 11 were affected with the early-onset parkinsonism resembling that of Kufor-Rakeb syndrome (KRS; 606693), Ramirez et al. (2006) found 2 mutations of the ATP13A2 gene in compound heterozygosity. The mutation inherited from the mother was deletion of a cytosine at nucleotide position 3057 in exon 26, leading to a frameshift and stop codon after 2 extraneous amino acids (3057delC, 1019GlyfsTer1021). The second mutation, inherited from the father, was a guanine-to-adenine transition at position +5 of the donor splice site of exon 13 (1306+5G-A; 610513.0002). </p><p>By confocal analysis of human, mouse, and rat cells transfected with ATP13A2 cDNA containing the 3057C deletion, Tan et al. (2011) found that the mutant protein was not targeted to lysosomes, but was retained in the endoplasmic reticulum. </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 KUFOR-RAKEB SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ATP13A2, IVS13, G-A, +5
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<br />
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SNP: rs786205056,
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ClinVar: RCV000001278, RCV001851532, RCV004719607
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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 splice site mutation in the ATP13A2 gene (1306+5G-A) that was found in compound heterozygous state in patients with Kufor-Rakeb syndrome (KRS; 606693) by Ramirez et al. (2006), see 610513.0001. </p><p>By confocal analysis of human, mouse, and rat cells transfected with ATP13A2 cDNA containing this splice site mutation, Tan et al. (2011) found that the mutant protein was not targeted to lysosomes, but was retained in the endoplasmic reticulum. </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 KUFOR-RAKEB SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ATP13A2, 22-BP DUP
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<br />
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SNP: rs2100817106,
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ClinVar: RCV000001279
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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 the originally described Jordanian family with Kufor-Rakeb syndrome (KRS; 606693), Ramirez et al. (2006) demonstrated that affected individuals had a homozygous 22-bp duplication (1632_1653dup22, 552LeufsTer788), leading to a frameshift and stop codon after 236 extraneous amino acids. </p><p>By confocal analysis of human, mouse, and rat cells transfected with ATP13A2 cDNA containing the 22-bp duplication, Tan et al. (2011) found that the mutant protein was not targeted to lysosomes, but was retained in the endoplasmic reticulum. Mutant ATP13A2 did not regulate intracellular Mn(2+) upon Mn(2+) overexposure or protect cells from Mn(2+)-induced cell death. </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>.0004 KUFOR-RAKEB SYNDROME</strong>
|
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</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ATP13A2, GLY504ARG
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<br />
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SNP: rs121918227,
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ClinVar: RCV000001280, RCV001851533, RCV002251851, RCV004766975
|
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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 man with Kufor-Rakeb syndrome (KRS; 606693), Di Fonzo et al. (2007) identified a homozygous 1510G-C transversion in exon 15 of the ATP13A2 gene, resulting in a gly504-to-arg (G504R) substitution in the larger cytosolic loop close to the predicted catalytic phosphorylation site. The unaffected parents were heterozygous for the mutation, which was not found in 654 control chromosomes. The patient was diagnosed with levodopa-responsive parkinsonism at age 12 years. On examination at the age of 18, he had severe akinetic-rigid parkinsonism with episodic levodopa-induced choreic dyskinesias, visual hallucinations, and aggressive behaviors. However, his mental status remained good, and he was cognitively intact between episodes. Other features included supranuclear vertical gaze paresis, diffuse cerebral atrophy, and lip/chin tremor. He did not have myoclonus or tremor in the limbs. Di Fonzo et al. (2007) postulated that the missense mutation may have resulted in a milder phenotype than that reported for frameshift or truncating 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">
|
|
<strong>.0005 KUFOR-RAKEB SYNDROME</strong>
|
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</span>
|
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</h4>
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</div>
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<div>
|
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<span class="mim-text-font">
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ATP13A2, 2-BP INS, 1103GA
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<br />
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SNP: rs762033589,
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gnomAD: rs762033589,
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ClinVar: RCV000023818
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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 40-year-old man, born of consanguineous Pakistani parents, with Kufor-Rakeb syndrome (KRS; 606693), Schneider et al. (2010) identified a homozygous 2-bp insertion (1103insGA) in the ATP13A2 gene, resulting in a frameshift and truncation. He had mild school difficulties in childhood, but onset of major symptoms occurred at age 16, when he presented with behavioral abnormalities and extrapyramidal symptoms. The disorder was progressive, and he developed severe parkinsonism, pyramidal signs, dystonia, restricted ocular movements, and hypomimia. Brain MRI showed diffuse brain atrophy, flattening of the caudate nuclei, and iron deposition in the basal ganglia. Cognition remained relatively intact. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0006 KUFOR-RAKEB SYNDROME</strong>
|
|
</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ATP13A2, 2-BP DEL, 2742TT
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<br />
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SNP: rs587776890,
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|
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ClinVar: RCV000023819
|
|
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|
|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a boy, born of consanguineous Afghan parents, with Kufor-Rakeb syndrome (KRS; 606693), Crosiers et al. (2011) identified a homozygous 2-bp deletion (2742delTT) in exon 23 of the ATP13A2 gene, resulting in a premature stop codon and truncation of the protein at residue 324, causing a loss of function. There was no evidence of nonsense-mediated mRNA decay on RT-PCR analysis. The patient had mild mental retardation before onset of fine tremor of the hands and dystonic posturing of the neck at age 10 years. He also had slow vertical saccades, hypomimia, facial myoclonus, and dystonia. Cognitive function deteriorated rapidly, and he had dementia by age 11. Bradykinesia and rigidity were partially responsive to L-DOPA therapy, but he developed dyskinesias. The patient also had visual hallucinations and psychosis, and nuclear imaging showed decreased dopamine transporter binding in the right caudate nucleus and bilateral putamina. The heterozygous deletion was also found in the parents, as well as in a brother who had mild mental retardation, tremor, and decreased dopamine transporter binding in the putamina. Crosiers et al. (2011) speculated that heterozygosity for the mutation may have contributed to the brother's phenotype. </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>.0007 KUFOR-RAKEB SYNDROME</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
ATP13A2, MET810ARG
|
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<br />
|
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|
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SNP: rs587777053,
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|
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ClinVar: RCV000056335
|
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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 3 Belgian sibs with Kufor-Rakeb syndrome (KRS; 606693), Bras et al. (2012) identified a homozygous c.2429T-G transversion in exon 22 of the ATP13A2 gene, resulting in a met810-to-arg (M810R) substitution at a highly conserved residue. The mutation was found by exome sequencing and segregated with the disorder in the family. It was not present in the dbSNP (build 135) or 1000 Genomes Project databases. Functional studies were not performed. The family was originally reported by Carlier and Dubru (1979). Because some of the patients in this family had neuropathologic findings suggestive of neuronal ceroid lipofuscinosis, Bras et al. (2012) designated the disorder CLN12. </p>
|
|
</span>
|
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</div>
|
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0008 KUFOR-RAKEB SYNDROME</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
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ATP13A2, GLY877ARG
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<br />
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SNP: rs144701072,
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|
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gnomAD: rs144701072,
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ClinVar: RCV000056336
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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 Italian brothers with Kufor-Rakeb syndrome (KRS; 606693), Santoro et al. (2011) identified a homozygous c.2629G-A transition in exon 24 of the ATP13A2 gene, resulting in a gly877-to-arg (G877R) substitution at a highly conserved residue in the catalytic autophosphorylation P2 domain in the large cytoplasmic loop between the M4 and M5 transmembrane domains. The unaffected parents were heterozygous for the mutation, which was not found in 336 control chromosomes. The brothers and their unaffected mother also carried a heterozygous R481C mutation in the FBXO7 gene (605648); biallelic mutation in the FBXO7 gene causes early-onset PARK15 (260300). The FBXO7 mutation occurred at a highly conserved residue and was not found in 318 control chromosomes, but the significance of this finding was unclear. The disease course in the 2 brothers showed phenotypic variability. The more severely affected brother, who had a history of perinatal asphyxia, developed slowly progressive parkinsonism at age 10 years, followed by pyramidal signs, extrapyramidal signs, and cognitive impairment. At age 41 years, he showed dysphagia, dysarthria, abnormal eye movements, hypomimia, mini-myoclonus of the facial muscles, dystonia, and spasticity. The 31-year-old brother had difficulty in school, mild gaze palsy, hyperreflexia, mildly increased axial tone, and mild rigidity, but was otherwise asymptomatic. Transcranial magnetic stimulation in both patients showed prolonged central motor conduction times, and brain imaging showed decreased dopamine transporter density in the striatum. There was also cerebral and cerebellar cortical atrophy. There was no evidence of iron accumulation in the basal ganglia. Santoro et al. (2011) concluded that unknown modifiers were responsible for the observed intrafamilial phenotypic variation. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
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</div>
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</div>
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<div>
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 SPASTIC PARAPLEGIA 78, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
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|
ATP13A2, 3-BP DEL, NT3017
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|
|
|
<br />
|
|
|
|
SNP: rs1057519290,
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|
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|
|
|
|
|
ClinVar: RCV000415585
|
|
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|
|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 46-year-old man (proband 41), born of consanguineous Pakistani parents, with autosomal recessive spastic paraplegia-78 (SPG78; 617225), Kara et al. (2016) identified a homozygous 3-bp deletion (c.3020_3022del, NM_001141974.2), resulting in an in-frame deletion (Phe1007del) near/in the transmembrane helix. The variant, which was found by targeted next generation sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP database and was not found in over 100,000 ExAC controls. Functional studies of the variant and studies of patients cells were not performed. (In the text of the article by Kara et al. (2016), the variant is given as c.3017_3019del; p.1006_1007del.) </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 SPASTIC PARAPLEGIA 78, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
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|
ATP13A2, THR512ILE
|
|
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|
|
<br />
|
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|
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SNP: rs1057519291,
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|
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|
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|
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ClinVar: RCV000415515
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|
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|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 brothers, born of Belgian parents (family HSP84), with autosomal recessive spastic paraplegia-78 (SPG78; 617225), Estrada-Cuzcano et al. (2017) identified a homozygous c.1535C-T transition (c.1535C-T, NM_001141973.1) in the ATP13A2 gene, resulting in a thr512-to-ile (T512I) substitution at a highly conserved residue in the autophosphorylation motif. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (build 135), Exome Variant Server (August 2014), and 1000 Genomes Project (2015) databases, and an in-house database. It was not found in 94 ethnically matched controls. The patients' unaffected father was heterozygous for the mutation; DNA from the unaffected mother was not available. Patient-derived fibroblasts had increased lysosomes that contained abnormal storage material, as well as increased mitochondrial mass with a reduction in mitochondrial membrane potential compared to controls. The mutant protein was mislocalized to the endoplasmic reticulum and was unable to undergo autophosphorylation. Estrada-Cuzcano et al. (2017) noted that the same homozygous mutation had previously been identified in a Lebanese patient (L6025) who was diagnosed with Kufor-Rakeb syndrome (KRS; 606693) based on genetic findings (Usenovic et al., 2012), but Estrada-Cuzcano et al. (2017) noted that the Lebanese patient had onset at age 44 years of features consistent with SPG78. Estrada-Cuzcano et al. (2017) stated that this variant was originally reported as c.1550C-T (NM_022089.2), resulting in a thr517-to-ile (T517I) substitution. </p><p>Usenovic et al. (2012) found that fibroblasts derived from the Lebanese patient homozygous for the c.1550C-T mutation had accumulation of enlarged lysosomes and impaired lysosomal degradation activity compared to controls. Grunewald et al. (2012) found that fibroblasts derived from the Lebanese patient had mitochondrial dysfunction as manifest by decreased ATP production, increased oxygen consumption, fragmentation of the mitochondrial network, and increased mtDNA, suggesting impaired mitophagy. These cellular defects could be rescued by expression of wildtype ATP13A2. </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>.0011 SPASTIC PARAPLEGIA 78, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
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ATP13A2, GLN122TER
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<br />
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SNP: rs1057519292,
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ClinVar: RCV000415546, RCV004767251
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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 Serbian woman (family HIH21480) with autosomal recessive spastic paraplegia-78 (SPG78; 617225), Estrada-Cuzcano et al. (2017) identified a homozygous c.364C-T transition (c.364C-T, NM_001141973.1) in exon 5 of the ATP13A2 gene, resulting in a gln122-to-ter (Q122X) substitution. The mutation was found by direct sequencing of the ATP13A2 gene in a cohort of 795 probands with spastic paraplegia. The unaffected parents were deceased and DNA was not available for segregation studies. The mutation was predicted to result in nonsense-mediated mRNA decay and a null allele, but 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>
|
|
<span class="mim-font">
|
|
<strong>.0012 SPASTIC PARAPLEGIA 78, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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|
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ATP13A2, ARG444TER
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<br />
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SNP: rs1057519293,
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gnomAD: rs1057519293,
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ClinVar: RCV000415578, RCV004767252
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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 Bosnian man (family HIH22132) with autosomal recessive spastic paraplegia-78 (SPG78; 617225), Estrada-Cuzcano et al. (2017) identified compound heterozygous mutations in the ATP13A2 gene: a c.1330C-T transition (c.1330C-T, NM_001141973.1), resulting in an arg444-to-ter (R444X) substitution, and a c.3403C-T transition, resulting in a gln1135-to-ter (Q1135X; 610513.0013) substitution. The mutations were found by direct sequencing of the ATP13A2 gene in a cohort of 795 probands with spastic paraplegia. DNA from the unaffected parents was unavailable for segregation studies. The R444X mutation was predicted to result in nonsense-mediated mRNA decay (NMD) and a null allele, whereas the Q1135X mutation is located in the last exon and may potentially escape NMD. In vitro functional expression studies of the Q1135X mutation showed decreased expression of the mutant protein, loss of autophosphorylation, and mislocalization to the endoplasmic reticulum. </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>.0013 SPASTIC PARAPLEGIA 78, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
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ATP13A2, GLN1135TER
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<br />
|
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SNP: rs1057519289,
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ClinVar: RCV000415542, RCV002502449, RCV004767250
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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 c.3403C-T transition (c.3403C-T, NM_001141973.1) in the ATP13A2 gene, resulting in a gln1135-to-ter (Q1135X) substitution, that was found in compound heterozygous state in a patient with autosomal recessive spastic paraplegia-78 (SPG78; 617225) by Estrada-Cuzcano et al. (2017), see 610513.0012. </p>
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</span>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<p />
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Carlier, G., Dubru, J. M.
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<strong>Familial juvenile parkinsonism.</strong>
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Chan, A. Y. Y., Baum, L., Tang, N. L. S., Lau, C. Y. K., Ng, P. W., Hui, K. F., Mizuno, Y., Kwan, J. Y., Mok, V. C. T., Kuo, S.-H.
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<strong>The role of the Ala746Thr variant in the ATP13A2 gene among Chinese patients with Parkinson's disease.</strong>
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<strong>Juvenile dystonia-parkinsonism and dementia caused by a novel ATP13A2 frameshift mutation. (Letter)</strong>
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Di Fonzo, A., Chien, H. F., Socal, M., Giraudo, S., Tassorelli, C., Iliceto, G., Fabbrini, F., Marconi, R., Fincati, E., Abbruzzese, F., Marini, P., Squitieri, F., and 14 others.
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<strong>ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease.</strong>
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Estrada-Cuzcano, A., Martin, S., Chamova, T., Synofzik, M., Timmann, D., Holemans, T., Andreeva, A., Reichbauer, J., De Rycke, R., Chang, D.-I., van Veen, S., Samuel, J., and 10 others.
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<strong>Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78).</strong>
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Brain 140: 287-305, 2017.
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[PubMed: 28137957]
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Farias, F. H. G., Zeng, R., Johnson, G. S., Wininger, F. A., Taylor, J. F., Schnabel, R. D., McKay, S. D., Sanders, D. N., Lohi, H., Seppala, E. H., Wade, C. M., Lindblad-Toh, K., O'Brien, D. P., Katz, M. L.
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<strong>A truncating mutation in ATP13A2 is responsible for adult-onset neuronal ceroid lipofuscinosis in Tibetan terriers.</strong>
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Neurobiol. Dis. 42: 468-474, 2011.
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[PubMed: 21362476]
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[Full Text: https://doi.org/10.1016/j.nbd.2011.02.009]
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<p class="mim-text-font">
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Gitler, A. D., Chesi, A., Geddie, M. L., Strathearn, K. E., Hamamichi, S., Hill, K. J., Caldwell, K. A., Caldwell, G. A., Cooper, A. A., Rochet, J.-C., Lindquist, S.
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<strong>Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity.</strong>
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|
Nature Genet. 41: 308-315, 2009.
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[PubMed: 19182805]
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[Full Text: https://doi.org/10.1038/ng.300]
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<p class="mim-text-font">
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Grunewald, A., Arns, B., Seibler, P., Rakovic, A., Munchau, A., Ramirez, A., Sue, C. M., Klein, C.
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<strong>ATP13A2 mutations impair mitochondrial function in fibroblasts from patients with Kufor-Rakeb syndrome.</strong>
|
|
Neurobiol. Aging 33: 1843.e1-1843.e7, 2012. Note: Electronic Article.
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[PubMed: 22296644]
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[Full Text: https://doi.org/10.1016/j.neurobiolaging.2011.12.035]
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<p class="mim-text-font">
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Kara, E., Tucci, A., Manzoni, C., Lynch, D. S., Elpidorou, M., Bettencourt, C., Chelban, V., Manole, A., Hamed, S. A., Haridy, N. A., Federoff, M., Preza, E., and 17 others.
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|
<strong>genetic and phenotypic characterization of complex hereditary spastic paraplegia.</strong>
|
|
Brain 139: 1904-1918, 2016.
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[PubMed: 27217339]
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[Full Text: https://doi.org/10.1093/brain/aww111]
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<li>
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<p class="mim-text-font">
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Kong, S. M. Y., Chan, B. K. K., Park, J.-S., Hill, K. J., Aitken, J. B., Cottle, L., Farghaian, H., Cole, A. R., Lay, P. A., Sue, C. M., Cooper, A. A.
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<strong>Parkinson's disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes alpha-synuclein externalization via exosomes.</strong>
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Hum. Molec. Genet. 23: 2816-2833, 2014.
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[PubMed: 24603074]
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Lin, C. H., Tan, E. K., Chen, M. L., Tan, L. C., Lim, H. Q., Chen, G. S., Wu, R. M.
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<strong>Novel ATP13A2 variant associated with Parkinson disease in Taiwan and Singapore.</strong>
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Neurology 71: 1727-1732, 2008.
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[PubMed: 19015489]
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[Full Text: https://doi.org/10.1212/01.wnl.0000335167.72412.68]
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<p class="mim-text-font">
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Park, J.-S., Koentjoro, B., Veivers, D., Mackay-Sim, A., Sue, C. M.
|
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<strong>Parkinson's disease-associated human ATP13A2 (PARK9) deficiency causes zinc dyshomeostasis and mitochondrial dysfunction.</strong>
|
|
Hum. Molec. Genet. 23: 2802-2815, 2014.
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[PubMed: 24399444]
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[Full Text: https://doi.org/10.1093/hmg/ddt623]
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<p class="mim-text-font">
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Podhajska, A., Musso, A., Trancikova, A., Stafa, K., Moser, R., Sonnay, S., Glauser, L., Moore, D. J.
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<strong>Common pathogenic effects of missense mutations in the P-type ATPase ATP13A2 (PARK9) associated with early-onset parkinsonism.</strong>
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PLoS One 7: e39942, 2012. Note: Electronic Article.
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[PubMed: 22768177]
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[Full Text: https://doi.org/10.1371/journal.pone.0039942]
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<p class="mim-text-font">
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Ramirez, A., Heimbach, A., Grundemann, J., Stiller, B., Hampshire, D., Cid, L. P., Goebel, I., Mubaidin, A. F., Wriekat, A.-L., Roeper, J., Al-Din, A., Hillmer, A. M., Karsak, M., Liss, B., Woods, C. G., Behrens, M. I., Kubisch, C.
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<strong>Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase.</strong>
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|
Nature Genet. 38: 1184-1191, 2006.
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[PubMed: 16964263]
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Riis, R. C., Cummings, J. F., Loew, E. R., de Lahunta, A.
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<strong>Tibetan terrier model of canine ceroid lipofuscinosis.</strong>
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Am. J. Med. Genet. 42: 615-621, 1992.
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[PubMed: 1609844]
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<li>
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<p class="mim-text-font">
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Santoro, L., Breedveld, G. J., Manganelli, F., Iodice, R., Pisciotta, C., Nolano, M., Punzo, F., Quarantelli, M., Pappata, S., Di Fonzo, A., Oostra, B. A., Bonifati, V.
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<strong>Novel ATP13A2 (PARK9) homozygous mutation in a family with marked phenotype variability.</strong>
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<p class="mim-text-font">
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Schneider, S. A., Paisan-Ruiz, C., Quinn, N. P., Lees, A. J., Houlden, H., Hardy, J., Bhatia, K. P.
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<strong>ATP13A2 mutations (PARK9) cause neurodegeneration with brain iron accumulation.</strong>
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[PubMed: 20310007]
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<p class="mim-text-font">
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Schultheis, P. J., Hagen, T. T., O'Toole, K. K., Tachibana, A., Burke, C. R., McGill, D. L., Okunade, G. W., Shull, G. E.
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<strong>Characterization of the P5 subfamily of P-type transport ATPases in mice.</strong>
|
|
Biochem. Biophys. Res. Commun. 323: 731-738, 2004.
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[PubMed: 15381061]
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<li>
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<p class="mim-text-font">
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Tan, J., Zhang, T., Jiang, L., Chi, J., Hu, D., Pan, Q., Wang, D., Zhang, Z.
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<strong>Regulation of intracellular manganese homeostasis by Kufor-Rakeb syndrome-associated ATP13A2 protein.</strong>
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[PubMed: 21724849]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Tsunemi, T., Krainc, D.
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<strong>Zn(2+) dyshomeostasis caused by loss of ATP13A2/PARK9 leads to lysosomal dysfunction and alpha-synuclein accumulation.</strong>
|
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Hum. Molec. Genet. 23: 2791-2801, 2014.
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[PubMed: 24334770]
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[Full Text: https://doi.org/10.1093/hmg/ddt572]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Usenovic, M., Tresse, E., Mazzulli, J. R., Taylor, J. P., Krainc, D.
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<strong>Deficiency of ATP13A2 leads to lysosomal dysfunction, alpha-synuclein accumulation, and neurotoxicity.</strong>
|
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J. Neurosci. 32: 4240-4246, 2012.
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[PubMed: 22442086]
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[Full Text: https://doi.org/10.1523/JNEUROSCI.5575-11.2012]
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</li>
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<li>
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<p class="mim-text-font">
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van Veen, S., Martin, S., Van den Haute, C., Benoy, V., Lyons, J., Vanhoutte, R., Kahler, J. P., Decuypere, J.-P., Gelders, G., Lambie, E., Zielich, J., Swinnen, J. V., Annaert, W., Agostinis, P., Ghesquiere, B., Verhelst, S., Baekelandt, V., Eggermont, J., Vangheluwe, P.
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<strong>ATP13A2 deficiency disrupts lysosomal polyamine export.</strong>
|
|
Nature 578: 419-424, 2020.
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[PubMed: 31996848]
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[Full Text: https://doi.org/10.1038/s41586-020-1968-7]
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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Ada Hamosh - updated : 08/27/2020<br>Cassandra L. Kniffin - updated : 11/23/2016<br>Patricia A. Hartz - updated : 8/8/2014<br>Cassandra L. Kniffin - updated : 10/9/2013<br>Patricia A. Hartz - updated : 4/24/2012<br>Cassandra L. Kniffin - updated : 10/18/2011<br>Cassandra L. Kniffin - updated : 6/21/2011<br>Cassandra L. Kniffin - updated : 2/24/2011<br>Cassandra L. Kniffin - updated : 4/24/2009<br>Cassandra L. Kniffin - updated : 12/27/2007<br>Victor A. McKusick - updated : 10/26/2006
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<span class="mim-text-font">
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Patricia A. Hartz : 10/20/2006
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Edit History:
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mgross : 12/07/2020<br>alopez : 08/27/2020<br>carol : 07/21/2017<br>carol : 02/01/2017<br>carol : 01/11/2017<br>carol : 01/11/2017<br>carol : 01/10/2017<br>carol : 01/10/2017<br>ckniffin : 01/10/2017<br>ckniffin : 11/23/2016<br>carol : 05/27/2015<br>carol : 5/18/2015<br>mcolton : 5/8/2015<br>joanna : 9/5/2014<br>mgross : 8/8/2014<br>mcolton : 8/8/2014<br>mcolton : 2/24/2014<br>carol : 10/10/2013<br>carol : 10/10/2013<br>carol : 10/10/2013<br>ckniffin : 10/9/2013<br>mgross : 5/14/2012<br>terry : 4/24/2012<br>carol : 10/27/2011<br>ckniffin : 10/18/2011<br>wwang : 7/7/2011<br>ckniffin : 6/21/2011<br>wwang : 3/7/2011<br>ckniffin : 2/24/2011<br>carol : 6/23/2009<br>wwang : 5/4/2009<br>ckniffin : 4/24/2009<br>wwang : 1/15/2008<br>ckniffin : 12/27/2007<br>alopez : 10/30/2006<br>terry : 10/26/2006<br>mgross : 10/20/2006
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