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Entry
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- *608309 - PTEN-INDUCED KINASE 1; PINK1
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*608309</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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<li role="presentation">
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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="#biochemicalFeatures">Biochemical Features</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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<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/608309">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 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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</li>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div 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 class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000158828;t=ENST00000321556" 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=65018" 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=608309" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000158828;t=ENST00000321556" 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_032409" 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_032409" 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=608309" 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=10514&isoform_id=10514_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/PINK1" 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/13492052,14149100,14165272,16306928,20381329,22761177,48428484,119615340,119615341,310900647,2091690748" 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/Q9BXM7" 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=65018" 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=ENSG00000158828;t=ENST00000321556" 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=PINK1" 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=PINK1" 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+65018" 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/PINK1" 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:65018" 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/65018" 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=ENST00000321556.5&hgg_start=20633458&hgg_end=20651511&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 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:14581" 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:14581" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/pink1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=608309[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=608309[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000158828" 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=PINK1" 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=PINK1" 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=PINK1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.LOVD.nl/PINK1" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=PINK1&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/PA33325" 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:14581" 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/FBgn0029891.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:1916193" 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/PINK1#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:1916193" 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/65018/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/OMIA002361/" 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=65018" 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=WBGene00017137;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-041212-53" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:65018" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=PINK1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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608309
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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PTEN-INDUCED KINASE 1; PINK1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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PTEN-INDUCED PUTATIVE KINASE 1; PINK1
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=PINK1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PINK1</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/1/244?start=-3&limit=10&highlight=244">1p36.12</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:20633458-20651511&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'})">1:20,633,458-20,651,511</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/1/244?start=-3&limit=10&highlight=244">
|
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1p36.12
|
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</a>
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
Parkinson disease 6, early onset
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
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|
<a href="/entry/605909"> 605909 </a>
|
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/608309" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/608309" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
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</div>
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<p>The PINK1 gene encodes a mitochondrially located serine/threonine kinase (<a href="#34" class="mim-tip-reference" title="Poole, A. C., Thomas, R. E., Andrews, L. A., McBride, H. M., Whitworth, A. J., Pallanck, L. J. <strong>The PINK1/Parkin pathway regulates mitochondrial morphology.</strong> Proc. Nat. Acad. Sci. 105: 1638-1643, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18230723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18230723</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18230723[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0709336105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18230723">Poole et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18230723" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#26" class="mim-tip-reference" title="Matsushima-Nishiu, M., Unoki, M., Ono, K., Tsunoda, T., Minaguchi, T., Kuramoto, H., Nishida, M., Satoh, T., Tanaka, T., Nakamura, Y. <strong>Growth and gene expression profile analyses of endometrial cancer cells expressing exogenous PTEN.</strong> Cancer Res. 61: 3741-3749, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11325847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11325847</a>]" pmid="11325847">Matsushima-Nishiu et al. (2001)</a> analyzed expression profiles of cancer cells after the introduction of exogenous PTEN (<a href="/entry/601728">601728</a>), a tumor suppressor, and found that an EST, later identified as PINK1 by <a href="#45" class="mim-tip-reference" title="Unoki, M., Nakamura, Y. <strong>Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway.</strong> Oncogene 20: 4457-4465, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11494141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11494141</a>] [<a href="https://doi.org/10.1038/sj.onc.1204608" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11494141">Unoki and Nakamura (2001)</a>, was transcriptionally transactivated. <a href="#45" class="mim-tip-reference" title="Unoki, M., Nakamura, Y. <strong>Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway.</strong> Oncogene 20: 4457-4465, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11494141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11494141</a>] [<a href="https://doi.org/10.1038/sj.onc.1204608" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11494141">Unoki and Nakamura (2001)</a> used 5-prime RACE to clone a full-length PINK1 cDNA and found that it encodes a deduced 581-amino acid protein with a predicted molecular mass of 62.8 kD and a putative serine/threonine protein kinase catalytic domain. The protein shares 43% and 31% sequence identity with Drosophila CG4523 and C. elegans EEED8.9, respectively. Northern blot analysis detected ubiquitous expression of a 2.7-kb transcript, with highest expression in heart, skeletal muscle, and testis. RT-PCR analysis showed that expression of PINK1 was decreased in ovarian tumors compared with corresponding normal tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11325847+11494141" 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="#46" class="mim-tip-reference" title="Valente, E. M., Abou-Sleiman, P. M., Caputo, V., Muqit, M. M. K., Harvey, K., Gispert, S., Ali, Z., Del Turco, D., Bentivoglio, A. R., Healy, D. G., Albanese, A., Nussbaum, R., and 10 others. <strong>Hereditary early-onset Parkinson's disease caused by mutations in PINK1.</strong> Science 304: 1158-1160, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15087508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15087508</a>] [<a href="https://doi.org/10.1126/science.1096284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15087508">Valente et al. (2004)</a> determined that the PINK1 gene encodes a 581-amino acid protein. The ubiquitously expressed transcript was predicted to encode a 34-amino acid mitochondrial targeting motif and a highly conserved protein kinase domain from residues 156 to 509 that shows a high degree of homology to the serine/threonine kinases of the calcium/calmodulin family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15087508" 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>Two major PINK1 isoforms with apparent molecular mass of 66 kD and 55 kD, have been detected in human brain extracts and during cellular PINK1 overexpression. Both isoforms localize to the inner and outer mitochondrial membrane fractions. The 55-kD isoform appears to represent a mature form derived from the 66-kD isoform upon removal of the leader sequence (<a href="#2" class="mim-tip-reference" title="Beilina, A., Van Der Brug, M., Ahmad, R., Kesavapany, S., Miller, D. W., Petsko, G. A., Cookson, M. R. <strong>Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability.</strong> Proc. Nat. Acad. Sci. 102: 5703-5708, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15824318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15824318</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15824318[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0500617102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15824318">Beilina et al., 2005</a>). In cultured COS-7 and HEK293 cells, <a href="#50" class="mim-tip-reference" title="Weihofen, A., Ostaszewski, B., Minami, Y., Selkoe, D. J. <strong>Pink1 Parkinson mutations, the Cdc37/Hsp90 chaperones and parkin all influence the maturation or subcellular distribution of Pink1.</strong> Hum. Molec. Genet. 17: 602-616, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18003639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18003639</a>] [<a href="https://doi.org/10.1093/hmg/ddm334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18003639">Weihofen et al. (2008)</a> found an abundance of the immature 66-kD precursor compared to the 55-kD mature isoform, and suggested that the ratio of these isoforms may be important. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15824318+18003639" 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="#41" class="mim-tip-reference" title="Silvestri, L., Caputo, V., Bellacchio, E., Atorino, L., Dallapiccola, B., Valente, E. M., Casari, G. <strong>Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism.</strong> Hum. Molec. Genet. 14: 3477-3492, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16207731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16207731</a>] [<a href="https://doi.org/10.1093/hmg/ddi377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16207731">Silvestri et al. (2005)</a> characterized the different subdomains within the kinase domain of PINK1. Subdomains I to IV represent the N-terminal lobe that is involved in anchoring and orienting the ATP molecule, whereas subdomains VIa to XI represent the C-terminal lobe in charge of the binding of the peptide substrate and of phospho-transfer. They showed that PINK1 localized to mitochondria and that the N-terminal portion of PINK1 is sufficient for mitochondrial localization. Immunogold microscopy demonstrated that PINK1 faced the mitochondrial intermembrane space. Autophosphorylation assay with wildtype PINK1 and deletion constructs involving C-terminal residues 496 to 581 showed that the C-terminal sequence has a negative regulatory role on autophosphorylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16207731" 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="#46" class="mim-tip-reference" title="Valente, E. M., Abou-Sleiman, P. M., Caputo, V., Muqit, M. M. K., Harvey, K., Gispert, S., Ali, Z., Del Turco, D., Bentivoglio, A. R., Healy, D. G., Albanese, A., Nussbaum, R., and 10 others. <strong>Hereditary early-onset Parkinson's disease caused by mutations in PINK1.</strong> Science 304: 1158-1160, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15087508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15087508</a>] [<a href="https://doi.org/10.1126/science.1096284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15087508">Valente et al. (2004)</a> showed that PINK1 contains 8 exons spanning about 1.8 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15087508" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#38" class="mim-tip-reference" title="Schubert, A. F., Gladkova, C., Pardon, E., Wagstaff, J. L., Freund, S. M. V., Steyaert, J., Maslen, S. L., Komander, D. <strong>Structure of PINK1 in complex with its substrate ubiquitin.</strong> Nature 552: 51-56, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29160309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29160309</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29160309[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/nature24645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29160309">Schubert et al. (2017)</a> reported a crystal structure at 3.1-angstrom resolution of a nanobody-stabilized complex containing Pediculus humanus corporis (Ph)PINK1 bound to ubiquitin in the C-terminally retracted (Ub-CR) conformation. The structure revealed many peculiarities of PINK1, including the architecture of the C-terminal region, and revealed how the N lobe of PINK1 binds ubiquitin via a unique insertion. The flexible ser65 loop in the Ub-CR conformation contacts the activation segment, facilitating placement of ser65 in a phosphate-accepting position. The structure also explained how autophosphorylation in the N lobe stabilizes structurally and functionally important insertions, and revealed the molecular basis of mutations that cause autosomal recessive juvenile Parkinson disease, some of which disrupt ubiquitin binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29160309" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To elucidate how phosphorylation of parkin (PARK2; <a href="/entry/602544">602544</a>) by PINK1 activates the molecule, <a href="#12" class="mim-tip-reference" title="Gladkova, C., Maslen, S. L., Skehel, J. M., Komander, D. <strong>Mechanism of parkin activation by PINK1.</strong> Nature 559: 410-414, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29995846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29995846</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29995846[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/s41586-018-0224-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29995846">Gladkova et al. (2018)</a> followed the activation of full-length human parkin by hydrogen-deuterium exchange mass spectrometry, which revealed large-scale domain rearrangement in the activation process, during which the phospho-ubiquitin-like (Ubl) domain rebinds to the parkin core and releases the catalytic RING2 domain. A 1.8-angstrom crystal structure of phosphorylated human parkin revealed the binding site of the phospho-Ubl on the unique parkin domain, involving a phosphate-binding pocket lined by mutations causing autosomal recessive juvenile parkinsonism. Notably, a conserved linker region between the ubiquitin-like domain and the unique parkin domain acts as an activating element that contributes to RING2 release by mimicking RING2 interactions on the unique parkin domain, explaining further autosomal recessive juvenile Parkinson mutations. <a href="#12" class="mim-tip-reference" title="Gladkova, C., Maslen, S. L., Skehel, J. M., Komander, D. <strong>Mechanism of parkin activation by PINK1.</strong> Nature 559: 410-414, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29995846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29995846</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29995846[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/s41586-018-0224-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29995846">Gladkova et al. (2018)</a> concluded that their data showed how autoinhibition in parkin is resolved, and suggested a mechanism for how parkin ubiquitinates its substrates via an untethered RING2 domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29995846" 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="#46" class="mim-tip-reference" title="Valente, E. M., Abou-Sleiman, P. M., Caputo, V., Muqit, M. M. K., Harvey, K., Gispert, S., Ali, Z., Del Turco, D., Bentivoglio, A. R., Healy, D. G., Albanese, A., Nussbaum, R., and 10 others. <strong>Hereditary early-onset Parkinson's disease caused by mutations in PINK1.</strong> Science 304: 1158-1160, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15087508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15087508</a>] [<a href="https://doi.org/10.1126/science.1096284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15087508">Valente et al. (2004)</a> stated that the PINK1 gene is located on chromosome 1p36. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15087508" 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="#45" class="mim-tip-reference" title="Unoki, M., Nakamura, Y. <strong>Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway.</strong> Oncogene 20: 4457-4465, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11494141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11494141</a>] [<a href="https://doi.org/10.1038/sj.onc.1204608" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11494141">Unoki and Nakamura (2001)</a> excluded the involvement of PINK1 in the PTEN signaling pathway. Colony formation assays showed that PINK1 had no effect on cell growth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11494141" 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 immunofluorescence microscopy and Western blot analysis, <a href="#46" class="mim-tip-reference" title="Valente, E. M., Abou-Sleiman, P. M., Caputo, V., Muqit, M. M. K., Harvey, K., Gispert, S., Ali, Z., Del Turco, D., Bentivoglio, A. R., Healy, D. G., Albanese, A., Nussbaum, R., and 10 others. <strong>Hereditary early-onset Parkinson's disease caused by mutations in PINK1.</strong> Science 304: 1158-1160, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15087508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15087508</a>] [<a href="https://doi.org/10.1126/science.1096284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15087508">Valente et al. (2004)</a> demonstrated that PINK1 is localized to mitochondria. <a href="#46" class="mim-tip-reference" title="Valente, E. M., Abou-Sleiman, P. M., Caputo, V., Muqit, M. M. K., Harvey, K., Gispert, S., Ali, Z., Del Turco, D., Bentivoglio, A. R., Healy, D. G., Albanese, A., Nussbaum, R., and 10 others. <strong>Hereditary early-onset Parkinson's disease caused by mutations in PINK1.</strong> Science 304: 1158-1160, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15087508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15087508</a>] [<a href="https://doi.org/10.1126/science.1096284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15087508">Valente et al. (2004)</a> hypothesized that PINK1 may phosphorylate mitochondrial proteins in response to cellular stress, protecting against mitochondrial dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15087508" 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 human and murine neuronal cells lines, <a href="#32" class="mim-tip-reference" title="Petit, A., Kawarai, T., Paitel, E., Sanjo, N., Maj, M., Scheid, M., Chen, F., Gu, Y., Hasegawa, H., Salehi-Rad, S., Wang, L., Rogaeva, E., Fraser, P., Robinson, B., St George-Hyslop, P., Tandon, A. <strong>Wild-type PINK1 prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson disease-related mutations.</strong> J. Biol. Chem. 280: 34025-34032, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16079129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16079129</a>] [<a href="https://doi.org/10.1074/jbc.M505143200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16079129">Petit et al. (2005)</a> showed that wildtype PINK1 prevented basal and inducted neuronal apoptosis due to a PINK1-mediated reduction in cytochrome c oxidase release from mitochondria, which prevented the activation of caspase-3 (<a href="/entry/600636">600636</a>). Overexpression of PINK1 strongly reduced caspase-3 activity. Parkinson disease (PARK6; <a href="/entry/605909">605909</a>)-associated mutations abrogated the protective effect of PINK1, providing a possible mechanism for the degeneration of dopaminergic neurons in patients with the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16079129" 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 human dopaminergic cells, <a href="#43" class="mim-tip-reference" title="Tang, B., Xiong, H., Sun, P., Zhang, Y., Wang, D., Hu, Z., Zhu, Z., Ma, H., Pan, Q., Xia, J., Xia, K., Zhang, Z. <strong>Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease.</strong> Hum. Molec. Genet. 15: 1816-1825, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16632486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16632486</a>] [<a href="https://doi.org/10.1093/hmg/ddl104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16632486">Tang et al. (2006)</a> demonstrated that wildtype PINK1 and DJ1 (<a href="/entry/602533">602533</a>), mutation in which causes PARK7 (<a href="/entry/606324">606324</a>), coimmunoprecipitate and interact functionally to protect cells from toxic oxidative MPP-induced cell death. Overexpression of both proteins resulted in a synergistic protective effect, and mutations in both proteins resulted in increased cell death compared to either mutant protein alone, suggesting a common mechanism. Evidence also suggested that DJ1 helps to stabilize PINK1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16632486" 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 human neuroblastoma cells, <a href="#53" class="mim-tip-reference" title="Zhou, C., Huang, Y., Shao, Y., May, J., Prou, D., Perier, C., Dauer, W., Schon, E. A., Przedborski, S. <strong>The kinase domain of mitochondrial PINK1 faces the cytoplasm.</strong> Proc. Nat. Acad. Sci. 105: 12022-12027, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18687899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18687899</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18687899[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0802814105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18687899">Zhou et al. (2008)</a> demonstrated that the PINK1 protein spans the outer mitochondrial membrane with the C-terminal kinase domain facing the cytoplasm and the N-terminal end inside the mitochondria. Although deletion of the transmembrane domain disrupted this topology, common Parkinson disease-6 (PARK6; <a href="/entry/605909">605909</a>)-linked PINK1 mutations, such as A217D (<a href="#0011">608309.0011</a>) or T313M (<a href="#0010">608309.0010</a>), did not. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18687899" 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 cultured COS-7 and HEK293 cells, <a href="#50" class="mim-tip-reference" title="Weihofen, A., Ostaszewski, B., Minami, Y., Selkoe, D. J. <strong>Pink1 Parkinson mutations, the Cdc37/Hsp90 chaperones and parkin all influence the maturation or subcellular distribution of Pink1.</strong> Hum. Molec. Genet. 17: 602-616, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18003639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18003639</a>] [<a href="https://doi.org/10.1093/hmg/ddm334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18003639">Weihofen et al. (2008)</a> found evidence for low-level PINK1 expression in cytosolic and microsomal-rich fractions, in addition to mitochondrial localization. Further cellular studies showed that PINK1 interacted with and depended upon the chaperone HSP90AA1 (<a href="/entry/140571">140571</a>)/CDC37 (<a href="/entry/605065">605065</a>) complex. This chaperone system appeared to regulate the ratio of the 66-kD/55-kD PINK1 isoforms as well as the differential subcellular localization of these PINK1 isoforms. For example, overexpression of CDC37 resulted in decreased cytosolic PINK1 levels of both isoforms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18003639" 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 human and mouse neuronal cell cultures, <a href="#9" class="mim-tip-reference" title="Gandhi, S., Wood-Kaczmar, A., Yao, Z., Plun-Favreau, H., Deas, E., Klupsch, K., Downward, J., Latchman, D. S., Tabrizi, S. J., Wood, N. W., Duchen, M. R., Abramov, A. Y. <strong>PINK1-associated Parkinson's disease is caused by neuronal vulnerability to calcium-induced cell death.</strong> Molec. Cell 33: 627-638, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19285945/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19285945</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19285945[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.molcel.2009.02.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19285945">Gandhi et al. (2009)</a> found that PINK1 regulated a mitochondrial Na+/Ca(2+) exchanger (see SLC8A1; <a href="/entry/182305">182305</a>). RNA interference (RNAi)-induced PINK1 deficiency caused mitochondrial accumulation of calcium, and the resulting calcium overload stimulated reactive oxygen species (ROS) production via NADPH oxidase (see NOX1; <a href="/entry/300225">300225</a>). ROS production inhibited the glucose transporter (see SLC2A1; <a href="/entry/138140">138140</a>), reducing substrate delivery and impairing mitochondrial respiration. The reduced mitochondrial calcium capacity and increased ROS lowered the threshold of opening the mitochondrial permeability transition pore such that physiologic calcium stimuli led to premature pore opening, profound mitochondrial depolarization, and ultimately cell death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19285945" 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="#27" class="mim-tip-reference" title="Mei, Y., Zhang, Y., Yamamoto, K., Xie, W., Mak, T. W., You, H. <strong>FOXO3a-dependent regulation of Pink1 (Park6) mediates survival signaling in response to cytokine deprivation.</strong> Proc. Nat. Acad. Sci. 106: 5153-5158, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19276113/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19276113</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19276113[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0901104106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19276113">Mei et al. (2009)</a> found that mouse and human cells subjected to growth factor deprivation induced PINK1 expression via the FOXO3A (<a href="/entry/602681">602681</a>) transcription factor, which bound to an element in the PINK1 promoter. RNAi knockout of PINK1 in murine cytotoxic T cells accelerated apoptosis of cells triggered by growth factor withdrawal, and this apoptosis was associated with decreased glutathione levels. Overall, the findings indicated that PINK1 is an essential pro-survival factor of mitochondria in the face of pathologic oxidative stress, as well as a downstream modulator of the anti-oxidative stress functions of the family of FOX transcription factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19276113" 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="#51" class="mim-tip-reference" title="Xiong, H., Wang, D., Chen, L., Choo, Y. S., Ma, H., Tang, C., Xia, K., Jiang, W., Ronai, Z., Zhuang, X., Zhang, Z. <strong>Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation.</strong> J. Clin. Invest. 119: 650-660, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19229105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19229105</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19229105[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI37617" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19229105">Xiong et al. (2009)</a> demonstrated that parkin (PARK2; <a href="/entry/602544">602544</a>), PINK1, and DJ1 (<a href="/entry/602533">602533</a>) interact and form an approximately 200-kD functional ubiquitin E3 ligase complex in human primary neurons. PINK1 was shown to increase the activity of parkin, which degrades itself via the ubiquitin-proteasome system. Pathogenic PINK1 (G309D; <a href="#0001">608309.0001</a>) did not promote ubiquitination and degradation of parkin or the parkin substrate synphilin-1 (<a href="/entry/603779">603779</a>) in transfected cells. Expression of DJ1 increased PINK1 expression, perhaps acting as a stabilizer. Overexpression of parkin substrates or heat shock treatment resulted in parkin accumulation in Pink1- or Dj1-deficient murine cells, and pathogenic parkin mutations resulted in a reduced ability to promote degradation of parkin substrates, all suggesting a decrease in E3 ubiquitin activity. <a href="#51" class="mim-tip-reference" title="Xiong, H., Wang, D., Chen, L., Choo, Y. S., Ma, H., Tang, C., Xia, K., Jiang, W., Ronai, Z., Zhuang, X., Zhang, Z. <strong>Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation.</strong> J. Clin. Invest. 119: 650-660, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19229105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19229105</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19229105[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI37617" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19229105">Xiong et al. (2009)</a> suggested that this complex promotes degradation of un- or misfolded proteins, including parkin, and that disruption of the activity of this complex leads to accumulation of abnormal proteins and increased susceptibility to oxidative stress, which is toxic to neurons and may lead to Parkinson disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19229105" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Narendra, D. P., Jin, S. M., Tanaka, A., Suen, D.-F., Gautier, C. A., Shen, J., Cookson, M. R., Youle, R. J. <strong>PINK1 is selectively stabilized on impaired mitochondria to activate Parkin.</strong> PLoS Biol. 8: e1000298, 2010. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20126261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20126261</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20126261[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.pbio.1000298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20126261">Narendra et al. (2010)</a> found that the expression of PINK1 in mitochondria is regulated by voltage-dependent proteolysis to maintain low levels, and that depolarization results in rapid accumulation of PINK1 on damaged mitochondria. In HeLa cells and mouse and human neuronal cells, PINK1 accumulation was both necessary and sufficient to recruit parkin to the mitochondria, where parkin induced autophagy of damaged mitochondria. Parkinson disease-associated mutations in both PARK2 and PINK1 disrupted parkin recruitment and parkin-induced mitophagy at distinct steps. The findings indicated that PINK1 acts upstream of parkin in a conserved pathway critical for the maintenance of mitochondrial integrity and function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20126261" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In HeLa cells and human neuroblastoma cells, <a href="#11" class="mim-tip-reference" title="Geisler, S., Holmstrom, K. M., Skujat, D., Fiesel, F. C., Rothfuss, O. C., Kahle, P. J., Springer, W. <strong>PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1.</strong> Nature Cell Biol. 12: 119-131, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20098416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20098416</a>] [<a href="https://doi.org/10.1038/ncb2012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20098416">Geisler et al. (2010)</a> found that PD-associated parkin mutations disrupted the normal sequential translocation of parkin to the mitochondria and/or clearing of sequestered mitochondria in response to chemically-induced dissipation of the mitochondrial membrane potential. Parkin and PINK1 coimmunoprecipitated in neuroblastoma cells, and functional PINK1 kinase activity was required for proper translocation of parkin to damaged mitochondria for mitophagy. Wildtype parkin formed polyubiquitin chains linked through lys27 and lys63 of ubiquitin as a crucial step in autophagy of mitochondria. The ubiquitination required the ubiquitin-binding protein SQSTM1 (<a href="/entry/601530">601530</a>) and involved ubiquitination of VDAC1 (<a href="/entry/604492">604492</a>) on the mitochondrial membrane. Importantly, PD-associated parkin variants interrupted this mitophagy process at distinct steps. The findings described a link between mitochondrial damage, ubiquitination, and selective autophagy of mitochondria. Disruption of the process by mutations resulted in failure of mitochondrial clearance, which likely plays a role in the pathogenesis of PD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20098416" 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="#39" class="mim-tip-reference" title="Sha, D., Chin, L.-S., Li, L. <strong>Phosphorylation of parkin by Parkinson disease-linked kinase PINK1 activates parkin E3 ligase function and NF-kappa-B signaling.</strong> Hum. Molec. Genet. 19: 352-363, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19880420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19880420</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19880420[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/ddp501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19880420">Sha et al. (2010)</a> reported that PINK1 regulated the E3 ubiquitin-protein ligase function of parkin through direct phosphorylation. Phosphorylation of parkin by PINK1 activated parkin E3 ligase function for catalyzing K63-linked polyubiquitination and enhanced parkin-mediated ubiquitin signaling through the I-kappa-B kinase/nuclear factor kappa-B (NF-kappa-B) pathway. The ability of PINK1 to promote parkin phosphorylation and activate parkin-mediated ubiquitin signaling was impaired by PD-linked pathogenic PINK1 mutations. <a href="#39" class="mim-tip-reference" title="Sha, D., Chin, L.-S., Li, L. <strong>Phosphorylation of parkin by Parkinson disease-linked kinase PINK1 activates parkin E3 ligase function and NF-kappa-B signaling.</strong> Hum. Molec. Genet. 19: 352-363, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19880420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19880420</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19880420[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/ddp501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19880420">Sha et al. (2010)</a> proposed a direct link between PINK1-mediated phosphorylation and parkin-mediated ubiquitin signaling and implicated the deregulation of the PINK1/parkin/NF-kappa-B neuroprotective signaling pathway in the pathogenesis of PD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19880420" 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="Choo, Y. S., Tang, C., Zhang, Z. <strong>Critical role of PINK1 in regulating parkin protein levels in vivo. (Letter)</strong> Arch. Neurol. 68: 684-685, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21555650/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21555650</a>] [<a href="https://doi.org/10.1001/archneurol.2011.95" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21555650">Choo et al. (2011)</a> found that parkin was increased in the brains of Pink1-null mice due to a decrease in parkin's E3 ligase activity. Levels of another parkin substrate, JTV1 (AIMP2; <a href="/entry/600859">600859</a>), were also increased in Pink1-null mice. The findings supported a previous study (<a href="#51" class="mim-tip-reference" title="Xiong, H., Wang, D., Chen, L., Choo, Y. S., Ma, H., Tang, C., Xia, K., Jiang, W., Ronai, Z., Zhuang, X., Zhang, Z. <strong>Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation.</strong> J. Clin. Invest. 119: 650-660, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19229105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19229105</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19229105[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI37617" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19229105">Xiong et al., 2009</a>), which found that the parkin/PINK1/DJ1 complex functions as an E3 ligase to promote degradation of parkin substrates and that PINK1 plays a crucial role in regulating parkin E3 ligase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21555650+19229105" 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 human cells, <a href="#28" class="mim-tip-reference" title="Meissner, C., Lorenz, H., Weihofen, A., Selkoe, D. J., Lemberg, M. K. <strong>The mitochondrial intramembrane protease PARL cleaves human Pink1 to regulate Pink1 trafficking.</strong> J. Neurochem. 117: 856-867, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21426348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21426348</a>] [<a href="https://doi.org/10.1111/j.1471-4159.2011.07253.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21426348">Meissner et al. (2011)</a> demonstrated that PARL (<a href="/entry/607858">607858</a>) cleaves the 66-kD precursor of PINK1 to a 55-kD processed form within the mitochondria. PINK1-66 is targeted to both the outer and inner mitochondrial membranes, and PINK1-55 locates to both the mitochondrial intermembrane space and to the cytosol. PARL processes PINK1 in the transmembrane domain. <a href="#28" class="mim-tip-reference" title="Meissner, C., Lorenz, H., Weihofen, A., Selkoe, D. J., Lemberg, M. K. <strong>The mitochondrial intramembrane protease PARL cleaves human Pink1 to regulate Pink1 trafficking.</strong> J. Neurochem. 117: 856-867, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21426348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21426348</a>] [<a href="https://doi.org/10.1111/j.1471-4159.2011.07253.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21426348">Meissner et al. (2011)</a> suggested that mutations in PINK1 that affect this processing may contribute to the pathogenesis of Parkinson disease (see, e.g., PARK6, <a href="/entry/605909">605909</a>). <a href="#40" class="mim-tip-reference" title="Shi, G., Lee, J. R., Grimes, D. A., Racacho, L., Ye, D., Yang, H., Ross, O. A., Farrer, M., McQuibban, C. A., Bulman, D. E. <strong>Functional alteration of PARL contributes to mitochondrial dysregulation in Parkinson's disease.</strong> Hum. Molec. Genet. 20: 1966-1974, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21355049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21355049</a>] [<a href="https://doi.org/10.1093/hmg/ddr077" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21355049">Shi et al. (2011)</a> also demonstrated that PARL proteolytically processes PINK1 and is required for PINK1 release from the mitochondria after import. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21426348+21355049" 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>Human UBIAD1 (<a href="/entry/611632">611632</a>) localizes to mitochondria and converts vitamin K1 to vitamin K2. Vitamin K2 is best known as a cofactor in blood coagulation, but in bacteria it is a membrane-bound electron carrier. Whether vitamin K2 exerts a similar carrier function in eukaryotic cells was studied by <a href="#48" class="mim-tip-reference" title="Vos, M., Esposito, G., Edirisinghe, J. N., Vilain, S., Haddad, D. M., Slabbaert, J. R., Van Meensel, S., Schaap, O., De Strooper, B., Meganathan, R., Morais, V. A., Verstreken, P. <strong>Vitamin K2 is a mitochondrial electron carrier that rescues Pink1 deficiency.</strong> Science 336: 1306-1310, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22582012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22582012</a>] [<a href="https://doi.org/10.1126/science.1218632" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22582012">Vos et al. (2012)</a>, who identified Drosophila UBIAD1/Heix as a modifier of pink1, a gene mutated in Parkinson disease that affects mitochondrial function. <a href="#48" class="mim-tip-reference" title="Vos, M., Esposito, G., Edirisinghe, J. N., Vilain, S., Haddad, D. M., Slabbaert, J. R., Van Meensel, S., Schaap, O., De Strooper, B., Meganathan, R., Morais, V. A., Verstreken, P. <strong>Vitamin K2 is a mitochondrial electron carrier that rescues Pink1 deficiency.</strong> Science 336: 1306-1310, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22582012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22582012</a>] [<a href="https://doi.org/10.1126/science.1218632" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22582012">Vos et al. (2012)</a> found that vitamin K2 was necessary and sufficient to transfer electrons in Drosophila mitochondria. Heix mutants showed severe mitochondrial defects that were rescued by vitamin K2, and, similar to ubiquinone, vitamin K2 transferred electrons in Drosophila mitochondria, resulting in more efficient adenosine ATP production. Thus, <a href="#48" class="mim-tip-reference" title="Vos, M., Esposito, G., Edirisinghe, J. N., Vilain, S., Haddad, D. M., Slabbaert, J. R., Van Meensel, S., Schaap, O., De Strooper, B., Meganathan, R., Morais, V. A., Verstreken, P. <strong>Vitamin K2 is a mitochondrial electron carrier that rescues Pink1 deficiency.</strong> Science 336: 1306-1310, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22582012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22582012</a>] [<a href="https://doi.org/10.1126/science.1218632" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22582012">Vos et al. (2012)</a> concluded that mitochondrial dysfunction was rescued by vitamin K2 that serves as a mitochondrial electron carrier, helping to maintain normal ATP production. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22582012" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Chen, Y., Dorn, G. W., II. <strong>PINK1-phosphorylated mitofusin 2 is a parkin receptor for culling damaged mitochondria.</strong> Science 340: 471-475, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23620051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23620051</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23620051[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/10.1126/science.1231031" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23620051">Chen and Dorn (2013)</a> demonstrated that the mitochondrial outer membrane guanosine triphosphatase mitofusin-2 (MFN2; <a href="/entry/608507">608507</a>) mediates parkin (<a href="/entry/602544">602544</a>) recruitment to damaged mitochondria. Parkin bound to MFN2 in a PINK1-dependent manner; PINK1 phosphorylated MFN2 and promoted its parkin-mediated ubiquitination. Ablation of Mfn2 in mouse cardiac myocytes prevented depolarization-induced translocation of parkin to the mitochondria and suppressed mitophagy. Accumulation of morphologically and functionally abnormal mitochondria induced respiratory dysfunction in Mfn2-deficient mouse embryonic fibroblasts and cardiomyocytes and in parkin-deficient Drosophila heart tubes, causing dilated cardiomyopathy. Thus, <a href="#4" class="mim-tip-reference" title="Chen, Y., Dorn, G. W., II. <strong>PINK1-phosphorylated mitofusin 2 is a parkin receptor for culling damaged mitochondria.</strong> Science 340: 471-475, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23620051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23620051</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23620051[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/10.1126/science.1231031" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23620051">Chen and Dorn (2013)</a> concluded that MFN2 functions as a mitochondrial receptor for parkin and is required for quality control of cardiac mitochondria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23620051" 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="Hasson, S. A., Kane, L. A., Yamano, K., Huang, C.-H., Sliter, D. A., Buehler, E., Wang, C., Heman-Ackah, S. M., Hessa, T., Guha, R., Martin, S. E., Youle, R. J. <strong>High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy.</strong> Nature 504: 291-295, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24270810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24270810</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24270810[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/nature12748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24270810">Hasson et al. (2013)</a> elucidated regulators that have an impact on parkin translocation to damaged mitochondria with genomewide small interfering RNA (siRNA) screens coupled to high-content microscopy. Screening yielded gene candidates involved in diverse cellular processes that were subsequently validated in low-throughput assays. This led to characterization of TOMM7 (<a href="/entry/607980">607980</a>) as essential for stabilizing PINK1 on the outer mitochondrial membrane following mitochondrial damage. <a href="#14" class="mim-tip-reference" title="Hasson, S. A., Kane, L. A., Yamano, K., Huang, C.-H., Sliter, D. A., Buehler, E., Wang, C., Heman-Ackah, S. M., Hessa, T., Guha, R., Martin, S. E., Youle, R. J. <strong>High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy.</strong> Nature 504: 291-295, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24270810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24270810</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24270810[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/nature12748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24270810">Hasson et al. (2013)</a> also discovered that HSPA1L (<a href="/entry/140559">140559</a>) and BAG4 (<a href="/entry/603884">603884</a>) have mutually opposing roles in the regulation of parkin translocation. The screens revealed that SIAH3 (<a href="/entry/615609">615609</a>), found to localize to mitochondria, inhibits PINK1 accumulation after mitochondrial insult, reducing parkin translocation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24270810" 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>Under resting conditions, Pink1 knockout cells and cells derived from patients with PINK1 mutations display a loss of mitochondrial complex I reductive activity, causing a decrease in the mitochondrial membrane potential. Analyzing the phosphoproteome of complex I in liver and brain from Pink1-null mice, <a href="#29" class="mim-tip-reference" title="Morais, V. A., Haddad, D., Craessaerts, K., De Bock, P.-J., Swerts, J., Vilain, S., Aerts, L., Overbergh, L., Grunewald, A., Seibler, P., Klein, C., Gevaert, K., Verstreken, P., De Strooper, B. <strong>PINK1 loss-of-function mutations affect mitochondrial complex I activity via NdufA10 ubiquinone uncoupling.</strong> Science 344: 203-207, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24652937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24652937</a>] [<a href="https://doi.org/10.1126/science.1249161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24652937">Morais et al. (2014)</a> found specific loss of phosphorylation of ser250 in complex I subunit NdufA10 (<a href="/entry/603835">603835</a>). Phosphorylation of ser250 was needed for ubiquinone reduction by complex I. Phosphomimetic NdufA10 reversed Pink1 deficits in mouse knockout cells and rescued mitochondrial depolarization and synaptic transmission defects in pink(B9)-null mutant Drosophila. Complex I deficits and ATP synthesis were also rescued in cells derived from PINK1 patients. <a href="#29" class="mim-tip-reference" title="Morais, V. A., Haddad, D., Craessaerts, K., De Bock, P.-J., Swerts, J., Vilain, S., Aerts, L., Overbergh, L., Grunewald, A., Seibler, P., Klein, C., Gevaert, K., Verstreken, P., De Strooper, B. <strong>PINK1 loss-of-function mutations affect mitochondrial complex I activity via NdufA10 ubiquinone uncoupling.</strong> Science 344: 203-207, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24652937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24652937</a>] [<a href="https://doi.org/10.1126/science.1249161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24652937">Morais et al. (2014)</a> concluded that this evolutionarily conserved pathway may contribute to the pathogenic cascade that eventually leads to Parkinson disease (see <a href="/entry/605909">605909</a>) in patients with PINK1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24652937" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Bingol, B., Tea, J. S., Phu, L., Reichelt, M., Bakalarski, C. E., Song, Q., Foreman, O., Kirkpatrick, D. S., Sheng, M. <strong>The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy.</strong> Nature 510: 370-375, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24896179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24896179</a>] [<a href="https://doi.org/10.1038/nature13418" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24896179">Bingol et al. (2014)</a> reported that USP30 (<a href="/entry/612492">612492</a>), a deubiquitinase localized to mitochondria, antagonizes mitophagy driven by the ubiquitin ligase parkin (PARK2; <a href="/entry/602544">602544</a>) and protein kinase PINK1, which are encoded by 2 genes associated with Parkinson disease (see <a href="/entry/168600">168600</a>). Parkin ubiquitinates and tags damaged mitochondria for clearance. Overexpression of USP30 removes ubiquitin attached by parkin onto damaged mitochondria and blocks the parkin's ability to drive mitophagy, whereas reducing USP30 activity enhances mitochondrial degradation in neurons. Global ubiquitination site profiling identified multiple mitochondrial substrates oppositely regulated by parkin and USP30. Knockdown of USP30 rescues the defective mitophagy caused by pathogenic mutations in parkin and improves mitochondrial integrity in parkin- or Pink1-deficient flies. Knockdown of Usp30 in dopaminergic neurons protects flies against paraquat toxicity in vivo, ameliorating defects in dopamine levels, motor function, and organismal survival. <a href="#3" class="mim-tip-reference" title="Bingol, B., Tea, J. S., Phu, L., Reichelt, M., Bakalarski, C. E., Song, Q., Foreman, O., Kirkpatrick, D. S., Sheng, M. <strong>The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy.</strong> Nature 510: 370-375, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24896179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24896179</a>] [<a href="https://doi.org/10.1038/nature13418" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24896179">Bingol et al. (2014)</a> concluded that USP30 inhibition is potentially beneficial for treating Parkinson disease by promoting mitochondrial clearance and quality control. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24896179" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Koyano, F., Okatsu, K., Kosako, H., Tamura, Y., Go, E., Kimura, M., Kimura, Y., Tsuchiya, H., Yoshihara, H., Hirokawa, T., Endo, T., Fon, E. A., Trempe, J.-F., Saeki, Y., Tanaka, K., Matsuda, N. <strong>Ubiquitin is phosphorylated by PINK1 to activate parkin.</strong> Nature 510: 162-166, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24784582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24784582</a>] [<a href="https://doi.org/10.1038/nature13392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24784582">Koyano et al. (2014)</a> reported that ubiquitin is the genuine substrate of PINK1. PINK1 phosphorylated ubiquitin at ser65 both in vitro and in cells, and a ser65 phosphopeptide derived from endogenous ubiquitin was detected in cells only in the presence of PINK1 and following a decrease in mitochondrial membrane potential. Unexpectedly, phosphomimetic ubiquitin bypassed PINK1-dependent activation of a phosphomimetic parkin mutant in cells. Furthermore, phosphomimetic ubiquitin accelerates discharge of the thioester conjugate formed by UBCH7 (UBE2L3; <a href="/entry/603721">603721</a>) and ubiquitin in the presence of parkin in vitro, indicating that it acts allosterically. The phosphorylation-dependent interaction between ubiquitin and parkin suggests that phosphorylated ubiquitin unlocks autoinhibition of the catalytic cysteine. <a href="#20" class="mim-tip-reference" title="Koyano, F., Okatsu, K., Kosako, H., Tamura, Y., Go, E., Kimura, M., Kimura, Y., Tsuchiya, H., Yoshihara, H., Hirokawa, T., Endo, T., Fon, E. A., Trempe, J.-F., Saeki, Y., Tanaka, K., Matsuda, N. <strong>Ubiquitin is phosphorylated by PINK1 to activate parkin.</strong> Nature 510: 162-166, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24784582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24784582</a>] [<a href="https://doi.org/10.1038/nature13392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24784582">Koyano et al. (2014)</a> concluded that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity, and that phosphorylated ubiquitin is a parkin activator. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24784582" 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="Lazarou, M., Sliter, D. A., Kane, L. A., Sarraf, S. A., Wang, C., Burman, J. L., Sideris, D. P., Fogel, A. I., Youle, R. J. <strong>The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy.</strong> Nature 524: 309-314, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26266977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26266977</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26266977[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/nature14893" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26266977">Lazarou et al. (2015)</a> used genome editing to knock out 5 autophagy receptors in HeLa cells and demonstrated that 2 receptors previously linked to xenophagy, NDP52 (<a href="/entry/604587">604587</a>) and optineurin (<a href="/entry/602432">602432</a>), are the primary receptors for PINK1- and parkin (<a href="/entry/602544">602544</a>)-mediated mitophagy. PINK1 recruits NDP52 and optineurin but not p62 (SQSTM1; <a href="/entry/601530">601530</a>) to mitochondria to activate mitophagy directly, independently of parkin. Once recruited to mitochondria, NDP52 and optineurin recruit the autophagy factors ULK1 (<a href="/entry/603168">603168</a>), DFCP1 (ZNFN2A1; <a href="/entry/605471">605471</a>), and WIPI1 (<a href="/entry/609224">609224</a>) to focal spots proximal to mitochondria, revealing a function for these autophagy receptors upstream of LC3 (MAP1LC3A; <a href="/entry/601242">601242</a>). <a href="#22" class="mim-tip-reference" title="Lazarou, M., Sliter, D. A., Kane, L. A., Sarraf, S. A., Wang, C., Burman, J. L., Sideris, D. P., Fogel, A. I., Youle, R. J. <strong>The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy.</strong> Nature 524: 309-314, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26266977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26266977</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26266977[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/nature14893" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26266977">Lazarou et al. (2015)</a> concluded that their observations support a model in which PINK1-generated phosph-ubiquitin serves as the autophagy signal on mitochondria, and parkin then acts to amplify this signal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26266977" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Gong, G., Song, M., Csordas, G., Kelly, D. P., Matkovich, S. J., Dorn, G. W., II. <strong>Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice.</strong> Science 350: aad2459, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26785495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26785495</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26785495[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/10.1126/science.aad2459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26785495">Gong et al. (2015)</a> found that Pink1-Mfn2 (<a href="/entry/608507">608507</a>)-parkin-mediated mitophagy directs the change in mitochondrial substrate preference in developing mouse hearts from from carbohydrates to fatty acids. A Mfn2 mutant lacking Pink1 phosphorylation sites necessary for parkin binding (Mfn2 AA) inhibited mitochondrial parkin translocation, suppressing mitophagy without impairing mitochondrial fusion. Cardiac parkin deletion or expression of Mfn2 AA from birth, but not after weaning, prevented postnatal mitochondrial maturation essential to survival. Five-week-old Mfn2 AA hearts retained a fetal mitochondrial transcriptional signature without normal increases in fatty acid metabolism and mitochondrial biogenesis genes. Myocardial fatty acylcarnitine levels and cardiomyocyte respiration induced by palmitoylcarnitine were concordantly depressed. Thus, instead of transcriptional reprogramming, fetal cardiomyocyte mitochondria undergo perinatal parkin-mediated mitophagy and replacement by mature adult mitochondria. <a href="#13" class="mim-tip-reference" title="Gong, G., Song, M., Csordas, G., Kelly, D. P., Matkovich, S. J., Dorn, G. W., II. <strong>Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice.</strong> Science 350: aad2459, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26785495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26785495</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26785495[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/10.1126/science.aad2459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26785495">Gong et al. (2015)</a> concluded that mitophagic mitochondrial removal underlies developmental cardiomyocyte mitochondrial plasticity and metabolic transitioning of perinatal hearts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26785495" 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="#46" class="mim-tip-reference" title="Valente, E. M., Abou-Sleiman, P. M., Caputo, V., Muqit, M. M. K., Harvey, K., Gispert, S., Ali, Z., Del Turco, D., Bentivoglio, A. R., Healy, D. G., Albanese, A., Nussbaum, R., and 10 others. <strong>Hereditary early-onset Parkinson's disease caused by mutations in PINK1.</strong> Science 304: 1158-1160, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15087508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15087508</a>] [<a href="https://doi.org/10.1126/science.1096284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15087508">Valente et al. (2004)</a> identified 2 homozygous mutations affecting the PINK1 kinase domain in 3 consanguineous families with Parkinson disease (PARK6; <a href="/entry/605909">605909</a>): a missense mutation at a highly conserved amino acid (<a href="#0001">608309.0001</a>) and a nonsense mutation (<a href="#0002">608309.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15087508" 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 6 unrelated families (3 Japanese, 1 Israeli, 1 Filipino, and 1 Taiwanese) with PARK6, <a href="#15" class="mim-tip-reference" title="Hatano, Y., Li, Y., Sato, K., Asakawa, S., Yamamura, Y., Tomiyama, H., Yoshino, H., Asahina, M., Kobayashi, S., Hassin-Baer, S., Lu, C.-S., Ng, A. R., Rosales, R. L., Shimizu, N., Toda, T., Mizuno, Y., Hattori, N. <strong>Novel PINK1 mutations in early-onset parkinsonism.</strong> Ann. Neurol. 56: 424-427, 2004. Note: Erratum: Ann. Neurol. 56: 603 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15349870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15349870</a>] [<a href="https://doi.org/10.1002/ana.20251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15349870">Hatano et al. (2004)</a> identified 6 pathogenic mutations in the PINK1 gene (see, e.g., <a href="#0003">608309.0003</a>-<a href="#0005">608309.0005</a>). The authors suggested that PINK1 may be the second most common causative gene next to parkin (<a href="/entry/602544">602544</a>) in early-onset autosomal recessive Parkinson disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15349870" 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="#47" class="mim-tip-reference" title="Valente, E. M., Salvi, S., Ialongo, T., Marongiu, R., Elia, A. E., Caputo, V., Romito, L., Albanese, A., Dallapiccola, B., Bentivoglio, A. R. <strong>PINK1 mutations are associated with sporadic early-onset parkinsonism.</strong> Ann. Neurol. 56: 336-341, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15349860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15349860</a>] [<a href="https://doi.org/10.1002/ana.20256" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15349860">Valente et al. (2004)</a> found that among 90 patients with sporadic early-onset parkinsonism, 1 patient had a homozygous mutation in the PINK1 gene and a second was compound heterozygous for mutations in PINK1. Five of 90 patients and 2 of 200 healthy controls had a heterozygous PINK1 mutation; 1 of the patients and 1 control shared the same mutation. The 5 patients with a heterozygous mutation had a typical parkinsonian phenotype with a mean age at onset of 44 years. Three patients had mild mood disturbances. <a href="#47" class="mim-tip-reference" title="Valente, E. M., Salvi, S., Ialongo, T., Marongiu, R., Elia, A. E., Caputo, V., Romito, L., Albanese, A., Dallapiccola, B., Bentivoglio, A. R. <strong>PINK1 mutations are associated with sporadic early-onset parkinsonism.</strong> Ann. Neurol. 56: 336-341, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15349860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15349860</a>] [<a href="https://doi.org/10.1002/ana.20256" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15349860">Valente et al. (2004)</a> suggested that heterozygous PINK1 mutations may produce subclinical dopaminergic dysfunction and represent a risk factor for the development of Parkinson disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15349860" 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="#36" class="mim-tip-reference" title="Rogaeva, E., Johnson, J., Lang, A. E., Gulick, C., Gwinn-Hardy, K., Kawarai, T., Sato, C., Morgan, A., Werner, J., Nussbaum, R., Petit, A., Okun, M. S., and 13 others. <strong>Analysis of the PINK1 gene in a large cohort of cases with Parkinson disease.</strong> Arch. Neurol. 61: 1898-1904, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15596610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15596610</a>] [<a href="https://doi.org/10.1001/archneur.61.12.1898" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15596610">Rogaeva et al. (2004)</a> identified disease-causing PINK1 mutations in 2 of 289 unrelated North American patients with early- or late-onset PD, suggesting that mutations in this gene are a rare cause of early-onset PD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15596610" 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="#16" class="mim-tip-reference" title="Healy, D. G., Abou-Sleiman, P. M., Gibson, J. M., Ross, O. A., Jain, S., Gandhi, S., Gosal, D., Muqit, M. M. K., Wood, N. W., Lynch, T. <strong>PINK1 (PARK6) associated Parkinson disease in Ireland.</strong> Neurology 63: 1486-1488, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15505171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15505171</a>] [<a href="https://doi.org/10.1212/01.wnl.0000142089.38301.8e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15505171">Healy et al. (2004)</a> reported an Irish woman with early-onset PD who carried a heterozygous missense mutation in the PINK1 gene. The mutation occurred outside of the putative kinase domain, and was conserved between humans and various primates, but not in mouse or C. elegans. The mutation was not identified in 2,224 control or PD chromosomes, including 780 from Ireland. No other point mutations or gene rearrangements in the PINK1 gene were detected in this patient. <a href="#16" class="mim-tip-reference" title="Healy, D. G., Abou-Sleiman, P. M., Gibson, J. M., Ross, O. A., Jain, S., Gandhi, S., Gosal, D., Muqit, M. M. K., Wood, N. W., Lynch, T. <strong>PINK1 (PARK6) associated Parkinson disease in Ireland.</strong> Neurology 63: 1486-1488, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15505171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15505171</a>] [<a href="https://doi.org/10.1212/01.wnl.0000142089.38301.8e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15505171">Healy et al. (2004)</a> suggested that heterozygosity for mutations in the PINK1 gene may increase the risk for PD, but admitted that the data were inconclusive. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15505171" 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="#17" class="mim-tip-reference" title="Hedrich, K., Hagenah, J., Djarmati, A., Hiller, A., Lohnau, T., Lasek, K., Grunewald, A., Hilker, R., Steinlechner, S., Boston, H., Kock, N., Schneider-Gold, C., Kress, W., Siebner, H., Binkofski, F., Lencer, R., Munchau, A., Klein, C. <strong>Clinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit?</strong> Arch. Neurol. 63: 833-838, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16769864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16769864</a>] [<a href="https://doi.org/10.1001/archneur.63.6.833" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16769864">Hedrich et al. (2006)</a> identified a homozygous mutation (Q456X; <a href="#0012">608309.0012</a>) in the PINK1 gene in 4 affected members of a large German family with early-onset parkinsonism. Six heterozygous offspring of the homozygous patients were found to have subtle signs of disease, and 5 heterozygous offspring were considered to be unaffected. <a href="#17" class="mim-tip-reference" title="Hedrich, K., Hagenah, J., Djarmati, A., Hiller, A., Lohnau, T., Lasek, K., Grunewald, A., Hilker, R., Steinlechner, S., Boston, H., Kock, N., Schneider-Gold, C., Kress, W., Siebner, H., Binkofski, F., Lencer, R., Munchau, A., Klein, C. <strong>Clinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit?</strong> Arch. Neurol. 63: 833-838, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16769864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16769864</a>] [<a href="https://doi.org/10.1001/archneur.63.6.833" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16769864">Hedrich et al. (2006)</a> concluded that heterozygous PINK1 mutations confer susceptibility to the development of PD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16769864" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Abou-Sleiman, P. M., Muqit, M. M. K., McDonald, N. Q., Yang, Y. X., Gandhi, S., Healy, D. G., Harvey, K., Harvey, R. J., Deas, E., Bhatia, K., Quinn, N., Lees, A., Latchman, D. S., Wood, N. W. <strong>A heterozygous effect for PINK1 mutations in Parkinson's disease?</strong> Ann. Neurol. 60: 414-419, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16969854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16969854</a>] [<a href="https://doi.org/10.1002/ana.20960" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16969854">Abou-Sleiman et al. (2006)</a> identified heterozygous mutations in the PINK1 gene (see, e.g., <a href="#0013">608309.0013</a>) in 9 (1.2%) of 768 patients with sporadic PD. Heterozygous mutations were identified in 0.39% of a larger control group without PD, suggesting that heterozygous PINK1 mutations are a risk factor for PD. The mean age of symptom onset in the patients was 54 years, and the disorder showed very slow progression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16969854" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Choi, J. M., Woo, M. S., Ma, H.-I., Kang, S. Y., Sung, Y.-H., Yong, S. W., Chung, S. J., Kim, J.-S., Shin, H., Lyoo, C. H., Lee, P. H., Baik, J. S., and 9 others. <strong>Analysis of PARK genes in a Korean cohort of early-onset Parkinson disease.</strong> Neurogenetics 9: 263-269, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18704525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18704525</a>] [<a href="https://doi.org/10.1007/s10048-008-0138-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18704525">Choi et al. (2008)</a> identified mutations in the PINK1 gene (see, e.g., <a href="#0008">608309.0008</a>) in 4 of 72 unrelated Korean patients with onset of PD before age 50. Three patients were heterozygous, and 1 was compound heterozygous for the mutation(s). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18704525" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Kumazawa, R., Tomiyama, H., Li, Y., Imamichi, Y., Funayama, M., Yoshino, H., Yokochi, F., Fukusako, T., Takehisa, Y., Kashihara, K., Kondo, T., Elibol, B., Bostantjopoulou, S., Toda, T., Takahashi, H., Yoshii, F., Mizuno, Y., Hattori, N. <strong>Mutation analysis of the PINK1 gene in 391 patients with Parkinson disease.</strong> Arch. Neurol. 65: 802-808, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18541801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18541801</a>] [<a href="https://doi.org/10.1001/archneur.65.6.802" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18541801">Kumazawa et al. (2008)</a> identified mutations in the PINK1 gene in 10 (2.5%) of 391 unrelated parkin-negative PD patients from 13 countries. Eight of the 10 patients with mutations were from Japan. The frequency of homozygous mutations was 4.26% (2 of 47) in families with autosomal recessive PD and 0.53% (1 of 190) in patients with sporadic PD. The frequency of heterozygous mutations was 1.89% (2 of 106) in families with potential autosomal dominant PD and 1.05% (2 of 190) in patients with sporadic PD. The mean age at onset in patients with single heterozygous mutations was 53.6 years, compared to 34.0 years in patients with homozygous mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18541801" 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="#18" class="mim-tip-reference" title="Ishihara-Paul, L., Hulihan, M. M., Kachergus, J., Upmanyu, R., Warren, L., Amouri, R., Elango, R., Prinjha, R. K., Soto, A., Kefi, M., Zouari, M., Sassi, S. B., Yahmed, S. B., El Euch-Fayeche, G., Matthews, P. M., Middleton, L. T., Gibson, R. A., Hentati, F., Farrer, M. J. <strong>PINK1 mutations and parkinsonism.</strong> Neurology 71: 896-902, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18685134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18685134</a>] [<a href="https://doi.org/10.1212/01.wnl.0000323812.40708.1f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18685134">Ishihara-Paul et al. (2008)</a> identified 4 different homozygous mutations in the PINK1 gene (see, e.g., <a href="#0012">608309.0012</a>), including 3 novel mutations, in 14 (15%) of 92 Tunisian families with Parkinson disease. Six (2.5%) of 240 patients with no family history of PD were also found to carry homozygous mutations. There was no evidence that heterozygous PINK1 mutations contributed to development of PD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18685134" 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="#50" class="mim-tip-reference" title="Weihofen, A., Ostaszewski, B., Minami, Y., Selkoe, D. J. <strong>Pink1 Parkinson mutations, the Cdc37/Hsp90 chaperones and parkin all influence the maturation or subcellular distribution of Pink1.</strong> Hum. Molec. Genet. 17: 602-616, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18003639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18003639</a>] [<a href="https://doi.org/10.1093/hmg/ddm334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18003639">Weihofen et al. (2008)</a> presented evidence that an altered ratio of the 66-kD/55-kD isoforms of PINK1 may be involved in disease pathogenesis. In vitro studies in cultured COS-7 and HEK293 cells showed that PD-related loss of function mutations (e.g., G309D; <a href="#0001">608309.0001</a>) led to decreases in the 66-kD/55-kD ratio. Overexpression of PARK2 (<a href="/entry/602544">602544</a>) increased the ratio, whereas DJ1 (<a href="/entry/602533">602533</a>) had no effect. The findings identified PARK2 as a modulator of PINK1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18003639" 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 dermal fibroblasts originating from PD patients with various PINK1 mutations, <a href="#35" class="mim-tip-reference" title="Rakovic, A., Grunewald, A., Seibler, P., Ramirez, A., Kock, N., Orolicki, S., Lohmann, K., Klein, C. <strong>Effect of endogenous mutant and wild-type PINK1 on Parkin in fibroblasts from Parkinson disease patients.</strong> Hum. Molec. Genet. 19: 3124-3137, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20508036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20508036</a>] [<a href="https://doi.org/10.1093/hmg/ddq215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20508036">Rakovic et al. (2010)</a> showed that PINK1 regulates the stress-induced decrease of endogenous parkin (PARK2); that mitochondrially localized PINK1 mediates the stress-induced mitochondrial translocation of parkin; that endogenous PINK1 is stabilized on depolarized mitochondria; and that mitochondrial accumulation of full-length PINK1 is sufficient but not necessary for the stress-induced loss of Parkin and its mitochondrial translocation. Depolarizing or nondepolarizing stressors had the same effect on detectable parkin levels and its mitochondrial targeting. Although this effect on parkin was independent of mitochondrial membrane potential, <a href="#35" class="mim-tip-reference" title="Rakovic, A., Grunewald, A., Seibler, P., Ramirez, A., Kock, N., Orolicki, S., Lohmann, K., Klein, C. <strong>Effect of endogenous mutant and wild-type PINK1 on Parkin in fibroblasts from Parkinson disease patients.</strong> Hum. Molec. Genet. 19: 3124-3137, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20508036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20508036</a>] [<a href="https://doi.org/10.1093/hmg/ddq215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20508036">Rakovic et al. (2010)</a> demonstrated a differential effect of depolarizing versus nondepolarizing stressors on endogenous levels of PINK1. The study of <a href="#35" class="mim-tip-reference" title="Rakovic, A., Grunewald, A., Seibler, P., Ramirez, A., Kock, N., Orolicki, S., Lohmann, K., Klein, C. <strong>Effect of endogenous mutant and wild-type PINK1 on Parkin in fibroblasts from Parkinson disease patients.</strong> Hum. Molec. Genet. 19: 3124-3137, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20508036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20508036</a>] [<a href="https://doi.org/10.1093/hmg/ddq215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20508036">Rakovic et al. (2010)</a> demonstrated the effect of an environmental factor, stress, on the interaction of PINK1 and parkin in mutants versus controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20508036" 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="#44" class="mim-tip-reference" title="Trinh, J., Hicks, A. A., Konig, I. R., Delcambre, S., Luth, T., Schaake, S., Wasner, K., Ghelfi, J., Borsche, M., Vilarino-Guell, C., Hentati, F., Germer, E. L., and 15 others. <strong>Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson's disease.</strong> Brain 146: 2753-2765, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36478228/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36478228</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36478228[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/awac464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36478228">Trinh et al. (2023)</a> investigated mitochondrial DNA heteroplasmy in whole blood in patients with PD and biallelic mutations in the PINK1 or PRKN (<a href="/entry/602544">602544</a>) gene, patients with PD and heterozygous mutations in PINK1 or PRKN, patients with biallelic or heteroplasmic mutations in PINK1 or PRKN but without PD, patients with idiopathic PD, and control individuals. Individuals with PD and biallelic mutations in PINK1 or PRKN had significantly more mtDNA heteroplasmy compared to patients with PD and heterozygous mutations in PINK1 or PRKN or controls. Regardless of affected or unaffected status for PD, individuals with biallelic mutations in PINK1 or PRKN had significantly more mtDNA heteroplasmy compared to individuals with heterozygous mutations in PINK1 or PRKN. Patients with PD and heterozygous mutations in PINK1 or PRKN had more heteroplasmy compared to individuals without PD and heterozygous mutations in PINK1 or PRKN, or patients with idiopathic PD. Heteroplasmy load was also found to correlate to IL6 (<a href="/entry/147620">147620</a>) levels in PINK1 or PRKN mutation carriers, possibly demonstrating a link between mtDNA integrity and inflammation. <a href="#44" class="mim-tip-reference" title="Trinh, J., Hicks, A. A., Konig, I. R., Delcambre, S., Luth, T., Schaake, S., Wasner, K., Ghelfi, J., Borsche, M., Vilarino-Guell, C., Hentati, F., Germer, E. L., and 15 others. <strong>Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson's disease.</strong> Brain 146: 2753-2765, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36478228/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36478228</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36478228[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/awac464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36478228">Trinh et al. (2023)</a> concluded that PINK1 and PRKN mutations contribute to somatic mtDNA heteroplasmy in a dose-dependent manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36478228" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#10" class="mim-tip-reference" title="Gautier, C. A., Kitada, T., Shen, J. <strong>Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress.</strong> Proc. Nat. Acad. Sci. 105: 11364-11369, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18687901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18687901</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18687901[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0802076105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18687901">Gautier et al. (2008)</a> found that germline deletion of the Pink1 gene in mice significantly impaired mitochondrial function. Although there were no significant changes in mitochondrial morphology, functional assays showed impaired mitochondrial respiration in the striatum, but not in the cerebral cortex, at 3 to 4 months of age. Aconitase (ACO2; <a href="/entry/100850">100850</a>) activity associated with the Krebs cycle was also reduced in the striatum of Pink1-null mice. However, mitochondrial respiration activities in the cerebral cortex were decreased at age 2 years, indicating that aging can exacerbate mitochondrial dysfunction in these mice. Furthermore, mitochondrial respiration defects could be induced in the cerebral cortex of Pink1-null mice by cellular stress, such as exposure to hydrogen peroxide or mild heat shock. The findings demonstrated that Pink1 is important for mitochondrial function and provides critical protection against both intrinsic and environmental stress, suggesting a pathogenic mechanism by which loss of PINK1 may lead to nigrostriatal degeneration in PD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18687901" 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="#42" class="mim-tip-reference" title="Sliter, D. A., Martinez, J., Hao, L., Chen, X., Sun, N., Fischer, T. D., Burman, J. L., Li, Y., Zhang, Z., Narendra, D. P., Cai, H., Borsche, M., Klein, C., Youle, R. J. <strong>Parkin and PINK1 mitigate STING-induced inflammation.</strong> Nature 561: 258-262, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30135585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30135585</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30135585[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/s41586-018-0448-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30135585">Sliter et al. (2018)</a> reported a strong inflammatory phenotype in both parkin (<a href="/entry/602544">602544</a>)-null and Pink1-null mice following exhaustive exercise, and in Prkn-null;mutator mice, which accumulate mutations in mitochondrial DNA (mtDNA). Inflammation resulting from either exhaustive exercise or mtDNA mutation was completely rescued by concurrent loss of Sting (<a href="/entry/612374">612374</a>), a central regulator of the type I interferon response to cytosolic DNA. The loss of dopaminergic neurons from the substantia nigra pars compacta and the motor defect observed in aged Prkn-null;mutator mice were also rescued by loss of Sting, suggesting that inflammation facilitates this phenotype. Humans with mono- and biallelic PRKN mutations also displayed elevated cytokines. <a href="#42" class="mim-tip-reference" title="Sliter, D. A., Martinez, J., Hao, L., Chen, X., Sun, N., Fischer, T. D., Burman, J. L., Li, Y., Zhang, Z., Narendra, D. P., Cai, H., Borsche, M., Klein, C., Youle, R. J. <strong>Parkin and PINK1 mitigate STING-induced inflammation.</strong> Nature 561: 258-262, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30135585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30135585</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30135585[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/s41586-018-0448-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30135585">Sliter et al. (2018)</a> concluded that their results supported a role for PINK1- and parkin-mediated mitophagy in restraining innate immunity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30135585" 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="#25" class="mim-tip-reference" title="Matheoud, D., Cannon, T., Voisin, A., Penttinen, A.-M., Ramet, L., Fahmy, A. M., Ducrot, C., Laplante, A., Bourque, M.-J., Zhu, L., Cayrol, R., Le Campion, A., McBride, H. M., Gruenheid, S., Trudeau, L.-E., Desjardins, M. <strong>Intestinal infection triggers Parkinson's disease-like symptoms in Pink1(-/-) mice.</strong> Nature 571: 565-569, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31316206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31316206</a>] [<a href="https://doi.org/10.1038/s41586-019-1405-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31316206">Matheoud et al. (2019)</a> demonstrated that intestinal infection with gram-negative bacteria in Pink1 -/- mice engages mitochondrial antigen presentation and autoimmune mechanisms that elicit the establishment of cytotoxic mitochondria-specific CD8+ T cells in the periphery and in the brain. Notably, these mice showed a sharp decrease in the density of dopaminergic axonal varicosities in the striatum and were affected by motor impairment that was reversed after treatment with L-DOPA. <a href="#25" class="mim-tip-reference" title="Matheoud, D., Cannon, T., Voisin, A., Penttinen, A.-M., Ramet, L., Fahmy, A. M., Ducrot, C., Laplante, A., Bourque, M.-J., Zhu, L., Cayrol, R., Le Campion, A., McBride, H. M., Gruenheid, S., Trudeau, L.-E., Desjardins, M. <strong>Intestinal infection triggers Parkinson's disease-like symptoms in Pink1(-/-) mice.</strong> Nature 571: 565-569, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31316206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31316206</a>] [<a href="https://doi.org/10.1038/s41586-019-1405-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31316206">Matheoud et al. (2019)</a> concluded that their data supported the idea that PINK1 is a repressor of the immune system, and provided a pathophysiologic model in which intestinal infection acts as a triggering event in Parkinson disease, which highlighted the relevance of the gut-brain axis in the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31316206" 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>Drosophila Models</em></strong></p><p>
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<a href="#31" class="mim-tip-reference" title="Park, J., Lee, S. B., Lee, S., Kim, Y., Song, S., Kim, S., Bae, E., Kim, J., Shong, M., Kim, J.-M., Chung, J. <strong>Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin.</strong> Nature 441: 1157-1161, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16672980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16672980</a>] [<a href="https://doi.org/10.1038/nature04788" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16672980">Park et al. (2006)</a> generated and characterized loss of function mutants of Drosophila Pink1. Pink1 mutants exhibited indirect flight muscle and dopaminergic neuronal degeneration accompanied by locomotive defects. Transmission electron microscopy analysis and a rescue experiment with Drosophila Bcl2 (<a href="/entry/151430">151430</a>) demonstrated that mitochondrial dysfunction accounted for the degenerative changes in all phenotypes of Pink1 mutants. <a href="#31" class="mim-tip-reference" title="Park, J., Lee, S. B., Lee, S., Kim, Y., Song, S., Kim, S., Bae, E., Kim, J., Shong, M., Kim, J.-M., Chung, J. <strong>Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin.</strong> Nature 441: 1157-1161, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16672980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16672980</a>] [<a href="https://doi.org/10.1038/nature04788" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16672980">Park et al. (2006)</a> also found that Pink1 mutants shared phenotypic similarities with parkin (<a href="/entry/602544">602544</a>) mutants. Transgenic expression of parkin ameliorated all Pink1 loss-of-function phenotypes, but not vice versa, suggesting that parkin functions downstream of PINK1. <a href="#31" class="mim-tip-reference" title="Park, J., Lee, S. B., Lee, S., Kim, Y., Song, S., Kim, S., Bae, E., Kim, J., Shong, M., Kim, J.-M., Chung, J. <strong>Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin.</strong> Nature 441: 1157-1161, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16672980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16672980</a>] [<a href="https://doi.org/10.1038/nature04788" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16672980">Park et al. (2006)</a> concluded that parkin and PINK1 act in a common pathway in maintaining mitochondrial integrity and function in both muscles and dopaminergic neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16672980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Clark, I. E., Dodson, M. W., Jiang, C., Cao, J. H., Huh, J. R., Seol, J. H., Yoo, S. J., Hay, B. A., Guo, M. <strong>Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin.</strong> Nature 441: 1162-1166, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16672981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16672981</a>] [<a href="https://doi.org/10.1038/nature04779" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16672981">Clark et al. (2006)</a> showed that removal of Drosophila Pink1 function resulted in male sterility, apoptotic muscle degeneration, defects in mitochondrial morphology, and increased sensitivity to multiple stresses, including oxidative stress. Pink1 localized to mitochondria, and mitochondrial cristae were fragmented in Pink1 mutants. Expression of human PINK1 in Drosophila testes restored male fertility and normal mitochondrial morphology in a portion of Pink1 mutants, demonstrating functional conservation between human and Drosophila PINK1. Loss of Drosophila parkin resulted in phenotypes similar to those caused by loss of Pink1 function. Overexpression of parkin rescued the male sterility and mitochondrial morphology defects of Pink1 mutants, whereas double mutants removing both Pink1 and parkin showed muscle phenotypes identical to those observed in either mutant alone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16672981" 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="#52" class="mim-tip-reference" title="Yang, Y., Gehrke, S., Imai, Y., Huang, Z., Ouyang, Y., Wang, J.-W., Yang, L., Beal, M. F., Vogel, H., Lu, B. <strong>Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by parkin.</strong> Proc. Nat. Acad. Sci. 103: 10793-10798, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16818890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16818890</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16818890[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0602493103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16818890">Yang et al. (2006)</a> found that inactivation of Pink1 in Drosophila using RNAi resulted in abnormal wing posture, energy depletion, selective muscle degeneration, and shortened life span. The muscle degeneration was preceded by mitochondrial enlargement and disintegration. In addition, inactivation of Pink1 resulted in the degeneration of dopaminergic neurons in the brain. The level of parkin was significantly reduced in Pink1 RNAi flies compared to controls, and overexpression of human parkin was able to rescue most of the defects caused by Pink1 inactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16818890" 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="#49" class="mim-tip-reference" title="Wang, D., Qian, L., Xiong, H., Liu, J., Neckameyer, W. S., Oldham, S., Xia, K., Wang, J., Bodmer, R., Zhang, Z. <strong>Antioxidants protect PINK1-dependent dopaminergic neurons in Drosophila.</strong> Proc. Nat. Acad. Sci. 103: 13520-13525, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16938835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16938835</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16938835[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0604661103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16938835">Wang et al. (2006)</a> found that inactivation of Drosophila Pink1 using RNA inhibition resulted in progressive loss of dopaminergic neurons and ommatidial degeneration of the compound eye. Treatment with the antioxidants SOD (<a href="/entry/147450">147450</a>) and vitamin E significantly inhibited ommatidial degeneration, suggesting that Pink1 plays a role in protecting neurons from oxidative stress. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16938835" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In Drosophila, <a href="#34" class="mim-tip-reference" title="Poole, A. C., Thomas, R. E., Andrews, L. A., McBride, H. M., Whitworth, A. J., Pallanck, L. J. <strong>The PINK1/Parkin pathway regulates mitochondrial morphology.</strong> Proc. Nat. Acad. Sci. 105: 1638-1643, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18230723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18230723</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18230723[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0709336105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18230723">Poole et al. (2008)</a> provided evidence that parkin acts downstream of Pink1 in a linear pathway. Overexpression of parkin rescued muscle defects of Pink1 mutants, but not vice versa. Heterozygous mutations in Drp1 (DNM1L; <a href="/entry/603850">603850</a>), a key component of mitochondrial fission, enhanced Pink1 and parkin mutant phenotypes and were largely lethal. In contrast, increased Drp1 gene dosage or mutations affecting the mitochondrial fusion-promoting components Opa1 (<a href="/entry/605290">605290</a>) and Mfn2 (<a href="/entry/608507">608507</a>) suppressed the Pink1 and parkin mutant phenotypes. The findings suggested that the Pink1/parkin pathway promotes mitochondrial fission and that loss of activity of either gene results in decreased fission and impaired tissue integrity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18230723" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=608309[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET</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">rs74315355 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315355;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=rs74315355" 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=rs74315355" 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 consanguineous Spanish family with Parkinson disease (PARK6; <a href="/entry/605909">605909</a>), <a href="#46" class="mim-tip-reference" title="Valente, E. M., Abou-Sleiman, P. M., Caputo, V., Muqit, M. M. K., Harvey, K., Gispert, S., Ali, Z., Del Turco, D., Bentivoglio, A. R., Healy, D. G., Albanese, A., Nussbaum, R., and 10 others. <strong>Hereditary early-onset Parkinson's disease caused by mutations in PINK1.</strong> Science 304: 1158-1160, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15087508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15087508</a>] [<a href="https://doi.org/10.1126/science.1096284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15087508">Valente et al. (2004)</a> identified a homozygous 11185G-A transition in exon 4 of the PINK1 gene, resulting in a gly309-to-asp (G309D) substitution at a highly conserved position in the putative kinase domain. In vitro functional studies in human neuroblastoma cells transfected with the mutant protein had decreased mitochondrial membrane potential under stress conditions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15087508" 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="#41" class="mim-tip-reference" title="Silvestri, L., Caputo, V., Bellacchio, E., Atorino, L., Dallapiccola, B., Valente, E. M., Casari, G. <strong>Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism.</strong> Hum. Molec. Genet. 14: 3477-3492, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16207731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16207731</a>] [<a href="https://doi.org/10.1093/hmg/ddi377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16207731">Silvestri et al. (2005)</a> showed that, following deletion of the C-terminal regulatory sequence, G309D-mutant protein had reduced autophosphorylation activity compared to wildtype. G309D PINK1 localized to the mitochondria, and immunogold experiments revealed that both wildtype and G309D PINK1 proteins faced the mitochondrial intermembrane space. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16207731" 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 in COS-7 cells, <a href="#50" class="mim-tip-reference" title="Weihofen, A., Ostaszewski, B., Minami, Y., Selkoe, D. J. <strong>Pink1 Parkinson mutations, the Cdc37/Hsp90 chaperones and parkin all influence the maturation or subcellular distribution of Pink1.</strong> Hum. Molec. Genet. 17: 602-616, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18003639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18003639</a>] [<a href="https://doi.org/10.1093/hmg/ddm334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18003639">Weihofen et al. (2008)</a> found that the G309D mutation resulted in decreased expression of both PINK1 isoforms and also to a decrease in the 66-kD/55-kD PINK1 isoform ratio. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18003639" 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> rs74315356 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315356;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/rs74315356?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=rs74315356" 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=rs74315356" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 consanguineous Italian families with Parkinson disease (PARK6; <a href="/entry/605909">605909</a>), <a href="#46" class="mim-tip-reference" title="Valente, E. M., Abou-Sleiman, P. M., Caputo, V., Muqit, M. M. K., Harvey, K., Gispert, S., Ali, Z., Del Turco, D., Bentivoglio, A. R., Healy, D. G., Albanese, A., Nussbaum, R., and 10 others. <strong>Hereditary early-onset Parkinson's disease caused by mutations in PINK1.</strong> Science 304: 1158-1160, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15087508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15087508</a>] [<a href="https://doi.org/10.1126/science.1096284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15087508">Valente et al. (2004)</a> identified the same homozygous G-to-A transition in exon 7 of the PINK1 gene, which resulted in a trp-to-stop substitution at codon 437 (W437X). The mutation truncated the last 145 amino acids encoding the C terminus of the kinase domain. These families shared a common haplotype, implying common ancestry. This mutation was not found in 400 control chromosomes, including 200 from Sicilian individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15087508" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Piccoli, C., Ripoli, M., Quarato, G., Scrima, R., D'Aprile, A., Boffoli, D., Margaglione, M., Criscuolo, C., De Michele, G., Sardanelli, A., Papa, S., Capitanio, N. <strong>Coexistence of mutations in PINK1 and mitochondrial DNA in early onset parkinsonism. (Letter)</strong> J. Med. Genet. 45: 596-602, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18524835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18524835</a>] [<a href="https://doi.org/10.1136/jmg.2008.058628" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18524835">Piccoli et al. (2008)</a> reported a family with early-onset Parkinson disease associated with a W437X mutation. The proband, who had very early onset at age 22 years, was homozygous for the mutation, whereas both his parents were heterozygous. The father was unaffected at age 79, and the mother developed Parkinson disease at age 53. Biochemical studies of the proband's fibroblasts showed mitochondrial dysfunction, with decreased amounts of cytochrome c oxidase, impaired complex I activity, and increased hydrogen peroxide generation. Further analysis identified 2 mutations in mitochondrial genes: MTND5 (<a href="/entry/516005#0010">516005.0010</a>) and MTND6 (<a href="/entry/516006#0008">516006.0008</a>). Both the proband and his mother were homoplasmic for both mitochondrial mutations. <a href="#33" class="mim-tip-reference" title="Piccoli, C., Ripoli, M., Quarato, G., Scrima, R., D'Aprile, A., Boffoli, D., Margaglione, M., Criscuolo, C., De Michele, G., Sardanelli, A., Papa, S., Capitanio, N. <strong>Coexistence of mutations in PINK1 and mitochondrial DNA in early onset parkinsonism. (Letter)</strong> J. Med. Genet. 45: 596-602, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18524835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18524835</a>] [<a href="https://doi.org/10.1136/jmg.2008.058628" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18524835">Piccoli et al. (2008)</a> concluded that the presence of the mitochondrial mutations in combination with the PINK1 mutation may have accelerated the onset of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18524835" 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="#41" class="mim-tip-reference" title="Silvestri, L., Caputo, V., Bellacchio, E., Atorino, L., Dallapiccola, B., Valente, E. M., Casari, G. <strong>Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism.</strong> Hum. Molec. Genet. 14: 3477-3492, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16207731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16207731</a>] [<a href="https://doi.org/10.1093/hmg/ddi377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16207731">Silvestri et al. (2005)</a> showed that W437X-mutant protein had greater efficiency of autophosphorylation activity compared to wildtype. W437X PINK1 localized to the mitochondria, and immunogold experiments revealed that both wildtype and W437X PINK1 proteins faced the mitochondrial intermembrane space. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16207731" 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>.0003 PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315357 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315357;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/rs74315357?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=rs74315357" 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=rs74315357" 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=RCV000002508" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002508" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002508</a>
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<p>In affected members of 2 consanguineous families, 1 Japanese and 1 Israeli, with Parkinson disease (PARK6; <a href="/entry/605909">605909</a>), <a href="#15" class="mim-tip-reference" title="Hatano, Y., Li, Y., Sato, K., Asakawa, S., Yamamura, Y., Tomiyama, H., Yoshino, H., Asahina, M., Kobayashi, S., Hassin-Baer, S., Lu, C.-S., Ng, A. R., Rosales, R. L., Shimizu, N., Toda, T., Mizuno, Y., Hattori, N. <strong>Novel PINK1 mutations in early-onset parkinsonism.</strong> Ann. Neurol. 56: 424-427, 2004. Note: Erratum: Ann. Neurol. 56: 603 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15349870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15349870</a>] [<a href="https://doi.org/10.1002/ana.20251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15349870">Hatano et al. (2004)</a> identified a homozygous 736C-T transition in exon 3 of the PINK1 gene, resulting in an arg246-to-ter (R246X) substitution. The mutation was predicted to result in a truncated protein lacking 336 amino acids, including a highly conserved protein kinase domain. Two affected Israeli patients showed psychiatric disturbances at the onset of the disease. One unaffected Israeli family member was heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15349870" 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>.0004 PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET</strong>
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PINK1, HIS271GLN
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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> rs28940284 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940284;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/rs28940284?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=rs28940284" 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=rs28940284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002506" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002506" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002506</a>
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<p>In a Japanese patient with Parkinson disease (PARK6; <a href="/entry/605909">605909</a>) with onset at age 23 years, <a href="#15" class="mim-tip-reference" title="Hatano, Y., Li, Y., Sato, K., Asakawa, S., Yamamura, Y., Tomiyama, H., Yoshino, H., Asahina, M., Kobayashi, S., Hassin-Baer, S., Lu, C.-S., Ng, A. R., Rosales, R. L., Shimizu, N., Toda, T., Mizuno, Y., Hattori, N. <strong>Novel PINK1 mutations in early-onset parkinsonism.</strong> Ann. Neurol. 56: 424-427, 2004. Note: Erratum: Ann. Neurol. 56: 603 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15349870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15349870</a>] [<a href="https://doi.org/10.1002/ana.20251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15349870">Hatano et al. (2004)</a> identified a homozygous 813C-A transversion in exon 4 of the PINK1 gene, resulting in a his271-to-gln (H271Q) substitution. The patient's parents were consanguineous. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15349870" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0005" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0005 PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET</strong>
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PINK1, LEU347PRO
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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> rs28940285 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940285;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/rs28940285?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=rs28940285" 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=rs28940285" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002509 OR RCV002223750" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002509, RCV002223750" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002509...</a>
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<p>In 3 affected members of a Filipino family with Parkinson disease (PARK6; <a href="/entry/605909">605909</a>), <a href="#15" class="mim-tip-reference" title="Hatano, Y., Li, Y., Sato, K., Asakawa, S., Yamamura, Y., Tomiyama, H., Yoshino, H., Asahina, M., Kobayashi, S., Hassin-Baer, S., Lu, C.-S., Ng, A. R., Rosales, R. L., Shimizu, N., Toda, T., Mizuno, Y., Hattori, N. <strong>Novel PINK1 mutations in early-onset parkinsonism.</strong> Ann. Neurol. 56: 424-427, 2004. Note: Erratum: Ann. Neurol. 56: 603 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15349870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15349870</a>] [<a href="https://doi.org/10.1002/ana.20251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15349870">Hatano et al. (2004)</a> identified a homozygous 1040T-C transition in exon 5 of the PINK1 gene, resulting in a leu347-to-pro (L347P) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15349870" 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="#36" class="mim-tip-reference" title="Rogaeva, E., Johnson, J., Lang, A. E., Gulick, C., Gwinn-Hardy, K., Kawarai, T., Sato, C., Morgan, A., Werner, J., Nussbaum, R., Petit, A., Okun, M. S., and 13 others. <strong>Analysis of the PINK1 gene in a large cohort of cases with Parkinson disease.</strong> Arch. Neurol. 61: 1898-1904, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15596610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15596610</a>] [<a href="https://doi.org/10.1001/archneur.61.12.1898" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15596610">Rogaeva et al. (2004)</a> identified the homozygous L347P mutation in 1 of 289 North American patients with either early- or late-onset PD. The patient was Filipino, had disease onset in the fourth decade of life, and reportedly had 2 affected sibs. The authors noted that the L347P mutation occurs in a conserved residue within the kinase domain of the protein. Three of 50 Filipino control individuals were heterozygous for the L347P mutation, suggesting an allelic frequency of 3% in this population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15596610" 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 mammalian cells, <a href="#2" class="mim-tip-reference" title="Beilina, A., Van Der Brug, M., Ahmad, R., Kesavapany, S., Miller, D. W., Petsko, G. A., Cookson, M. R. <strong>Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability.</strong> Proc. Nat. Acad. Sci. 102: 5703-5708, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15824318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15824318</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15824318[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0500617102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15824318">Beilina et al. (2005)</a> found that the L347P mutation resulted in significantly decreased protein stability and in a drastic reduction of kinase activity. The mutation was predicted to occur in a helical segment that forms part of the cyclin binding surface. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15824318" 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>.0006 PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET</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">rs730880302 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs730880302;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=rs730880302" 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=rs730880302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002510" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002510" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002510</a>
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<p>In an Italian patient with Parkinson disease (PARK6; <a href="/entry/605909">605909</a>), <a href="#37" class="mim-tip-reference" title="Rohe, C. F., Montagna, P., Breedveld, G., Cortelli, P., Oostra, B. A., Bonifati, V. <strong>Homozygous PINK1 C-terminus mutation causing early-onset parkinsonism.</strong> Ann. Neurol. 56: 427-431, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15349871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15349871</a>] [<a href="https://doi.org/10.1002/ana.20247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15349871">Rohe et al. (2004)</a> identified a homozygous 4-bp insertion (1573insTTAG) in exon 8 of the PINK1 gene, resulting in a frameshift and truncation of the last 20 C-terminal amino acids of the protein. Both parents were heterozygous for the insertion. <a href="#37" class="mim-tip-reference" title="Rohe, C. F., Montagna, P., Breedveld, G., Cortelli, P., Oostra, B. A., Bonifati, V. <strong>Homozygous PINK1 C-terminus mutation causing early-onset parkinsonism.</strong> Ann. Neurol. 56: 427-431, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15349871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15349871</a>] [<a href="https://doi.org/10.1002/ana.20247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15349871">Rohe et al. (2004)</a> noted that the mutation occurs outside of the known functional protein kinase domain of PINK1. The patient had psychiatric symptoms, including anxiety and depression, both of which were present in the mother. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15349871" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET</strong>
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PINK1, 3-BP INS, 1602CAA
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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> rs750664040 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs750664040;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/rs750664040?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=rs750664040" 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=rs750664040" 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=RCV000002511" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002511" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002511</a>
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<p>In 2 of 65 unrelated Italian patients with early-onset parkinsonism, <a href="#19" class="mim-tip-reference" title="Klein, C., Djarmati, A., Hedrich, K., Schafer, N., Scaglione, C., Marchese, R., Kock, N., Schule, B., Hiller, A., Lohnau, T., Winkler, S., Wiegers, K., Hering, R., Bauer, P., Riess, O., Abbruzzese, G., Martinelli, P., Pramstaller, P. P. <strong>PINK1, parkin, and DJ-1 mutations in Italian patients with early-onset parkinsonism.</strong> Europ. J. Hum. Genet. 13: 1086-1093, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15970950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15970950</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201455" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15970950">Klein et al. (2005)</a> identified a 3-bp insertion (1602insCAA) in exon 8 of the PINK1 gene, consistent with PARK6 (<a href="/entry/605909">605909</a>). The insertion resulted in the incorporation of an extra glutamine residue (glu534) after 2 glutamines, very close to the C terminus of the protein. One patient was heterozygous for the mutation and the other was homozygous. The patient who was heterozygous had earlier age at onset (25 vs 32 years). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15970950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 PARKINSON DISEASE 6, EARLY-ONSET</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315358 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315358;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/rs74315358?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=rs74315358" 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=rs74315358" 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=RCV000002512 OR RCV002292454" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002512, RCV002292454" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002512...</a>
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<p>In 1 of 65 unrelated Italian patients with early-onset parkinsonism, <a href="#19" class="mim-tip-reference" title="Klein, C., Djarmati, A., Hedrich, K., Schafer, N., Scaglione, C., Marchese, R., Kock, N., Schule, B., Hiller, A., Lohnau, T., Winkler, S., Wiegers, K., Hering, R., Bauer, P., Riess, O., Abbruzzese, G., Martinelli, P., Pramstaller, P. P. <strong>PINK1, parkin, and DJ-1 mutations in Italian patients with early-onset parkinsonism.</strong> Europ. J. Hum. Genet. 13: 1086-1093, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15970950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15970950</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201455" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15970950">Klein et al. (2005)</a> identified a heterozygous 836G-A transition in exon 4 of the PINK1 gene, resulting in an arg279-to-his (R279H) substitution in the functional ser/thr protein kinase domain of the protein. The findings were consistent with PARK6 (<a href="/entry/605909">605909</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15970950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Choi, J. M., Woo, M. S., Ma, H.-I., Kang, S. Y., Sung, Y.-H., Yong, S. W., Chung, S. J., Kim, J.-S., Shin, H., Lyoo, C. H., Lee, P. H., Baik, J. S., and 9 others. <strong>Analysis of PARK genes in a Korean cohort of early-onset Parkinson disease.</strong> Neurogenetics 9: 263-269, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18704525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18704525</a>] [<a href="https://doi.org/10.1007/s10048-008-0138-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18704525">Choi et al. (2008)</a> identified a heterozygous R279H mutation in 1 of 72 unrelated Korean patients with onset of PD before age 50. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18704525" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0009" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0009 PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET</strong>
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</span>
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</h4>
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PINK1, EX6-8DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002513" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002513" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002513</a>
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<p>In a Japanese patient with early-onset parkinsonism (PARK6; <a href="/entry/605909">605909</a>), <a href="#24" class="mim-tip-reference" title="Li, Y., Tomiyama, H., Sato, K., Hatano, Y., Yoshino, H., Atsumi, M., Kitaguchi, M., Sasaki, S., Kawaguchi, S., Miyajima, H., Toda, T., Mizuno, Y., Hattori, N. <strong>Clinicogenetic study of PINK1 mutations in autosomal recessive early-onset parkinsonism.</strong> Neurology 64: 1955-1957, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15955953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15955953</a>] [<a href="https://doi.org/10.1212/01.WNL.0000164009.36740.4E" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15955953">Li et al. (2005)</a> identified a homozygous deletion of exons 6 through 8 of the PINK1 gene. In addition to parkinsonism, the patient also had depression, hallucinations, and dementia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15955953" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0010" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0010 PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET</strong>
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PINK1, THR313MET
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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> rs74315359 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315359;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/rs74315359?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=rs74315359" 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=rs74315359" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002514" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002514" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002514</a>
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<p>In 2 affected members of a large consanguineous Saudi Arabian family with early-onset parkinsonism (PARK6; <a href="/entry/605909">605909</a>), <a href="#5" class="mim-tip-reference" title="Chishti, M. A., Bohlega, S., Ahmed, M., Loualich, A., Carroll, P., Sato, C., St. George-Hyslop, P., Westaway, D., Rogaeva, E. <strong>T313M PINK1 mutation in an extended highly consanguineous Saudi family with early-onset Parkinson disease.</strong> Arch. Neurol. 63: 1483-1485, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17030667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17030667</a>] [<a href="https://doi.org/10.1001/archneur.63.10.1483" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17030667">Chishti et al. (2006)</a> identified a homozygous 1032C-T transition in exon 4 of the PINK1 gene, resulting in a thr313-to-met (T313M) substitution in the kinase domain. The 2 patients had onset at age 34 and 30 years, respectively, and had no cognitive impairment or major axial symptoms. Two additional family members were reportedly similarly affected. Study of 13 carriers of the T313M mutation found no neurologic abnormalities, suggesting that heterozygosity for the mutation does not act as a susceptibility factor for development of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17030667" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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<strong>.0011 PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET</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">rs74315360 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315360;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=rs74315360" 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=rs74315360" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002515" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002515" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002515</a>
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<p>In 5 affected members of a large consanguineous Sudanese family with early-onset parkinsonism (PARK6; <a href="/entry/605909">605909</a>), <a href="#23" class="mim-tip-reference" title="Leutenegger, A.-L., Salih, M. A. M., Ibanez, P., Mukhtar, M. M., Lesage, S., Arabi, A., Lohmann, E., Durr, A., Ahmed, A. E. M., Brice, A. <strong>Juvenile-onset parkinsonism as a result of the first mutation in the adenosine triphosphate orientation domain of PINK1.</strong> Arch. Neurol. 63: 1257-1261, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16966503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16966503</a>] [<a href="https://doi.org/10.1001/archneur.63.9.1257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16966503">Leutenegger et al. (2006)</a> identified a homozygous 650C-A transversion in exon 2 of the PINK1 gene, resulting in an ala217-to-asp (A217D) substitution in the highly conserved LAIK amino acid sequence corresponding to the ATP orientation domain. Age at disease onset was very early, between 9 and 14 years of age. Two patients had dystonia, and all had diurnal fluctuations; none had other atypical neurologic signs. None of the heterozygous carriers had signs of parkinsonism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16966503" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0012" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0012 PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET</strong>
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PINK1, GLN456TER
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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> rs45539432 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs45539432;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/rs45539432?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=rs45539432" 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=rs45539432" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002516 OR RCV000627238 OR RCV004739278" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002516, RCV000627238, RCV004739278" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002516...</a>
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<p>In 4 affected sibs of a large German family with early-onset parkinsonism (PARK6; <a href="/entry/605909">605909</a>), <a href="#17" class="mim-tip-reference" title="Hedrich, K., Hagenah, J., Djarmati, A., Hiller, A., Lohnau, T., Lasek, K., Grunewald, A., Hilker, R., Steinlechner, S., Boston, H., Kock, N., Schneider-Gold, C., Kress, W., Siebner, H., Binkofski, F., Lencer, R., Munchau, A., Klein, C. <strong>Clinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit?</strong> Arch. Neurol. 63: 833-838, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16769864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16769864</a>] [<a href="https://doi.org/10.1001/archneur.63.6.833" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16769864">Hedrich et al. (2006)</a> identified a homozygous 1366C-T transition in exon 7 of the PINK1 gene, resulting in a gln456-to-ter (Q456X) substitution. Six heterozygous offspring of the homozygous patients were found to have subtle signs of disease, and 5 heterozygous offspring were considered to be unaffected. The 6 affected heterozygous offspring were not aware of their signs, but clinical examination showed unilaterally reduced or absent arm swing and rigidity. <a href="#17" class="mim-tip-reference" title="Hedrich, K., Hagenah, J., Djarmati, A., Hiller, A., Lohnau, T., Lasek, K., Grunewald, A., Hilker, R., Steinlechner, S., Boston, H., Kock, N., Schneider-Gold, C., Kress, W., Siebner, H., Binkofski, F., Lencer, R., Munchau, A., Klein, C. <strong>Clinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit?</strong> Arch. Neurol. 63: 833-838, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16769864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16769864</a>] [<a href="https://doi.org/10.1001/archneur.63.6.833" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16769864">Hedrich et al. (2006)</a> concluded that heterozygous PINK1 mutations confer susceptibility to the development of PD. Of clinical note, parkinsonian signs were more marked on the dominant right-hand side in all mutation carriers, and 10 of 15 mutation carriers had psychiatric disturbances. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16769864" 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="#18" class="mim-tip-reference" title="Ishihara-Paul, L., Hulihan, M. M., Kachergus, J., Upmanyu, R., Warren, L., Amouri, R., Elango, R., Prinjha, R. K., Soto, A., Kefi, M., Zouari, M., Sassi, S. B., Yahmed, S. B., El Euch-Fayeche, G., Matthews, P. M., Middleton, L. T., Gibson, R. A., Hentati, F., Farrer, M. J. <strong>PINK1 mutations and parkinsonism.</strong> Neurology 71: 896-902, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18685134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18685134</a>] [<a href="https://doi.org/10.1212/01.wnl.0000323812.40708.1f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18685134">Ishihara-Paul et al. (2008)</a> identified homozygosity for the Q456X mutation in 7 (7.8%) of 92 Tunisian families with Parkinson disease and in 5 (2.1%) of 240 patients with no family history of PD. There was no evidence that heterozygosity for the mutation contributed to development of PD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18685134" 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 PARKINSON DISEASE 6, LATE-ONSET, SUSCEPTIBILITY TO</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">rs74315361 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315361;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=rs74315361" 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=rs74315361" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an 80-year-old sporadic patient with relatively late onset of parkinsonism (PARK6; <a href="/entry/605909">605909</a>) at age 59 years, <a href="#1" class="mim-tip-reference" title="Abou-Sleiman, P. M., Muqit, M. M. K., McDonald, N. Q., Yang, Y. X., Gandhi, S., Healy, D. G., Harvey, K., Harvey, R. J., Deas, E., Bhatia, K., Quinn, N., Lees, A., Latchman, D. S., Wood, N. W. <strong>A heterozygous effect for PINK1 mutations in Parkinson's disease?</strong> Ann. Neurol. 60: 414-419, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16969854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16969854</a>] [<a href="https://doi.org/10.1002/ana.20960" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16969854">Abou-Sleiman et al. (2006)</a> identified a heterozygous mutation in the PINK1 gene, resulting in a tyr431-to-his (Y431H) substitution. The patient showed tremor, bradykinesia, rigidity, mild anxiety and depression, and excellent response to L-DOPA treatment. In vitro functional studies in human neuroblastoma cells transfected with the mutant protein showed decreased mitochondrial membrane potential under stress conditions. <a href="#1" class="mim-tip-reference" title="Abou-Sleiman, P. M., Muqit, M. M. K., McDonald, N. Q., Yang, Y. X., Gandhi, S., Healy, D. G., Harvey, K., Harvey, R. J., Deas, E., Bhatia, K., Quinn, N., Lees, A., Latchman, D. S., Wood, N. W. <strong>A heterozygous effect for PINK1 mutations in Parkinson's disease?</strong> Ann. Neurol. 60: 414-419, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16969854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16969854</a>] [<a href="https://doi.org/10.1002/ana.20960" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16969854">Abou-Sleiman et al. (2006)</a> concluded that heterozygous mutations in the PINK1 gene may contribute to increased risk for late-onset PD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16969854" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 PARKINSON DISEASE, AUTOSOMAL RECESSIVE EARLY-ONSET, DIGENIC, PINK1/DJ1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs119451946 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119451946;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/rs119451946?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=rs119451946" 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=rs119451946" 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=RCV000002518 OR RCV000372794" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002518, RCV000372794" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002518...</a>
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<p>In 2 Chinese sibs with early-onset Parkinson disease (see <a href="/entry/605909">605909</a>), <a href="#43" class="mim-tip-reference" title="Tang, B., Xiong, H., Sun, P., Zhang, Y., Wang, D., Hu, Z., Zhu, Z., Ma, H., Pan, Q., Xia, J., Xia, K., Zhang, Z. <strong>Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease.</strong> Hum. Molec. Genet. 15: 1816-1825, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16632486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16632486</a>] [<a href="https://doi.org/10.1093/hmg/ddl104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16632486">Tang et al. (2006)</a> identified compound heterozygosity for 2 mutations in 2 different genes: a 1196C-T transition in exon 6 of the PINK1 gene resulting in a pro399-to-leu (P399L) substitution in the predicted kinase domain, and an A39S mutation (<a href="/entry/602533#0007">602533.0007</a>) in the DJ1 gene. The DJ1 and PINK1 mutations were not observed in 240 and 568 control chromosomes, respectively, and both were located in highly conserved residues. The findings were consistent with digenic inheritance of Parkinson disease. A 42-year-old unaffected family member also carried both mutations, suggesting incomplete penetrance. Coimmunoprecipitation studies showed that both wildtype and mutant PINK1 interacted with both wildtype and mutant DJ1. Expression of wildtype DJ1 increased steady-state levels of both mutant and wildtype PINK1, but mutant DJ1 decreased steady-state levels of both mutant and wildtype PINK1, suggesting that wildtype DJ1 can enhance PINK1 stability. Human neuroblastoma cells expressing either mutant PINK1 or DJ1 showed reduced viability following oxidative challenge with MPP compared to control cells, indicating that both proteins protect against cell stress. Coexpression of both wildtype proteins resulted in a synergistic increase in cell viability against MPP-induced stress. In addition, coexpression of both mutant proteins significantly increased susceptibility of cells to death, compared to either mutant alone. These findings indicated that DJ1 and PINK1 function collaboratively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16632486" 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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Abou-Sleiman, P. M., Muqit, M. M. K., McDonald, N. Q., Yang, Y. X., Gandhi, S., Healy, D. G., Harvey, K., Harvey, R. J., Deas, E., Bhatia, K., Quinn, N., Lees, A., Latchman, D. S., Wood, N. W.
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<strong>A heterozygous effect for PINK1 mutations in Parkinson's disease?</strong>
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Ann. Neurol. 60: 414-419, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16969854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16969854</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16969854" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.20960" target="_blank">Full Text</a>]
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Beilina, A., Van Der Brug, M., Ahmad, R., Kesavapany, S., Miller, D. W., Petsko, G. A., Cookson, M. R.
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<strong>Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability.</strong>
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Proc. Nat. Acad. Sci. 102: 5703-5708, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15824318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15824318</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15824318[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=15824318" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0500617102" target="_blank">Full Text</a>]
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Bingol, B., Tea, J. S., Phu, L., Reichelt, M., Bakalarski, C. E., Song, Q., Foreman, O., Kirkpatrick, D. S., Sheng, M.
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<strong>The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy.</strong>
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Nature 510: 370-375, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24896179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24896179</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24896179" 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/nature13418" target="_blank">Full Text</a>]
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Chen, Y., Dorn, G. W., II.
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<strong>PINK1-phosphorylated mitofusin 2 is a parkin receptor for culling damaged mitochondria.</strong>
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Science 340: 471-475, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23620051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23620051</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23620051[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=23620051" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1231031" target="_blank">Full Text</a>]
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Chishti, M. A., Bohlega, S., Ahmed, M., Loualich, A., Carroll, P., Sato, C., St. George-Hyslop, P., Westaway, D., Rogaeva, E.
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<strong>T313M PINK1 mutation in an extended highly consanguineous Saudi family with early-onset Parkinson disease.</strong>
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Arch. Neurol. 63: 1483-1485, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17030667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17030667</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17030667" 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/10.1001/archneur.63.10.1483" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10048-008-0138-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneurol.2011.95" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature04779" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.molcel.2009.02.013" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0802076105" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ncb2012" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/s41586-018-0224-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000142089.38301.8e" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.63.6.833" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.20247" target="_blank">Full Text</a>]
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<a id="53" class="mim-anchor"></a>
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<a id="Zhou2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhou, C., Huang, Y., Shao, Y., May, J., Prou, D., Perier, C., Dauer, W., Schon, E. A., Przedborski, S.
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<strong>The kinase domain of mitochondrial PINK1 faces the cytoplasm.</strong>
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Proc. Nat. Acad. Sci. 105: 12022-12027, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18687899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18687899</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18687899[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=18687899" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0802814105" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 01/25/2024
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Ada Hamosh - updated : 03/26/2020<br>Ada Hamosh - updated : 10/09/2019<br>Ada Hamosh - updated : 10/08/2019<br>Ada Hamosh - updated : 09/18/2018<br>Ada Hamosh - updated : 03/14/2018<br>Cassandra L. Kniffin - updated : 11/18/2015<br>Ada Hamosh - updated : 9/11/2015<br>Ada Hamosh - updated : 7/17/2014<br>Ada Hamosh - updated : 7/15/2014<br>Ada Hamosh - updated : 5/6/2014<br>Ada Hamosh - updated : 1/13/2014<br>George E. Tiller - updated : 9/4/2013<br>Ada Hamosh - updated : 5/29/2013<br>Cassandra L. Kniffin - updated : 5/15/2013<br>Ada Hamosh - updated : 6/21/2012<br>George E. Tiller - updated : 12/29/2010<br>Cassandra L. Kniffin - updated : 4/5/2010<br>Cassandra L. Kniffin - updated : 3/1/2010<br>Cassandra L. Kniffin - updated : 10/15/2009<br>Cassandra L. Kniffin - updated : 10/14/2009<br>George E. Tiller - updated : 9/3/2009<br>Patricia A. Hartz - updated : 8/5/2009<br>Cassandra L. Kniffin - updated : 5/29/2009<br>Cassandra L. Kniffin - updated : 4/6/2009<br>Cassandra L. Kniffin - updated : 1/14/2009<br>Cassandra L. Kniffin - updated : 10/28/2008<br>Cassandra L. Kniffin - updated : 10/6/2008<br>Cassandra L. Kniffin - updated : 2/20/2008<br>Cassandra L. Kniffin - updated : 11/8/2007<br>Cassandra L. Kniffin - updated : 2/19/2007<br>Cassandra L. Kniffin - updated : 11/3/2006<br>Cassandra L. Kniffin - updated : 9/19/2006<br>Cassandra L. Kniffin - updated : 8/23/2006<br>Ada Hamosh - updated : 7/10/2006<br>Cassandra L. Kniffin - updated : 11/7/2005<br>Cassandra L. Kniffin - updated : 9/20/2005<br>Cassandra L. Kniffin - updated : 3/11/2005<br>Cassandra L. Kniffin - updated : 11/30/2004<br>Ada Hamosh - updated : 6/9/2004
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Carol A. Bocchini : 12/2/2003
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 01/25/2024
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<div class="row collapse" id="mimCollapseEditHistory">
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carol : 02/01/2021<br>carol : 08/12/2020<br>alopez : 03/26/2020<br>alopez : 10/09/2019<br>alopez : 10/08/2019<br>alopez : 09/18/2018<br>carol : 03/15/2018<br>alopez : 03/14/2018<br>carol : 11/23/2015<br>ckniffin : 11/18/2015<br>alopez : 9/11/2015<br>alopez : 4/21/2015<br>mcolton : 2/10/2015<br>alopez : 7/17/2014<br>alopez : 7/15/2014<br>alopez : 5/6/2014<br>mcolton : 2/24/2014<br>mgross : 1/22/2014<br>alopez : 1/13/2014<br>alopez : 9/10/2013<br>tpirozzi : 9/4/2013<br>tpirozzi : 9/3/2013<br>alopez : 5/29/2013<br>carol : 5/20/2013<br>ckniffin : 5/15/2013<br>alopez : 6/28/2012<br>terry : 6/21/2012<br>wwang : 1/12/2011<br>terry : 12/29/2010<br>wwang : 4/12/2010<br>ckniffin : 4/5/2010<br>ckniffin : 3/1/2010<br>wwang : 10/27/2009<br>ckniffin : 10/15/2009<br>ckniffin : 10/14/2009<br>wwang : 9/17/2009<br>terry : 9/3/2009<br>mgross : 8/13/2009<br>terry : 8/5/2009<br>wwang : 6/4/2009<br>ckniffin : 5/29/2009<br>wwang : 4/13/2009<br>ckniffin : 4/6/2009<br>wwang : 1/16/2009<br>ckniffin : 1/14/2009<br>wwang : 11/7/2008<br>ckniffin : 10/28/2008<br>wwang : 10/7/2008<br>ckniffin : 10/6/2008<br>wwang : 3/6/2008<br>ckniffin : 2/20/2008<br>wwang : 11/26/2007<br>ckniffin : 11/8/2007<br>wwang : 6/6/2007<br>wwang : 2/22/2007<br>ckniffin : 2/19/2007<br>carol : 1/31/2007<br>wwang : 11/9/2006<br>ckniffin : 11/3/2006<br>wwang : 10/10/2006<br>ckniffin : 9/19/2006<br>wwang : 8/29/2006<br>ckniffin : 8/23/2006<br>alopez : 7/18/2006<br>terry : 7/10/2006<br>ckniffin : 11/7/2005<br>carol : 10/5/2005<br>wwang : 10/4/2005<br>ckniffin : 9/20/2005<br>wwang : 3/21/2005<br>wwang : 3/17/2005<br>ckniffin : 3/11/2005<br>ckniffin : 3/11/2005<br>tkritzer : 12/6/2004<br>ckniffin : 11/30/2004<br>alopez : 6/10/2004<br>terry : 6/9/2004<br>tkritzer : 12/3/2003<br>carol : 12/2/2003
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<span class="mim-font">
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<strong>*</strong> 608309
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<h3>
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<span class="mim-font">
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PTEN-INDUCED KINASE 1; PINK1
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<em>Alternative titles; symbols</em>
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<span class="mim-font">
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PTEN-INDUCED PUTATIVE KINASE 1; PINK1
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: PINK1</em></strong>
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<strong>
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<em>
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Cytogenetic location: 1p36.12
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:20,633,458-20,651,511 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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1p36.12
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<span class="mim-font">
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Parkinson disease 6, early onset
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<span class="mim-font">
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605909
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<span class="mim-font">
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Autosomal recessive
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<td>
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<span class="mim-font">
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<strong>Description</strong>
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</div>
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<span class="mim-text-font">
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<p>The PINK1 gene encodes a mitochondrially located serine/threonine kinase (Poole et al., 2008). </p>
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</span>
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<div>
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<br />
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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<p>Matsushima-Nishiu et al. (2001) analyzed expression profiles of cancer cells after the introduction of exogenous PTEN (601728), a tumor suppressor, and found that an EST, later identified as PINK1 by Unoki and Nakamura (2001), was transcriptionally transactivated. Unoki and Nakamura (2001) used 5-prime RACE to clone a full-length PINK1 cDNA and found that it encodes a deduced 581-amino acid protein with a predicted molecular mass of 62.8 kD and a putative serine/threonine protein kinase catalytic domain. The protein shares 43% and 31% sequence identity with Drosophila CG4523 and C. elegans EEED8.9, respectively. Northern blot analysis detected ubiquitous expression of a 2.7-kb transcript, with highest expression in heart, skeletal muscle, and testis. RT-PCR analysis showed that expression of PINK1 was decreased in ovarian tumors compared with corresponding normal tissues. </p><p>Valente et al. (2004) determined that the PINK1 gene encodes a 581-amino acid protein. The ubiquitously expressed transcript was predicted to encode a 34-amino acid mitochondrial targeting motif and a highly conserved protein kinase domain from residues 156 to 509 that shows a high degree of homology to the serine/threonine kinases of the calcium/calmodulin family. </p><p>Two major PINK1 isoforms with apparent molecular mass of 66 kD and 55 kD, have been detected in human brain extracts and during cellular PINK1 overexpression. Both isoforms localize to the inner and outer mitochondrial membrane fractions. The 55-kD isoform appears to represent a mature form derived from the 66-kD isoform upon removal of the leader sequence (Beilina et al., 2005). In cultured COS-7 and HEK293 cells, Weihofen et al. (2008) found an abundance of the immature 66-kD precursor compared to the 55-kD mature isoform, and suggested that the ratio of these isoforms may be important. </p><p>Silvestri et al. (2005) characterized the different subdomains within the kinase domain of PINK1. Subdomains I to IV represent the N-terminal lobe that is involved in anchoring and orienting the ATP molecule, whereas subdomains VIa to XI represent the C-terminal lobe in charge of the binding of the peptide substrate and of phospho-transfer. They showed that PINK1 localized to mitochondria and that the N-terminal portion of PINK1 is sufficient for mitochondrial localization. Immunogold microscopy demonstrated that PINK1 faced the mitochondrial intermembrane space. Autophosphorylation assay with wildtype PINK1 and deletion constructs involving C-terminal residues 496 to 581 showed that the C-terminal sequence has a negative regulatory role on autophosphorylation. </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>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>Valente et al. (2004) showed that PINK1 contains 8 exons spanning about 1.8 kb. </p>
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<div>
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<br />
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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<span class="mim-text-font">
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<p><strong><em>Crystal Structure</em></strong></p><p>
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Schubert et al. (2017) reported a crystal structure at 3.1-angstrom resolution of a nanobody-stabilized complex containing Pediculus humanus corporis (Ph)PINK1 bound to ubiquitin in the C-terminally retracted (Ub-CR) conformation. The structure revealed many peculiarities of PINK1, including the architecture of the C-terminal region, and revealed how the N lobe of PINK1 binds ubiquitin via a unique insertion. The flexible ser65 loop in the Ub-CR conformation contacts the activation segment, facilitating placement of ser65 in a phosphate-accepting position. The structure also explained how autophosphorylation in the N lobe stabilizes structurally and functionally important insertions, and revealed the molecular basis of mutations that cause autosomal recessive juvenile Parkinson disease, some of which disrupt ubiquitin binding. </p><p>To elucidate how phosphorylation of parkin (PARK2; 602544) by PINK1 activates the molecule, Gladkova et al. (2018) followed the activation of full-length human parkin by hydrogen-deuterium exchange mass spectrometry, which revealed large-scale domain rearrangement in the activation process, during which the phospho-ubiquitin-like (Ubl) domain rebinds to the parkin core and releases the catalytic RING2 domain. A 1.8-angstrom crystal structure of phosphorylated human parkin revealed the binding site of the phospho-Ubl on the unique parkin domain, involving a phosphate-binding pocket lined by mutations causing autosomal recessive juvenile parkinsonism. Notably, a conserved linker region between the ubiquitin-like domain and the unique parkin domain acts as an activating element that contributes to RING2 release by mimicking RING2 interactions on the unique parkin domain, explaining further autosomal recessive juvenile Parkinson mutations. Gladkova et al. (2018) concluded that their data showed how autoinhibition in parkin is resolved, and suggested a mechanism for how parkin ubiquitinates its substrates via an untethered RING2 domain. </p>
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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>Valente et al. (2004) stated that the PINK1 gene is located on chromosome 1p36. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Unoki and Nakamura (2001) excluded the involvement of PINK1 in the PTEN signaling pathway. Colony formation assays showed that PINK1 had no effect on cell growth. </p><p>By immunofluorescence microscopy and Western blot analysis, Valente et al. (2004) demonstrated that PINK1 is localized to mitochondria. Valente et al. (2004) hypothesized that PINK1 may phosphorylate mitochondrial proteins in response to cellular stress, protecting against mitochondrial dysfunction. </p><p>In human and murine neuronal cells lines, Petit et al. (2005) showed that wildtype PINK1 prevented basal and inducted neuronal apoptosis due to a PINK1-mediated reduction in cytochrome c oxidase release from mitochondria, which prevented the activation of caspase-3 (600636). Overexpression of PINK1 strongly reduced caspase-3 activity. Parkinson disease (PARK6; 605909)-associated mutations abrogated the protective effect of PINK1, providing a possible mechanism for the degeneration of dopaminergic neurons in patients with the disease. </p><p>In human dopaminergic cells, Tang et al. (2006) demonstrated that wildtype PINK1 and DJ1 (602533), mutation in which causes PARK7 (606324), coimmunoprecipitate and interact functionally to protect cells from toxic oxidative MPP-induced cell death. Overexpression of both proteins resulted in a synergistic protective effect, and mutations in both proteins resulted in increased cell death compared to either mutant protein alone, suggesting a common mechanism. Evidence also suggested that DJ1 helps to stabilize PINK1. </p><p>In human neuroblastoma cells, Zhou et al. (2008) demonstrated that the PINK1 protein spans the outer mitochondrial membrane with the C-terminal kinase domain facing the cytoplasm and the N-terminal end inside the mitochondria. Although deletion of the transmembrane domain disrupted this topology, common Parkinson disease-6 (PARK6; 605909)-linked PINK1 mutations, such as A217D (608309.0011) or T313M (608309.0010), did not. </p><p>In cultured COS-7 and HEK293 cells, Weihofen et al. (2008) found evidence for low-level PINK1 expression in cytosolic and microsomal-rich fractions, in addition to mitochondrial localization. Further cellular studies showed that PINK1 interacted with and depended upon the chaperone HSP90AA1 (140571)/CDC37 (605065) complex. This chaperone system appeared to regulate the ratio of the 66-kD/55-kD PINK1 isoforms as well as the differential subcellular localization of these PINK1 isoforms. For example, overexpression of CDC37 resulted in decreased cytosolic PINK1 levels of both isoforms. </p><p>Using human and mouse neuronal cell cultures, Gandhi et al. (2009) found that PINK1 regulated a mitochondrial Na+/Ca(2+) exchanger (see SLC8A1; 182305). RNA interference (RNAi)-induced PINK1 deficiency caused mitochondrial accumulation of calcium, and the resulting calcium overload stimulated reactive oxygen species (ROS) production via NADPH oxidase (see NOX1; 300225). ROS production inhibited the glucose transporter (see SLC2A1; 138140), reducing substrate delivery and impairing mitochondrial respiration. The reduced mitochondrial calcium capacity and increased ROS lowered the threshold of opening the mitochondrial permeability transition pore such that physiologic calcium stimuli led to premature pore opening, profound mitochondrial depolarization, and ultimately cell death. </p><p>Mei et al. (2009) found that mouse and human cells subjected to growth factor deprivation induced PINK1 expression via the FOXO3A (602681) transcription factor, which bound to an element in the PINK1 promoter. RNAi knockout of PINK1 in murine cytotoxic T cells accelerated apoptosis of cells triggered by growth factor withdrawal, and this apoptosis was associated with decreased glutathione levels. Overall, the findings indicated that PINK1 is an essential pro-survival factor of mitochondria in the face of pathologic oxidative stress, as well as a downstream modulator of the anti-oxidative stress functions of the family of FOX transcription factors. </p><p>Xiong et al. (2009) demonstrated that parkin (PARK2; 602544), PINK1, and DJ1 (602533) interact and form an approximately 200-kD functional ubiquitin E3 ligase complex in human primary neurons. PINK1 was shown to increase the activity of parkin, which degrades itself via the ubiquitin-proteasome system. Pathogenic PINK1 (G309D; 608309.0001) did not promote ubiquitination and degradation of parkin or the parkin substrate synphilin-1 (603779) in transfected cells. Expression of DJ1 increased PINK1 expression, perhaps acting as a stabilizer. Overexpression of parkin substrates or heat shock treatment resulted in parkin accumulation in Pink1- or Dj1-deficient murine cells, and pathogenic parkin mutations resulted in a reduced ability to promote degradation of parkin substrates, all suggesting a decrease in E3 ubiquitin activity. Xiong et al. (2009) suggested that this complex promotes degradation of un- or misfolded proteins, including parkin, and that disruption of the activity of this complex leads to accumulation of abnormal proteins and increased susceptibility to oxidative stress, which is toxic to neurons and may lead to Parkinson disease. </p><p>Narendra et al. (2010) found that the expression of PINK1 in mitochondria is regulated by voltage-dependent proteolysis to maintain low levels, and that depolarization results in rapid accumulation of PINK1 on damaged mitochondria. In HeLa cells and mouse and human neuronal cells, PINK1 accumulation was both necessary and sufficient to recruit parkin to the mitochondria, where parkin induced autophagy of damaged mitochondria. Parkinson disease-associated mutations in both PARK2 and PINK1 disrupted parkin recruitment and parkin-induced mitophagy at distinct steps. The findings indicated that PINK1 acts upstream of parkin in a conserved pathway critical for the maintenance of mitochondrial integrity and function. </p><p>In HeLa cells and human neuroblastoma cells, Geisler et al. (2010) found that PD-associated parkin mutations disrupted the normal sequential translocation of parkin to the mitochondria and/or clearing of sequestered mitochondria in response to chemically-induced dissipation of the mitochondrial membrane potential. Parkin and PINK1 coimmunoprecipitated in neuroblastoma cells, and functional PINK1 kinase activity was required for proper translocation of parkin to damaged mitochondria for mitophagy. Wildtype parkin formed polyubiquitin chains linked through lys27 and lys63 of ubiquitin as a crucial step in autophagy of mitochondria. The ubiquitination required the ubiquitin-binding protein SQSTM1 (601530) and involved ubiquitination of VDAC1 (604492) on the mitochondrial membrane. Importantly, PD-associated parkin variants interrupted this mitophagy process at distinct steps. The findings described a link between mitochondrial damage, ubiquitination, and selective autophagy of mitochondria. Disruption of the process by mutations resulted in failure of mitochondrial clearance, which likely plays a role in the pathogenesis of PD. </p><p>Sha et al. (2010) reported that PINK1 regulated the E3 ubiquitin-protein ligase function of parkin through direct phosphorylation. Phosphorylation of parkin by PINK1 activated parkin E3 ligase function for catalyzing K63-linked polyubiquitination and enhanced parkin-mediated ubiquitin signaling through the I-kappa-B kinase/nuclear factor kappa-B (NF-kappa-B) pathway. The ability of PINK1 to promote parkin phosphorylation and activate parkin-mediated ubiquitin signaling was impaired by PD-linked pathogenic PINK1 mutations. Sha et al. (2010) proposed a direct link between PINK1-mediated phosphorylation and parkin-mediated ubiquitin signaling and implicated the deregulation of the PINK1/parkin/NF-kappa-B neuroprotective signaling pathway in the pathogenesis of PD. </p><p>Choo et al. (2011) found that parkin was increased in the brains of Pink1-null mice due to a decrease in parkin's E3 ligase activity. Levels of another parkin substrate, JTV1 (AIMP2; 600859), were also increased in Pink1-null mice. The findings supported a previous study (Xiong et al., 2009), which found that the parkin/PINK1/DJ1 complex functions as an E3 ligase to promote degradation of parkin substrates and that PINK1 plays a crucial role in regulating parkin E3 ligase activity. </p><p>In human cells, Meissner et al. (2011) demonstrated that PARL (607858) cleaves the 66-kD precursor of PINK1 to a 55-kD processed form within the mitochondria. PINK1-66 is targeted to both the outer and inner mitochondrial membranes, and PINK1-55 locates to both the mitochondrial intermembrane space and to the cytosol. PARL processes PINK1 in the transmembrane domain. Meissner et al. (2011) suggested that mutations in PINK1 that affect this processing may contribute to the pathogenesis of Parkinson disease (see, e.g., PARK6, 605909). Shi et al. (2011) also demonstrated that PARL proteolytically processes PINK1 and is required for PINK1 release from the mitochondria after import. </p><p>Human UBIAD1 (611632) localizes to mitochondria and converts vitamin K1 to vitamin K2. Vitamin K2 is best known as a cofactor in blood coagulation, but in bacteria it is a membrane-bound electron carrier. Whether vitamin K2 exerts a similar carrier function in eukaryotic cells was studied by Vos et al. (2012), who identified Drosophila UBIAD1/Heix as a modifier of pink1, a gene mutated in Parkinson disease that affects mitochondrial function. Vos et al. (2012) found that vitamin K2 was necessary and sufficient to transfer electrons in Drosophila mitochondria. Heix mutants showed severe mitochondrial defects that were rescued by vitamin K2, and, similar to ubiquinone, vitamin K2 transferred electrons in Drosophila mitochondria, resulting in more efficient adenosine ATP production. Thus, Vos et al. (2012) concluded that mitochondrial dysfunction was rescued by vitamin K2 that serves as a mitochondrial electron carrier, helping to maintain normal ATP production. </p><p>Chen and Dorn (2013) demonstrated that the mitochondrial outer membrane guanosine triphosphatase mitofusin-2 (MFN2; 608507) mediates parkin (602544) recruitment to damaged mitochondria. Parkin bound to MFN2 in a PINK1-dependent manner; PINK1 phosphorylated MFN2 and promoted its parkin-mediated ubiquitination. Ablation of Mfn2 in mouse cardiac myocytes prevented depolarization-induced translocation of parkin to the mitochondria and suppressed mitophagy. Accumulation of morphologically and functionally abnormal mitochondria induced respiratory dysfunction in Mfn2-deficient mouse embryonic fibroblasts and cardiomyocytes and in parkin-deficient Drosophila heart tubes, causing dilated cardiomyopathy. Thus, Chen and Dorn (2013) concluded that MFN2 functions as a mitochondrial receptor for parkin and is required for quality control of cardiac mitochondria. </p><p>Hasson et al. (2013) elucidated regulators that have an impact on parkin translocation to damaged mitochondria with genomewide small interfering RNA (siRNA) screens coupled to high-content microscopy. Screening yielded gene candidates involved in diverse cellular processes that were subsequently validated in low-throughput assays. This led to characterization of TOMM7 (607980) as essential for stabilizing PINK1 on the outer mitochondrial membrane following mitochondrial damage. Hasson et al. (2013) also discovered that HSPA1L (140559) and BAG4 (603884) have mutually opposing roles in the regulation of parkin translocation. The screens revealed that SIAH3 (615609), found to localize to mitochondria, inhibits PINK1 accumulation after mitochondrial insult, reducing parkin translocation. </p><p>Under resting conditions, Pink1 knockout cells and cells derived from patients with PINK1 mutations display a loss of mitochondrial complex I reductive activity, causing a decrease in the mitochondrial membrane potential. Analyzing the phosphoproteome of complex I in liver and brain from Pink1-null mice, Morais et al. (2014) found specific loss of phosphorylation of ser250 in complex I subunit NdufA10 (603835). Phosphorylation of ser250 was needed for ubiquinone reduction by complex I. Phosphomimetic NdufA10 reversed Pink1 deficits in mouse knockout cells and rescued mitochondrial depolarization and synaptic transmission defects in pink(B9)-null mutant Drosophila. Complex I deficits and ATP synthesis were also rescued in cells derived from PINK1 patients. Morais et al. (2014) concluded that this evolutionarily conserved pathway may contribute to the pathogenic cascade that eventually leads to Parkinson disease (see 605909) in patients with PINK1 mutations. </p><p>Bingol et al. (2014) reported that USP30 (612492), a deubiquitinase localized to mitochondria, antagonizes mitophagy driven by the ubiquitin ligase parkin (PARK2; 602544) and protein kinase PINK1, which are encoded by 2 genes associated with Parkinson disease (see 168600). Parkin ubiquitinates and tags damaged mitochondria for clearance. Overexpression of USP30 removes ubiquitin attached by parkin onto damaged mitochondria and blocks the parkin's ability to drive mitophagy, whereas reducing USP30 activity enhances mitochondrial degradation in neurons. Global ubiquitination site profiling identified multiple mitochondrial substrates oppositely regulated by parkin and USP30. Knockdown of USP30 rescues the defective mitophagy caused by pathogenic mutations in parkin and improves mitochondrial integrity in parkin- or Pink1-deficient flies. Knockdown of Usp30 in dopaminergic neurons protects flies against paraquat toxicity in vivo, ameliorating defects in dopamine levels, motor function, and organismal survival. Bingol et al. (2014) concluded that USP30 inhibition is potentially beneficial for treating Parkinson disease by promoting mitochondrial clearance and quality control. </p><p>Koyano et al. (2014) reported that ubiquitin is the genuine substrate of PINK1. PINK1 phosphorylated ubiquitin at ser65 both in vitro and in cells, and a ser65 phosphopeptide derived from endogenous ubiquitin was detected in cells only in the presence of PINK1 and following a decrease in mitochondrial membrane potential. Unexpectedly, phosphomimetic ubiquitin bypassed PINK1-dependent activation of a phosphomimetic parkin mutant in cells. Furthermore, phosphomimetic ubiquitin accelerates discharge of the thioester conjugate formed by UBCH7 (UBE2L3; 603721) and ubiquitin in the presence of parkin in vitro, indicating that it acts allosterically. The phosphorylation-dependent interaction between ubiquitin and parkin suggests that phosphorylated ubiquitin unlocks autoinhibition of the catalytic cysteine. Koyano et al. (2014) concluded that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity, and that phosphorylated ubiquitin is a parkin activator. </p><p>Lazarou et al. (2015) used genome editing to knock out 5 autophagy receptors in HeLa cells and demonstrated that 2 receptors previously linked to xenophagy, NDP52 (604587) and optineurin (602432), are the primary receptors for PINK1- and parkin (602544)-mediated mitophagy. PINK1 recruits NDP52 and optineurin but not p62 (SQSTM1; 601530) to mitochondria to activate mitophagy directly, independently of parkin. Once recruited to mitochondria, NDP52 and optineurin recruit the autophagy factors ULK1 (603168), DFCP1 (ZNFN2A1; 605471), and WIPI1 (609224) to focal spots proximal to mitochondria, revealing a function for these autophagy receptors upstream of LC3 (MAP1LC3A; 601242). Lazarou et al. (2015) concluded that their observations support a model in which PINK1-generated phosph-ubiquitin serves as the autophagy signal on mitochondria, and parkin then acts to amplify this signal. </p><p>Gong et al. (2015) found that Pink1-Mfn2 (608507)-parkin-mediated mitophagy directs the change in mitochondrial substrate preference in developing mouse hearts from from carbohydrates to fatty acids. A Mfn2 mutant lacking Pink1 phosphorylation sites necessary for parkin binding (Mfn2 AA) inhibited mitochondrial parkin translocation, suppressing mitophagy without impairing mitochondrial fusion. Cardiac parkin deletion or expression of Mfn2 AA from birth, but not after weaning, prevented postnatal mitochondrial maturation essential to survival. Five-week-old Mfn2 AA hearts retained a fetal mitochondrial transcriptional signature without normal increases in fatty acid metabolism and mitochondrial biogenesis genes. Myocardial fatty acylcarnitine levels and cardiomyocyte respiration induced by palmitoylcarnitine were concordantly depressed. Thus, instead of transcriptional reprogramming, fetal cardiomyocyte mitochondria undergo perinatal parkin-mediated mitophagy and replacement by mature adult mitochondria. Gong et al. (2015) concluded that mitophagic mitochondrial removal underlies developmental cardiomyocyte mitochondrial plasticity and metabolic transitioning of perinatal hearts. </p>
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<strong>Molecular Genetics</strong>
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<p>Valente et al. (2004) identified 2 homozygous mutations affecting the PINK1 kinase domain in 3 consanguineous families with Parkinson disease (PARK6; 605909): a missense mutation at a highly conserved amino acid (608309.0001) and a nonsense mutation (608309.0002). </p><p>In 6 unrelated families (3 Japanese, 1 Israeli, 1 Filipino, and 1 Taiwanese) with PARK6, Hatano et al. (2004) identified 6 pathogenic mutations in the PINK1 gene (see, e.g., 608309.0003-608309.0005). The authors suggested that PINK1 may be the second most common causative gene next to parkin (602544) in early-onset autosomal recessive Parkinson disease. </p><p>Valente et al. (2004) found that among 90 patients with sporadic early-onset parkinsonism, 1 patient had a homozygous mutation in the PINK1 gene and a second was compound heterozygous for mutations in PINK1. Five of 90 patients and 2 of 200 healthy controls had a heterozygous PINK1 mutation; 1 of the patients and 1 control shared the same mutation. The 5 patients with a heterozygous mutation had a typical parkinsonian phenotype with a mean age at onset of 44 years. Three patients had mild mood disturbances. Valente et al. (2004) suggested that heterozygous PINK1 mutations may produce subclinical dopaminergic dysfunction and represent a risk factor for the development of Parkinson disease. </p><p>Rogaeva et al. (2004) identified disease-causing PINK1 mutations in 2 of 289 unrelated North American patients with early- or late-onset PD, suggesting that mutations in this gene are a rare cause of early-onset PD. </p><p>Healy et al. (2004) reported an Irish woman with early-onset PD who carried a heterozygous missense mutation in the PINK1 gene. The mutation occurred outside of the putative kinase domain, and was conserved between humans and various primates, but not in mouse or C. elegans. The mutation was not identified in 2,224 control or PD chromosomes, including 780 from Ireland. No other point mutations or gene rearrangements in the PINK1 gene were detected in this patient. Healy et al. (2004) suggested that heterozygosity for mutations in the PINK1 gene may increase the risk for PD, but admitted that the data were inconclusive. </p><p>Hedrich et al. (2006) identified a homozygous mutation (Q456X; 608309.0012) in the PINK1 gene in 4 affected members of a large German family with early-onset parkinsonism. Six heterozygous offspring of the homozygous patients were found to have subtle signs of disease, and 5 heterozygous offspring were considered to be unaffected. Hedrich et al. (2006) concluded that heterozygous PINK1 mutations confer susceptibility to the development of PD. </p><p>Abou-Sleiman et al. (2006) identified heterozygous mutations in the PINK1 gene (see, e.g., 608309.0013) in 9 (1.2%) of 768 patients with sporadic PD. Heterozygous mutations were identified in 0.39% of a larger control group without PD, suggesting that heterozygous PINK1 mutations are a risk factor for PD. The mean age of symptom onset in the patients was 54 years, and the disorder showed very slow progression. </p><p>Choi et al. (2008) identified mutations in the PINK1 gene (see, e.g., 608309.0008) in 4 of 72 unrelated Korean patients with onset of PD before age 50. Three patients were heterozygous, and 1 was compound heterozygous for the mutation(s). </p><p>Kumazawa et al. (2008) identified mutations in the PINK1 gene in 10 (2.5%) of 391 unrelated parkin-negative PD patients from 13 countries. Eight of the 10 patients with mutations were from Japan. The frequency of homozygous mutations was 4.26% (2 of 47) in families with autosomal recessive PD and 0.53% (1 of 190) in patients with sporadic PD. The frequency of heterozygous mutations was 1.89% (2 of 106) in families with potential autosomal dominant PD and 1.05% (2 of 190) in patients with sporadic PD. The mean age at onset in patients with single heterozygous mutations was 53.6 years, compared to 34.0 years in patients with homozygous mutations. </p><p>Ishihara-Paul et al. (2008) identified 4 different homozygous mutations in the PINK1 gene (see, e.g., 608309.0012), including 3 novel mutations, in 14 (15%) of 92 Tunisian families with Parkinson disease. Six (2.5%) of 240 patients with no family history of PD were also found to carry homozygous mutations. There was no evidence that heterozygous PINK1 mutations contributed to development of PD. </p><p>Weihofen et al. (2008) presented evidence that an altered ratio of the 66-kD/55-kD isoforms of PINK1 may be involved in disease pathogenesis. In vitro studies in cultured COS-7 and HEK293 cells showed that PD-related loss of function mutations (e.g., G309D; 608309.0001) led to decreases in the 66-kD/55-kD ratio. Overexpression of PARK2 (602544) increased the ratio, whereas DJ1 (602533) had no effect. The findings identified PARK2 as a modulator of PINK1. </p><p>Using primary dermal fibroblasts originating from PD patients with various PINK1 mutations, Rakovic et al. (2010) showed that PINK1 regulates the stress-induced decrease of endogenous parkin (PARK2); that mitochondrially localized PINK1 mediates the stress-induced mitochondrial translocation of parkin; that endogenous PINK1 is stabilized on depolarized mitochondria; and that mitochondrial accumulation of full-length PINK1 is sufficient but not necessary for the stress-induced loss of Parkin and its mitochondrial translocation. Depolarizing or nondepolarizing stressors had the same effect on detectable parkin levels and its mitochondrial targeting. Although this effect on parkin was independent of mitochondrial membrane potential, Rakovic et al. (2010) demonstrated a differential effect of depolarizing versus nondepolarizing stressors on endogenous levels of PINK1. The study of Rakovic et al. (2010) demonstrated the effect of an environmental factor, stress, on the interaction of PINK1 and parkin in mutants versus controls. </p><p>Trinh et al. (2023) investigated mitochondrial DNA heteroplasmy in whole blood in patients with PD and biallelic mutations in the PINK1 or PRKN (602544) gene, patients with PD and heterozygous mutations in PINK1 or PRKN, patients with biallelic or heteroplasmic mutations in PINK1 or PRKN but without PD, patients with idiopathic PD, and control individuals. Individuals with PD and biallelic mutations in PINK1 or PRKN had significantly more mtDNA heteroplasmy compared to patients with PD and heterozygous mutations in PINK1 or PRKN or controls. Regardless of affected or unaffected status for PD, individuals with biallelic mutations in PINK1 or PRKN had significantly more mtDNA heteroplasmy compared to individuals with heterozygous mutations in PINK1 or PRKN. Patients with PD and heterozygous mutations in PINK1 or PRKN had more heteroplasmy compared to individuals without PD and heterozygous mutations in PINK1 or PRKN, or patients with idiopathic PD. Heteroplasmy load was also found to correlate to IL6 (147620) levels in PINK1 or PRKN mutation carriers, possibly demonstrating a link between mtDNA integrity and inflammation. Trinh et al. (2023) concluded that PINK1 and PRKN mutations contribute to somatic mtDNA heteroplasmy in a dose-dependent manner. </p>
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<p><strong><em>Mouse Models</em></strong></p><p>
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Gautier et al. (2008) found that germline deletion of the Pink1 gene in mice significantly impaired mitochondrial function. Although there were no significant changes in mitochondrial morphology, functional assays showed impaired mitochondrial respiration in the striatum, but not in the cerebral cortex, at 3 to 4 months of age. Aconitase (ACO2; 100850) activity associated with the Krebs cycle was also reduced in the striatum of Pink1-null mice. However, mitochondrial respiration activities in the cerebral cortex were decreased at age 2 years, indicating that aging can exacerbate mitochondrial dysfunction in these mice. Furthermore, mitochondrial respiration defects could be induced in the cerebral cortex of Pink1-null mice by cellular stress, such as exposure to hydrogen peroxide or mild heat shock. The findings demonstrated that Pink1 is important for mitochondrial function and provides critical protection against both intrinsic and environmental stress, suggesting a pathogenic mechanism by which loss of PINK1 may lead to nigrostriatal degeneration in PD. </p><p>Sliter et al. (2018) reported a strong inflammatory phenotype in both parkin (602544)-null and Pink1-null mice following exhaustive exercise, and in Prkn-null;mutator mice, which accumulate mutations in mitochondrial DNA (mtDNA). Inflammation resulting from either exhaustive exercise or mtDNA mutation was completely rescued by concurrent loss of Sting (612374), a central regulator of the type I interferon response to cytosolic DNA. The loss of dopaminergic neurons from the substantia nigra pars compacta and the motor defect observed in aged Prkn-null;mutator mice were also rescued by loss of Sting, suggesting that inflammation facilitates this phenotype. Humans with mono- and biallelic PRKN mutations also displayed elevated cytokines. Sliter et al. (2018) concluded that their results supported a role for PINK1- and parkin-mediated mitophagy in restraining innate immunity. </p><p>Matheoud et al. (2019) demonstrated that intestinal infection with gram-negative bacteria in Pink1 -/- mice engages mitochondrial antigen presentation and autoimmune mechanisms that elicit the establishment of cytotoxic mitochondria-specific CD8+ T cells in the periphery and in the brain. Notably, these mice showed a sharp decrease in the density of dopaminergic axonal varicosities in the striatum and were affected by motor impairment that was reversed after treatment with L-DOPA. Matheoud et al. (2019) concluded that their data supported the idea that PINK1 is a repressor of the immune system, and provided a pathophysiologic model in which intestinal infection acts as a triggering event in Parkinson disease, which highlighted the relevance of the gut-brain axis in the disease. </p><p><strong><em>Drosophila Models</em></strong></p><p>
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Park et al. (2006) generated and characterized loss of function mutants of Drosophila Pink1. Pink1 mutants exhibited indirect flight muscle and dopaminergic neuronal degeneration accompanied by locomotive defects. Transmission electron microscopy analysis and a rescue experiment with Drosophila Bcl2 (151430) demonstrated that mitochondrial dysfunction accounted for the degenerative changes in all phenotypes of Pink1 mutants. Park et al. (2006) also found that Pink1 mutants shared phenotypic similarities with parkin (602544) mutants. Transgenic expression of parkin ameliorated all Pink1 loss-of-function phenotypes, but not vice versa, suggesting that parkin functions downstream of PINK1. Park et al. (2006) concluded that parkin and PINK1 act in a common pathway in maintaining mitochondrial integrity and function in both muscles and dopaminergic neurons. </p><p>Clark et al. (2006) showed that removal of Drosophila Pink1 function resulted in male sterility, apoptotic muscle degeneration, defects in mitochondrial morphology, and increased sensitivity to multiple stresses, including oxidative stress. Pink1 localized to mitochondria, and mitochondrial cristae were fragmented in Pink1 mutants. Expression of human PINK1 in Drosophila testes restored male fertility and normal mitochondrial morphology in a portion of Pink1 mutants, demonstrating functional conservation between human and Drosophila PINK1. Loss of Drosophila parkin resulted in phenotypes similar to those caused by loss of Pink1 function. Overexpression of parkin rescued the male sterility and mitochondrial morphology defects of Pink1 mutants, whereas double mutants removing both Pink1 and parkin showed muscle phenotypes identical to those observed in either mutant alone. </p><p>Yang et al. (2006) found that inactivation of Pink1 in Drosophila using RNAi resulted in abnormal wing posture, energy depletion, selective muscle degeneration, and shortened life span. The muscle degeneration was preceded by mitochondrial enlargement and disintegration. In addition, inactivation of Pink1 resulted in the degeneration of dopaminergic neurons in the brain. The level of parkin was significantly reduced in Pink1 RNAi flies compared to controls, and overexpression of human parkin was able to rescue most of the defects caused by Pink1 inactivation. </p><p>Wang et al. (2006) found that inactivation of Drosophila Pink1 using RNA inhibition resulted in progressive loss of dopaminergic neurons and ommatidial degeneration of the compound eye. Treatment with the antioxidants SOD (147450) and vitamin E significantly inhibited ommatidial degeneration, suggesting that Pink1 plays a role in protecting neurons from oxidative stress. </p><p>In Drosophila, Poole et al. (2008) provided evidence that parkin acts downstream of Pink1 in a linear pathway. Overexpression of parkin rescued muscle defects of Pink1 mutants, but not vice versa. Heterozygous mutations in Drp1 (DNM1L; 603850), a key component of mitochondrial fission, enhanced Pink1 and parkin mutant phenotypes and were largely lethal. In contrast, increased Drp1 gene dosage or mutations affecting the mitochondrial fusion-promoting components Opa1 (605290) and Mfn2 (608507) suppressed the Pink1 and parkin mutant phenotypes. The findings suggested that the Pink1/parkin pathway promotes mitochondrial fission and that loss of activity of either gene results in decreased fission and impaired tissue integrity. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>14 Selected Examples):</strong>
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<strong>.0001 PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET</strong>
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PINK1, GLY309ASP
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SNP: rs74315355,
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ClinVar: RCV000002505
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<p>In a consanguineous Spanish family with Parkinson disease (PARK6; 605909), Valente et al. (2004) identified a homozygous 11185G-A transition in exon 4 of the PINK1 gene, resulting in a gly309-to-asp (G309D) substitution at a highly conserved position in the putative kinase domain. In vitro functional studies in human neuroblastoma cells transfected with the mutant protein had decreased mitochondrial membrane potential under stress conditions. </p><p>Silvestri et al. (2005) showed that, following deletion of the C-terminal regulatory sequence, G309D-mutant protein had reduced autophosphorylation activity compared to wildtype. G309D PINK1 localized to the mitochondria, and immunogold experiments revealed that both wildtype and G309D PINK1 proteins faced the mitochondrial intermembrane space. </p><p>In cellular studies in COS-7 cells, Weihofen et al. (2008) found that the G309D mutation resulted in decreased expression of both PINK1 isoforms and also to a decrease in the 66-kD/55-kD PINK1 isoform ratio. </p>
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<strong>.0002 PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET</strong>
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</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PINK1, TRP437TER
|
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|
|
|
<br />
|
|
|
|
SNP: rs74315356,
|
|
|
|
|
|
gnomAD: rs74315356,
|
|
|
|
|
|
ClinVar: RCV000002507
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 consanguineous Italian families with Parkinson disease (PARK6; 605909), Valente et al. (2004) identified the same homozygous G-to-A transition in exon 7 of the PINK1 gene, which resulted in a trp-to-stop substitution at codon 437 (W437X). The mutation truncated the last 145 amino acids encoding the C terminus of the kinase domain. These families shared a common haplotype, implying common ancestry. This mutation was not found in 400 control chromosomes, including 200 from Sicilian individuals. </p><p>Piccoli et al. (2008) reported a family with early-onset Parkinson disease associated with a W437X mutation. The proband, who had very early onset at age 22 years, was homozygous for the mutation, whereas both his parents were heterozygous. The father was unaffected at age 79, and the mother developed Parkinson disease at age 53. Biochemical studies of the proband's fibroblasts showed mitochondrial dysfunction, with decreased amounts of cytochrome c oxidase, impaired complex I activity, and increased hydrogen peroxide generation. Further analysis identified 2 mutations in mitochondrial genes: MTND5 (516005.0010) and MTND6 (516006.0008). Both the proband and his mother were homoplasmic for both mitochondrial mutations. Piccoli et al. (2008) concluded that the presence of the mitochondrial mutations in combination with the PINK1 mutation may have accelerated the onset of the disease. </p><p>Silvestri et al. (2005) showed that W437X-mutant protein had greater efficiency of autophosphorylation activity compared to wildtype. W437X PINK1 localized to the mitochondria, and immunogold experiments revealed that both wildtype and W437X PINK1 proteins faced the mitochondrial intermembrane space. </p>
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
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|
|
|
PINK1, ARG246TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315357,
|
|
|
|
|
|
gnomAD: rs74315357,
|
|
|
|
|
|
ClinVar: RCV000002508
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 2 consanguineous families, 1 Japanese and 1 Israeli, with Parkinson disease (PARK6; 605909), Hatano et al. (2004) identified a homozygous 736C-T transition in exon 3 of the PINK1 gene, resulting in an arg246-to-ter (R246X) substitution. The mutation was predicted to result in a truncated protein lacking 336 amino acids, including a highly conserved protein kinase domain. Two affected Israeli patients showed psychiatric disturbances at the onset of the disease. One unaffected Israeli family member was heterozygous for the mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PINK1, HIS271GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28940284,
|
|
|
|
|
|
gnomAD: rs28940284,
|
|
|
|
|
|
ClinVar: RCV000002506
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese patient with Parkinson disease (PARK6; 605909) with onset at age 23 years, Hatano et al. (2004) identified a homozygous 813C-A transversion in exon 4 of the PINK1 gene, resulting in a his271-to-gln (H271Q) substitution. The patient's parents were consanguineous. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PINK1, LEU347PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28940285,
|
|
|
|
|
|
gnomAD: rs28940285,
|
|
|
|
|
|
ClinVar: RCV000002509, RCV002223750
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 affected members of a Filipino family with Parkinson disease (PARK6; 605909), Hatano et al. (2004) identified a homozygous 1040T-C transition in exon 5 of the PINK1 gene, resulting in a leu347-to-pro (L347P) substitution. </p><p>Rogaeva et al. (2004) identified the homozygous L347P mutation in 1 of 289 North American patients with either early- or late-onset PD. The patient was Filipino, had disease onset in the fourth decade of life, and reportedly had 2 affected sibs. The authors noted that the L347P mutation occurs in a conserved residue within the kinase domain of the protein. Three of 50 Filipino control individuals were heterozygous for the L347P mutation, suggesting an allelic frequency of 3% in this population. </p><p>In mammalian cells, Beilina et al. (2005) found that the L347P mutation resulted in significantly decreased protein stability and in a drastic reduction of kinase activity. The mutation was predicted to occur in a helical segment that forms part of the cyclin binding surface. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PINK1, 4-BP INS, 1573TTAG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs730880302,
|
|
|
|
|
|
|
|
ClinVar: RCV000002510
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Italian patient with Parkinson disease (PARK6; 605909), Rohe et al. (2004) identified a homozygous 4-bp insertion (1573insTTAG) in exon 8 of the PINK1 gene, resulting in a frameshift and truncation of the last 20 C-terminal amino acids of the protein. Both parents were heterozygous for the insertion. Rohe et al. (2004) noted that the mutation occurs outside of the known functional protein kinase domain of PINK1. The patient had psychiatric symptoms, including anxiety and depression, both of which were present in the mother. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PINK1, 3-BP INS, 1602CAA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs750664040,
|
|
|
|
|
|
gnomAD: rs750664040,
|
|
|
|
|
|
ClinVar: RCV000002511
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 of 65 unrelated Italian patients with early-onset parkinsonism, Klein et al. (2005) identified a 3-bp insertion (1602insCAA) in exon 8 of the PINK1 gene, consistent with PARK6 (605909). The insertion resulted in the incorporation of an extra glutamine residue (glu534) after 2 glutamines, very close to the C terminus of the protein. One patient was heterozygous for the mutation and the other was homozygous. The patient who was heterozygous had earlier age at onset (25 vs 32 years). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 PARKINSON DISEASE 6, EARLY-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PINK1, ARG279HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315358,
|
|
|
|
|
|
gnomAD: rs74315358,
|
|
|
|
|
|
ClinVar: RCV000002512, RCV002292454
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 1 of 65 unrelated Italian patients with early-onset parkinsonism, Klein et al. (2005) identified a heterozygous 836G-A transition in exon 4 of the PINK1 gene, resulting in an arg279-to-his (R279H) substitution in the functional ser/thr protein kinase domain of the protein. The findings were consistent with PARK6 (605909). </p><p>Choi et al. (2008) identified a heterozygous R279H mutation in 1 of 72 unrelated Korean patients with onset of PD before age 50. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PINK1, EX6-8DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000002513
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese patient with early-onset parkinsonism (PARK6; 605909), Li et al. (2005) identified a homozygous deletion of exons 6 through 8 of the PINK1 gene. In addition to parkinsonism, the patient also had depression, hallucinations, and dementia. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PINK1, THR313MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315359,
|
|
|
|
|
|
gnomAD: rs74315359,
|
|
|
|
|
|
ClinVar: RCV000002514
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 affected members of a large consanguineous Saudi Arabian family with early-onset parkinsonism (PARK6; 605909), Chishti et al. (2006) identified a homozygous 1032C-T transition in exon 4 of the PINK1 gene, resulting in a thr313-to-met (T313M) substitution in the kinase domain. The 2 patients had onset at age 34 and 30 years, respectively, and had no cognitive impairment or major axial symptoms. Two additional family members were reportedly similarly affected. Study of 13 carriers of the T313M mutation found no neurologic abnormalities, suggesting that heterozygosity for the mutation does not act as a susceptibility factor for development of the disease. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PINK1, ALA217ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315360,
|
|
|
|
|
|
|
|
ClinVar: RCV000002515
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 affected members of a large consanguineous Sudanese family with early-onset parkinsonism (PARK6; 605909), Leutenegger et al. (2006) identified a homozygous 650C-A transversion in exon 2 of the PINK1 gene, resulting in an ala217-to-asp (A217D) substitution in the highly conserved LAIK amino acid sequence corresponding to the ATP orientation domain. Age at disease onset was very early, between 9 and 14 years of age. Two patients had dystonia, and all had diurnal fluctuations; none had other atypical neurologic signs. None of the heterozygous carriers had signs of parkinsonism. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PINK1, GLN456TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs45539432,
|
|
|
|
|
|
gnomAD: rs45539432,
|
|
|
|
|
|
ClinVar: RCV000002516, RCV000627238, RCV004739278
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 affected sibs of a large German family with early-onset parkinsonism (PARK6; 605909), Hedrich et al. (2006) identified a homozygous 1366C-T transition in exon 7 of the PINK1 gene, resulting in a gln456-to-ter (Q456X) substitution. Six heterozygous offspring of the homozygous patients were found to have subtle signs of disease, and 5 heterozygous offspring were considered to be unaffected. The 6 affected heterozygous offspring were not aware of their signs, but clinical examination showed unilaterally reduced or absent arm swing and rigidity. Hedrich et al. (2006) concluded that heterozygous PINK1 mutations confer susceptibility to the development of PD. Of clinical note, parkinsonian signs were more marked on the dominant right-hand side in all mutation carriers, and 10 of 15 mutation carriers had psychiatric disturbances. </p><p>Ishihara-Paul et al. (2008) identified homozygosity for the Q456X mutation in 7 (7.8%) of 92 Tunisian families with Parkinson disease and in 5 (2.1%) of 240 patients with no family history of PD. There was no evidence that heterozygosity for the mutation contributed to development of PD. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 PARKINSON DISEASE 6, LATE-ONSET, SUSCEPTIBILITY TO</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PINK1, TYR431HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74315361,
|
|
|
|
|
|
|
|
ClinVar: RCV000002517
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 80-year-old sporadic patient with relatively late onset of parkinsonism (PARK6; 605909) at age 59 years, Abou-Sleiman et al. (2006) identified a heterozygous mutation in the PINK1 gene, resulting in a tyr431-to-his (Y431H) substitution. The patient showed tremor, bradykinesia, rigidity, mild anxiety and depression, and excellent response to L-DOPA treatment. In vitro functional studies in human neuroblastoma cells transfected with the mutant protein showed decreased mitochondrial membrane potential under stress conditions. Abou-Sleiman et al. (2006) concluded that heterozygous mutations in the PINK1 gene may contribute to increased risk for late-onset PD. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 PARKINSON DISEASE, AUTOSOMAL RECESSIVE EARLY-ONSET, DIGENIC, PINK1/DJ1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PINK1, PRO399LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs119451946,
|
|
|
|
|
|
gnomAD: rs119451946,
|
|
|
|
|
|
ClinVar: RCV000002518, RCV000372794
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Chinese sibs with early-onset Parkinson disease (see 605909), Tang et al. (2006) identified compound heterozygosity for 2 mutations in 2 different genes: a 1196C-T transition in exon 6 of the PINK1 gene resulting in a pro399-to-leu (P399L) substitution in the predicted kinase domain, and an A39S mutation (602533.0007) in the DJ1 gene. The DJ1 and PINK1 mutations were not observed in 240 and 568 control chromosomes, respectively, and both were located in highly conserved residues. The findings were consistent with digenic inheritance of Parkinson disease. A 42-year-old unaffected family member also carried both mutations, suggesting incomplete penetrance. Coimmunoprecipitation studies showed that both wildtype and mutant PINK1 interacted with both wildtype and mutant DJ1. Expression of wildtype DJ1 increased steady-state levels of both mutant and wildtype PINK1, but mutant DJ1 decreased steady-state levels of both mutant and wildtype PINK1, suggesting that wildtype DJ1 can enhance PINK1 stability. Human neuroblastoma cells expressing either mutant PINK1 or DJ1 showed reduced viability following oxidative challenge with MPP compared to control cells, indicating that both proteins protect against cell stress. Coexpression of both wildtype proteins resulted in a synergistic increase in cell viability against MPP-induced stress. In addition, coexpression of both mutant proteins significantly increased susceptibility of cells to death, compared to either mutant alone. These findings indicated that DJ1 and PINK1 function collaboratively. </p>
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Hilary J. Vernon - updated : 01/25/2024<br>Ada Hamosh - updated : 03/26/2020<br>Ada Hamosh - updated : 10/09/2019<br>Ada Hamosh - updated : 10/08/2019<br>Ada Hamosh - updated : 09/18/2018<br>Ada Hamosh - updated : 03/14/2018<br>Cassandra L. Kniffin - updated : 11/18/2015<br>Ada Hamosh - updated : 9/11/2015<br>Ada Hamosh - updated : 7/17/2014<br>Ada Hamosh - updated : 7/15/2014<br>Ada Hamosh - updated : 5/6/2014<br>Ada Hamosh - updated : 1/13/2014<br>George E. Tiller - updated : 9/4/2013<br>Ada Hamosh - updated : 5/29/2013<br>Cassandra L. Kniffin - updated : 5/15/2013<br>Ada Hamosh - updated : 6/21/2012<br>George E. Tiller - updated : 12/29/2010<br>Cassandra L. Kniffin - updated : 4/5/2010<br>Cassandra L. Kniffin - updated : 3/1/2010<br>Cassandra L. Kniffin - updated : 10/15/2009<br>Cassandra L. Kniffin - updated : 10/14/2009<br>George E. Tiller - updated : 9/3/2009<br>Patricia A. Hartz - updated : 8/5/2009<br>Cassandra L. Kniffin - updated : 5/29/2009<br>Cassandra L. Kniffin - updated : 4/6/2009<br>Cassandra L. Kniffin - updated : 1/14/2009<br>Cassandra L. Kniffin - updated : 10/28/2008<br>Cassandra L. Kniffin - updated : 10/6/2008<br>Cassandra L. Kniffin - updated : 2/20/2008<br>Cassandra L. Kniffin - updated : 11/8/2007<br>Cassandra L. Kniffin - updated : 2/19/2007<br>Cassandra L. Kniffin - updated : 11/3/2006<br>Cassandra L. Kniffin - updated : 9/19/2006<br>Cassandra L. Kniffin - updated : 8/23/2006<br>Ada Hamosh - updated : 7/10/2006<br>Cassandra L. Kniffin - updated : 11/7/2005<br>Cassandra L. Kniffin - updated : 9/20/2005<br>Cassandra L. Kniffin - updated : 3/11/2005<br>Cassandra L. Kniffin - updated : 11/30/2004<br>Ada Hamosh - updated : 6/9/2004
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Carol A. Bocchini : 12/2/2003
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carol : 01/25/2024<br>carol : 02/01/2021<br>carol : 08/12/2020<br>alopez : 03/26/2020<br>alopez : 10/09/2019<br>alopez : 10/08/2019<br>alopez : 09/18/2018<br>carol : 03/15/2018<br>alopez : 03/14/2018<br>carol : 11/23/2015<br>ckniffin : 11/18/2015<br>alopez : 9/11/2015<br>alopez : 4/21/2015<br>mcolton : 2/10/2015<br>alopez : 7/17/2014<br>alopez : 7/15/2014<br>alopez : 5/6/2014<br>mcolton : 2/24/2014<br>mgross : 1/22/2014<br>alopez : 1/13/2014<br>alopez : 9/10/2013<br>tpirozzi : 9/4/2013<br>tpirozzi : 9/3/2013<br>alopez : 5/29/2013<br>carol : 5/20/2013<br>ckniffin : 5/15/2013<br>alopez : 6/28/2012<br>terry : 6/21/2012<br>wwang : 1/12/2011<br>terry : 12/29/2010<br>wwang : 4/12/2010<br>ckniffin : 4/5/2010<br>ckniffin : 3/1/2010<br>wwang : 10/27/2009<br>ckniffin : 10/15/2009<br>ckniffin : 10/14/2009<br>wwang : 9/17/2009<br>terry : 9/3/2009<br>mgross : 8/13/2009<br>terry : 8/5/2009<br>wwang : 6/4/2009<br>ckniffin : 5/29/2009<br>wwang : 4/13/2009<br>ckniffin : 4/6/2009<br>wwang : 1/16/2009<br>ckniffin : 1/14/2009<br>wwang : 11/7/2008<br>ckniffin : 10/28/2008<br>wwang : 10/7/2008<br>ckniffin : 10/6/2008<br>wwang : 3/6/2008<br>ckniffin : 2/20/2008<br>wwang : 11/26/2007<br>ckniffin : 11/8/2007<br>wwang : 6/6/2007<br>wwang : 2/22/2007<br>ckniffin : 2/19/2007<br>carol : 1/31/2007<br>wwang : 11/9/2006<br>ckniffin : 11/3/2006<br>wwang : 10/10/2006<br>ckniffin : 9/19/2006<br>wwang : 8/29/2006<br>ckniffin : 8/23/2006<br>alopez : 7/18/2006<br>terry : 7/10/2006<br>ckniffin : 11/7/2005<br>carol : 10/5/2005<br>wwang : 10/4/2005<br>ckniffin : 9/20/2005<br>wwang : 3/21/2005<br>wwang : 3/17/2005<br>ckniffin : 3/11/2005<br>ckniffin : 3/11/2005<br>tkritzer : 12/6/2004<br>ckniffin : 11/30/2004<br>alopez : 6/10/2004<br>terry : 6/9/2004<br>tkritzer : 12/3/2003<br>carol : 12/2/2003
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