6478 lines
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Entry
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- *609007 - LEUCINE-RICH REPEAT KINASE 2; LRRK2
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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">*609007</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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<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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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</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/609007">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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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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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000188906;t=ENST00000298910" 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=120892" 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=609007" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000188906;t=ENST00000298910" 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_198578,XM_005268629,XM_011537877,XM_011537881,XM_011537882,XM_017018786,XM_017018787,XM_024448833,XM_047428277,XM_047428278,XM_047428279,XR_007063041" 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_198578" 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=609007" 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=10613&isoform_id=10613_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/LRRK2" 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/21740356,34365325,55740398,109658494,125660016,294862450,530399725,767973113,767973121,767973123,1034577895,1034577897,1212783573,1212783575,1212783577,1370461153,1519473490,2217287385,2217287388,2217287391,2462529879,2462529881,2462529883,2462529886,2462529888,2462529890,2462529892,2462529894,2462529896,2462529898" 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/Q5S007" 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=120892" 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=ENSG00000188906;t=ENST00000298910" 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=LRRK2" 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=LRRK2" 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+120892" 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/LRRK2" 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:120892" 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/120892" 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=chr12&hgg_gene=ENST00000298910.12&hgg_start=40224997&hgg_end=40369285&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:18618" 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/lrrk2" 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=609007[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=609007[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/ENSG00000188906" 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=LRRK2" 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=LRRK2" 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=LRRK2" 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/LRRK2" 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=LRRK2&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/PA134968052" 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:18618" 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://www.mousephenotype.org/data/genes/MGI:1913975" 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/LRRK2#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:1913975" 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/120892/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/OMIA002379/" 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=120892" 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://zfin.org/ZDB-GENE-071218-6" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
|
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
|
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</div>
|
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:609007" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
|
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</span>
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</span>
|
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:120892" 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=LRRK2&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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609007
|
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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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LEUCINE-RICH REPEAT KINASE 2; LRRK2
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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">
|
|
DARDARIN
|
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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">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=LRRK2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">LRRK2</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/12/290?start=-3&limit=10&highlight=290">12q12</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr12:40224997-40369285&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'})">12:40,224,997-40,369,285</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
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|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/12/290?start=-3&limit=10&highlight=290">
|
|
12q12
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Parkinson disease 8}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/607060"> 607060 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
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</td>
|
|
|
|
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</tr>
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<p>The LRRK2 gene encodes a protein with 5 putative functional domains: an N-terminal leucine-rich repeat (LRR) domain, a Roc (Ras of complex protein) domain that shares sequence homology to the Ras-related GTPase superfamily, a COR (C-terminal of Roc) domain, a mitogen-activated protein kinase kinase kinase (MAPKKK) domain, and a C-terminal WD40 repeat domain. Mutation in this gene is one of the most common causes of inherited Parkinson disease (PARK8; <a href="/entry/607060">607060</a>) (summary by <a href="#23" class="mim-tip-reference" title="Gandhi, P. N., Wang, X., Zhu, X., Chen, S. G., Wilson-Delfosse, A. L. <strong>The Roc domain of leucine-rich repeat kinase 2 is sufficient for interaction with microtubules.</strong> J. Neurosci. Res. 86: 1711-1720, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18214993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18214993</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18214993[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/jnr.21622" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18214993">Gandhi et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18214993" 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="#59" class="mim-tip-reference" title="Paisan-Ruiz, C., Jain, S., Evans, E. W., Gilks, W. P., Simon, J., van der Brug, M., Lopez de Munain, A., Aparicio, S., Martinez Gil, A., Khan, N., Johnson, J., Martinez, J. R., and 9 others. <strong>Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease.</strong> Neuron 44: 595-600, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15541308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15541308</a>] [<a href="https://doi.org/10.1016/j.neuron.2004.10.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15541308">Paisan-Ruiz et al. (2004)</a> identified a putative disease-causing transcript (DKFZp434H2111) within a 2.6-Mb region encompassing a locus for Parkinson disease-8 (PARK8; <a href="/entry/607060">607060</a>). The predicted transcript encodes a deduced 2,482-amino acid protein with a leucine-rich repeat, a kinase domain, a RAS domain, and a WD40 domain. Northern blot analysis detected a 9-kb mRNA transcript in all tissues tested, including brain. The authors named the protein product dardarin, derived from the Basque word dardara, meaning tremor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15541308" 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="#88" class="mim-tip-reference" title="Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln, S., Kachergus, J., Hulihan, M., Uitti, R. J., Calne, D. B., Stoessl, A. J., Pfeiffer, R. F., Patenge, N., Carballo Carbajal, I., Vieregge, P., Asmus, F., Muller-Myhsok, B., Dickson, D. W., Meitinger, T., Strom, T. M., Wszolek, Z. K., Gasser, T. <strong>Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.</strong> Neuron 44: 601-607, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15541309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15541309</a>] [<a href="https://doi.org/10.1016/j.neuron.2004.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15541309">Zimprich et al. (2004)</a> cloned LRRK2 from a human brain cDNA library and found that it encodes a 2,527-amino acid protein with a molecular mass of approximately 250-kD. Northern blot analysis detected a major 9-kb transcript at low levels in most brain regions. Highest transcript levels were obtained in the putamen, substantia nigra, and lung. The appearance of smaller bands suggested alternative splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15541309" 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 5-prime RACE of human brain cDNA, <a href="#80" class="mim-tip-reference" title="West, A. B., Moore, D. J., Biskup, S., Bugayenko, A., Smith, W. W., Ross, C. A., Dawson, V. L., Dawson, T. M. <strong>Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity.</strong> Proc. Nat. Acad. Sci. 102: 16842-16847, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16269541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16269541</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16269541[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.0507360102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16269541">West et al. (2005)</a> found LRRK2 transcripts with at least 6 transcription start sites upstream of the predicted Kozak sequence. They also identified a splice variant, resulting from utilization of a cryptic splice site within intron 50, that encodes a protein lacking 6 amino acids near the C-terminal WD40 domain. In transfected human embryonic kidney cells, LRRK2 was largely excluded from the nucleus and localized to the cytosol, but about 10% of LRRK2 was associated with the outer mitochondrial membrane. LRRK2 migrated at an apparent molecular mass of 280 kD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16269541" 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 fractionation analysis of rat brain, <a href="#66" class="mim-tip-reference" title="Shani, V., Safory, H., Szargel, R., Wang, N., Cohen, T., Elghani, F. A., Hamza, H., Savyon, M., Radzishevsky, I., Shaulov, L., Rott, R., Lim, K. L., Ross, C. A., Bandopadhyay, R., Zhang, H., Engelender, S. <strong>Physiological and pathological roles of LRRK2 in the nuclear envelope integrity.</strong> Hum. Molec. Genet. 28: 3982-3996, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31626293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31626293</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31626293[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/ddz245" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31626293">Shani et al. (2019)</a> showed that endogenous Lrrk2 was present in cytosol and nucleus. Immunofluorescence and immunocytochemical analyses confirmed the nuclear presence of LRRK2 transfected HEK293 cells and transfected rat primary cortical neurons. Nuclear subfractionation further revealed that LRRK2 was present in the nuclear cytoskeleton fraction, which contains lamin A/C (LMNA; <a href="/entry/150330">150330</a>). LRRK2 contains 3 putative nuclear translocation signals, but mutation analysis showed that they were not relevant to nuclear localization of LRRK2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31626293" 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="#88" class="mim-tip-reference" title="Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln, S., Kachergus, J., Hulihan, M., Uitti, R. J., Calne, D. B., Stoessl, A. J., Pfeiffer, R. F., Patenge, N., Carballo Carbajal, I., Vieregge, P., Asmus, F., Muller-Myhsok, B., Dickson, D. W., Meitinger, T., Strom, T. M., Wszolek, Z. K., Gasser, T. <strong>Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.</strong> Neuron 44: 601-607, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15541309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15541309</a>] [<a href="https://doi.org/10.1016/j.neuron.2004.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15541309">Zimprich et al. (2004)</a> determined that the LRRK2 gene contains 51 exons spanning 144 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15541309" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By genomic sequence analysis, <a href="#88" class="mim-tip-reference" title="Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln, S., Kachergus, J., Hulihan, M., Uitti, R. J., Calne, D. B., Stoessl, A. J., Pfeiffer, R. F., Patenge, N., Carballo Carbajal, I., Vieregge, P., Asmus, F., Muller-Myhsok, B., Dickson, D. W., Meitinger, T., Strom, T. M., Wszolek, Z. K., Gasser, T. <strong>Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.</strong> Neuron 44: 601-607, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15541309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15541309</a>] [<a href="https://doi.org/10.1016/j.neuron.2004.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15541309">Zimprich et al. (2004)</a> mapped the LRRK2 gene to chromosome 12q12. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15541309" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By measuring the activity of LRRK2 against myelin basic protein (<a href="/entry/159430">159430</a>) as a test substrate, <a href="#80" class="mim-tip-reference" title="West, A. B., Moore, D. J., Biskup, S., Bugayenko, A., Smith, W. W., Ross, C. A., Dawson, V. L., Dawson, T. M. <strong>Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity.</strong> Proc. Nat. Acad. Sci. 102: 16842-16847, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16269541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16269541</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16269541[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.0507360102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16269541">West et al. (2005)</a> determined that LRRK2 possesses mixed-lineage kinase activity. LRRK2 also showed autophosphorylation activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16269541" 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="#69" class="mim-tip-reference" title="Smith, W. W., Pei, Z., Jiang, H., Moore, D. J., Liang, Y., West, A. B., Dawson, V. L., Dawson, T. M., Ross, C. A. <strong>Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin and mutant LRRK2 induces neuronal degeneration.</strong> Proc. Nat. Acad. Sci. 102: 18676-18681, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16352719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16352719</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16352719[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.0508052102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16352719">Smith et al. (2005)</a> demonstrated that LRRK2 is primarily cytoplasmic and interacts with parkin (PARK2; <a href="/entry/602544">602544</a>). LRRK2 interacted preferentially with the C-terminal R2 RING finger domain of parkin, and parkin interacted with the COR domain of LRRK2. Coexpression of LRRK2 and parkin increased cytoplasmic protein aggregates that contained LRRK2 and enhanced the ubiquitination of these aggregates. Expression of mutant LRRK2 induced apoptotic cell death in human SH-SY5Y neuroblastoma cells and in mouse cortical neurons in vitro. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16352719" 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 oligonucleotide probes, <a href="#22" class="mim-tip-reference" title="Galter, D., Westerlund, M., Carmine, A., Lindqvist, E., Sydow, O., Olson, L. <strong>LRRK2 expression linked to dopamine-innervated areas.</strong> Ann. Neurol. 59: 714-719, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16532471/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16532471</a>] [<a href="https://doi.org/10.1002/ana.20808" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16532471">Galter et al. (2006)</a> detected LRRK2 expression in medium-sized spiny neurons of the caudate and putamen. Larger, presumably cholinergic neurons and dopamine neurons were devoid of LRRK2 signal. No differences were observed between normal brains and those from individuals with Parkinson disease. Similar studies on rodent brain showed Lrrk2 expression in the striatum and absence of Lrrk2 expression in the midbrain. The findings demonstrated LRRK2 expression in brain dopaminoceptive areas, suggesting to the authors that LRRK2 dysfunction in these areas may diminish trophic support of dopamine neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16532471" 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 immunohistochemistry and Western blot analysis, <a href="#7" class="mim-tip-reference" title="Biskup, S., Moore, D. J., Celsi, F., Higashi, S. West, A. B., Andrabi, S. A., Kurkinen, K., Yu, S.-W., Savitt, J. M., Waldvogel, H. J., Faull, R. L. M., Emson, P. C., Torp, R., Ottersen, O. P., Dawson, T. M., Dawson, V. L. <strong>Localization of LRRK2 to membranous and vesicular structures in mammalian brain.</strong> Ann. Neurol. 60: 557-569, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17120249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17120249</a>] [<a href="https://doi.org/10.1002/ana.21019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17120249">Biskup et al. (2006)</a> detected Lrrk2 in multiple areas throughout rat brain. Lrrk2 localization was neuron-specific, detected in microsomal, synaptic vesicle-enriched and synaptosomal cytosolic fractions, as well as the mitochondrial outer membrane. Lrrk2 was also detected in the kidney. Further studies in human and rat brain showed LRRK2 in punctate structures within neuronal perikarya, dendrites, and axons. LRRK2 immunoreactivity was associated with membranous and vesicular intracellular structures, including lysosomes, endosomes, transport vesicles, and mitochondria. <a href="#7" class="mim-tip-reference" title="Biskup, S., Moore, D. J., Celsi, F., Higashi, S. West, A. B., Andrabi, S. A., Kurkinen, K., Yu, S.-W., Savitt, J. M., Waldvogel, H. J., Faull, R. L. M., Emson, P. C., Torp, R., Ottersen, O. P., Dawson, T. M., Dawson, V. L. <strong>Localization of LRRK2 to membranous and vesicular structures in mammalian brain.</strong> Ann. Neurol. 60: 557-569, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17120249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17120249</a>] [<a href="https://doi.org/10.1002/ana.21019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17120249">Biskup et al. (2006)</a> concluded that LRRK2 has an affinity for lipids or lipid-associated proteins and may play a role in the biogenesis or regulation of membranous intracellular structures in the brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17120249" 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 HEK293 cells, <a href="#31" class="mim-tip-reference" title="Gloeckner, C. J., Kinkl, N., Schumacher, A., Braun, R. J., O'Neill. E., Meitinger, T., Kolch, W., Prokisch, H., Ueffing, M. <strong>The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity.</strong> Hum. Molec. Genet. 15: 223-232, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16321986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16321986</a>] [<a href="https://doi.org/10.1093/hmg/ddi439" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16321986">Gloeckner et al. (2006)</a> demonstrated that LRRK2 was associated with particulate membrane structures within the cytoplasm, such as mitochondria, microsomal membranes, endoplasmic reticulum, and the Golgi apparatus. However, LRRK2 did not appear to be integrated into membranes. Further studies showed that LRRK2 dimerizes, shows kinase activity, and is able to phosphorylate itself. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16321986" 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 a combination of protein pull-down assays, mass spectrometry, Western blotting, and immunofluorescence microscopy, <a href="#23" class="mim-tip-reference" title="Gandhi, P. N., Wang, X., Zhu, X., Chen, S. G., Wilson-Delfosse, A. L. <strong>The Roc domain of leucine-rich repeat kinase 2 is sufficient for interaction with microtubules.</strong> J. Neurosci. Res. 86: 1711-1720, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18214993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18214993</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18214993[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/jnr.21622" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18214993">Gandhi et al. (2008)</a> found that the ROC, or GTPase-like, domain of LRRK2 interacted with alpha (see TUBA1A; <a href="/entry/602529">602529</a>)/beta (see TUBB2B; <a href="/entry/612850">612850</a>)-tubulin heterodimers that form microtubules. The interaction was guanine-nucleotide independent. Endogenous LRRK2 protein was found to colocalize with alpha/beta-tubulin in the cell body and neuronal processes of rat primary hippocampal neurons. These findings linked LRRK2 with microtubules, a structural component of the cell critically involved in the pathogenesis of several neurodegenerative diseases, including Parkinson disease. However, the pathogenic R1441C LRRK2 mutation (<a href="#0003">609007.0003</a>), located within the ROC domain, retained interaction with alpha/beta-tubulin heterodimers, suggesting that disruption of this interaction is not the pathogenic mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18214993" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Gillardon, F. <strong>Leucine-rich repeat kinase 2 phosphorylates brain tubulin-beta isoforms and modulates microtubule stability--a point of convergence in parkinsonian neurodegeneration?</strong> J. Neurochem. 110: 1514-1522, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19545277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19545277</a>] [<a href="https://doi.org/10.1111/j.1471-4159.2009.06235.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19545277">Gillardon (2009)</a> showed that recombinant human LRRK2 preferentially phosphorylated bovine brain beta-tubulin at the highly conserved residue thr107. Tubulin becomes phosphorylated during neurite outgrowth, and phosphorylation may stabilize the microtubule cytoskeleton. <a href="#29" class="mim-tip-reference" title="Gillardon, F. <strong>Leucine-rich repeat kinase 2 phosphorylates brain tubulin-beta isoforms and modulates microtubule stability--a point of convergence in parkinsonian neurodegeneration?</strong> J. Neurochem. 110: 1514-1522, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19545277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19545277</a>] [<a href="https://doi.org/10.1111/j.1471-4159.2009.06235.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19545277">Gillardon (2009)</a> found that LRRK2 coimmunoprecipitated with tubulin-beta in both wildtype mouse brain and nonneuronal HEK293 cells, and in vitro coincubation of brain tubulins with LRRK2 increased microtubule stability in the presence of microtubule-associated proteins. Lrrk2-deficient murine neuron cultures showed a significant decrease in neurite length compared to wildtype neurons. The findings suggested that stabilization of microtubules by tubulin-beta phosphorylation may represent a physiologic function of LRRK2 in neurons. Phosphorylation of tubulin was enhanced 3-fold by the LRRK2 G2019S mutation (<a href="#0006">609007.0006</a>), which suggested that mutant LRRK2-induced neurodegeneration in PD may be partly mediated by increased phosphorylation of tubulin-beta, which may interfere with neurite outgrowth, axonal transport, and synapse formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19545277" 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="#65" class="mim-tip-reference" title="Sancho, R. M., Law, B. M. H., Harvey, K. <strong>Mutations in the LRRK2 Roc-COR tandem domain link Parkinson's disease to Wnt signalling pathways.</strong> Hum. Molec. Genet. 18: 3955-3968, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19625296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19625296</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19625296[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/ddp337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19625296">Sancho et al. (2009)</a> reported interaction of LRRK2 with the dishevelled family of phosphoproteins, DVL1 (<a href="/entry/601365">601365</a>), DVL2 (<a href="/entry/602151">602151</a>), and DVL3 (<a href="/entry/601368">601368</a>), key regulators of Wnt (Wingless/Int; <a href="/entry/164820">164820</a>) signaling pathways important for axon guidance, synapse formation, and neuronal maintenance. The LRRK2 Roc-COR domain and the DVL1 (<a href="/entry/601365">601365</a>) DEP domain were necessary and sufficient for LRRK2-DVL1 interaction. Coexpression of DVL1 increased LRRK2 steady-state protein levels, an effect that was dependent on the DEP domain. LRRK2-DVL1-3 interactions were disrupted by the LRRK2 Y1699C mutation (<a href="#0002">609007.0002</a>), whereas pathogenic mutations at residues arg1441 (see, e.g., <a href="#0001">609007.0001</a>) and arg1728 strengthened LRRK2-DVL1 interactions. Coexpression of DVL1 with LRRK2 in mammalian cells resulted in the redistribution of LRRK2 to typical cytoplasmic DVL1 aggregates in HEK293 and SH-SY5Y cells and colocalization in neurites and growth cones of differentiated dopaminergic SH-SY5Y cells. Since the DVL1 DEP domain is known to be involved in the regulation of small GTPases, <a href="#65" class="mim-tip-reference" title="Sancho, R. M., Law, B. M. H., Harvey, K. <strong>Mutations in the LRRK2 Roc-COR tandem domain link Parkinson's disease to Wnt signalling pathways.</strong> Hum. Molec. Genet. 18: 3955-3968, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19625296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19625296</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19625296[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/ddp337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19625296">Sancho et al. (2009)</a> proposed that DVLs may influence LRRK2 GTPase activity, and that Roc-COR domain mutations modulating LRRK2-DVL interactions indirectly influence kinase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19625296" 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="Gehrke, S., Imai, Y., Sokol, N., Lu, B. <strong>Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression.</strong> Nature 466: 637-641, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20671708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20671708</a>] [<a href="https://doi.org/10.1038/nature09191" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20671708">Gehrke et al. (2010)</a> found that LRRK2 interacted with the microRNA (miRNA) pathway to regulate protein synthesis. They showed that mRNAs for Drosophila E2f1 (<a href="/entry/189971">189971</a>) and Dp (TFDP1; <a href="/entry/189902">189902</a>), which had previously been implicated in cell cycle and survival control (<a href="#30" class="mim-tip-reference" title="Girling, R., Partridge, J. F., Bandara, L. R., Burden, N., Totty, N. F., Hsuan, J. J., La Thangue, N. B. <strong>A new component of the transcription factor DRTF1/E2F.</strong> Nature 362: 83-87, 1993. Note: Erratum: Nature 365: 468 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8446173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8446173</a>] [<a href="https://doi.org/10.1038/362083a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8446173">Girling et al., 1993</a>), were translationally repressed by the miRNAs Let7 (MIRLET7A1; <a href="/entry/605386">605386</a>) and miR184* (<a href="/entry/613146">613146</a>), respectively. Pathogenic human LRRK2 antagonized Let7 and miR184*, leading to overproduction of E2f1 and Dp, which was critical for LRRK2 pathogenesis. In Drosophila, genetic deletion of Let7, antagomir-mediated blockage of Let7 and miR184* action, transgenic expression of Dp target protector, or replacement of endogenous Dp with a Dp transgene nonresponsive to Let7 each had toxic effects similar to those of pathogenic LRRK2. Conversely, increasing the level of Let7 or miR184* attenuated pathogenic LRRK2 effects. Human LRRK2 associated with Drosophila Argonaute-1 (EIF2C1, or AGO1; <a href="/entry/606228">606228</a>) or human Argonaute-2 (EIF2C2, or AGO2; <a href="/entry/606229">606229</a>) of the RNA-induced silencing complex (RISC). In aged fly brain, Ago1 protein level was negatively regulated by human LRRK2. Furthermore, pathogenic LRRK2 promoted the association of phosphorylated 4EBP1 (EIF4EPB1; <a href="/entry/602223">602223</a>) with human AGO2. <a href="#27" class="mim-tip-reference" title="Gehrke, S., Imai, Y., Sokol, N., Lu, B. <strong>Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression.</strong> Nature 466: 637-641, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20671708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20671708</a>] [<a href="https://doi.org/10.1038/nature09191" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20671708">Gehrke et al. (2010)</a> concluded that deregulated synthesis of E2F1 and DP caused by miRNA pathway impairment is a key event in LRRK2 pathogenesis, suggesting that novel miRNA-based therapeutic strategies may be useful for Parkinson disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8446173+20671708" 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 a human LRRK2-Ypet genomic reporter system, immunofluorescence microscopy, and immunoelectron microscopy, <a href="#4" class="mim-tip-reference" title="Alegre-Abarrategui, J., Christian, H., Lufino, M. M. P., Mutihac, R., Venda, L. L., Ansorge, O., Wade-Martins, R. <strong>LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model.</strong> Hum. Molec. Genet. 18: 4022-4034, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19640926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19640926</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19640926[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/ddp346" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19640926">Alegre-Abarrategui et al. (2009)</a> found that LRRK2 was located to membrane microdomains such as the neck of caveolae, microvilli/filopodia and intraluminal vesicles of multivesicular bodies (MVBs). In human brain and in cultured human cells, LRRK2 was present in cytoplasmic puncta corresponding to MVBs and autophagic vacuoles (AVs). Expression of the common R1441C mutation (<a href="#0003">609007.0003</a>) from a genomic DNA construct caused impaired autophagic balance evident by the accumulation of MVBs and large AVs containing incompletely degraded material and increased levels of p62 (SQSTM1; <a href="/entry/601530">601530</a>). The R1441C mutation induced the formation of skein-like abnormal MVBs. Conversely, LRRK2 siRNA knockdown increased autophagic activity and prevented cell death caused by inhibition of autophagy in starvation conditions. <a href="#4" class="mim-tip-reference" title="Alegre-Abarrategui, J., Christian, H., Lufino, M. M. P., Mutihac, R., Venda, L. L., Ansorge, O., Wade-Martins, R. <strong>LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model.</strong> Hum. Molec. Genet. 18: 4022-4034, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19640926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19640926</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19640926[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/ddp346" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19640926">Alegre-Abarrategui et al. (2009)</a> proposed a functional involvement of LRRK2 in the endosomal-autophagic pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19640926" 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 microarray and RT-PCR analyses, <a href="#24" class="mim-tip-reference" title="Gardet, A., Benita, Y., Li, C., Sands, B. E., Ballester, I., Stevens, C., Korzenik, J. R., Rioux, J. D., Daly, M. J., Xavier, R. J., Podolsky, D. K. <strong>LRRK2 is involved in the IFN-gamma response and host response to pathogens.</strong> J. Immun. 185: 5577-5585, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20921534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20921534</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20921534[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/10.4049/jimmunol.1000548" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20921534">Gardet et al. (2010)</a> detected increased LRRK2 expression in monocytes and B cells and upregulation of LRRK2 after IFNG (<a href="/entry/147570">147570</a>) stimulation. Analysis of the LRRK2 promoter region revealed a conserved binding site for IFN response factors. Examination of lamina propria tissue from Crohn disease (CD; <a href="/entry/266600">266600</a>) patient specimens revealed upregulated LRRK2 expression in inflamed tissue compared with noninflamed tissue. Reporter assays showed that LRRK2 activated NFKB (see <a href="/entry/164011">164011</a>) in an IKK (see <a href="/entry/603258">603258</a>)-dependent manner. Confocal microscopy demonstrated colocalization of Lrrk2 with Salmonella typhimurium in infected murine macrophages. Lrrk2 knockdown interfered with the production of reactive oxygen species. <a href="#24" class="mim-tip-reference" title="Gardet, A., Benita, Y., Li, C., Sands, B. E., Ballester, I., Stevens, C., Korzenik, J. R., Rioux, J. D., Daly, M. J., Xavier, R. J., Podolsky, D. K. <strong>LRRK2 is involved in the IFN-gamma response and host response to pathogens.</strong> J. Immun. 185: 5577-5585, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20921534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20921534</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20921534[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/10.4049/jimmunol.1000548" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20921534">Gardet et al. (2010)</a> proposed that LRRK2 is an IFNG target gene that may be involved in signaling pathways relevant to Crohn disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20921534" 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 mutant flies and fly cell lines and the human SH-SY5Y neuroblastoma cell line, <a href="#39" class="mim-tip-reference" title="Kanao, T., Venderova, K., Park, D. S., Unterman, T., Lu, B., Imai, Y. <strong>Activation of FoxO by LRRK2 induces expression of proapoptotic proteins and alters survival of postmitotic dopaminergic neuron in Drosophila.</strong> Hum. Molec. Genet. 19: 3747-3758, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20624856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20624856</a>] [<a href="https://doi.org/10.1093/hmg/ddq289" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20624856">Kanao et al. (2010)</a> showed that the apoptotic effect of LRRK2 involved LRRK2-mediated phosphorylation of FOXO1 (FOXO1A; <a href="/entry/136533">136533</a>) and downstream FOXO signaling through the proapoptotic protein BIM (BCL2L11; <a href="/entry/603827">603827</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20624856" 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 a yeast 2-hybrid assay to screen a human cDNA library, <a href="#5" class="mim-tip-reference" title="Angeles, D. C., Gan, B.-H., Onstead, L., Zhao, Y., Lim, K.-L., Dachsel, J., Melrose, H., Farrer, M., Wszolek, Z. K., Dickson, D. W., Tan, E.-K. <strong>Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death.</strong> Hum. Mutat. 32: 1390-1397, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21850687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21850687</a>] [<a href="https://doi.org/10.1002/humu.21582" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21850687">Angeles et al. (2011)</a> found that LRRK2 interacts with PRDX3 (<a href="/entry/604769">604769</a>), an important antioxidant scavenger of hydrogen peroxide in the mitochondria. Mutations in the kinase domain of LRRK2, particularly G2019S, significantly increased the phosphorylation of PRDX3 compared to wildtype LRRK2, resulting in decreased peroxidase activity and increased death in LRRK2-expressing cells, but not in LRRK2-depleted cells. This resulted in dysregulation of mitochondrial function and increased oxidative damage. These damaging effects were exacerbated in PRDX3-depleted cells, suggesting that PRDX3 normally can rescue LRRK2-induced oxidative stress. The findings suggested that loss of endogenous antioxidant function may contribute to neurodegeneration induced by mutant LRRK2, as seen in Parkinson disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21850687" 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="#79" class="mim-tip-reference" title="Wang, X., Yan, M. H., Fujioka, H., Liu, J., Wilson-Delfosse, A., Chen, S. G., Perry, G., Casadesus, G., Zhu, X. <strong>LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1.</strong> Hum. Molec. Genet. 21: 1931-1944, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22228096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22228096</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22228096[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/dds003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22228096">Wang et al. (2012)</a> found that overexpression of wildtype LRRK2 in human neuronal cell lines caused mitochondrial fragmentation associated with increased levels of DLP1 (<a href="/entry/603850">603850</a>), a mitochondrial fission protein, and that these processes were exacerbated by expression of PD-associated mutants R1441C (<a href="#0003">609007.0003</a>) or G2019S (<a href="#0006">609007.0006</a>). LRRK2 directly interacted with DLP1, and this interaction was enhanced by LRRK2 PD-associated mutations. Increased mitochondrial fragmentation was associated with mitochondrial dysfunction and enhanced susceptibility to oxidative stress, which was inhibited with coexpression of a dominant-negative DLP1 mutant. These mitochondrial features were not apparent with LRRK2 mutants that had lost kinase activity. <a href="#79" class="mim-tip-reference" title="Wang, X., Yan, M. H., Fujioka, H., Liu, J., Wilson-Delfosse, A., Chen, S. G., Perry, G., Casadesus, G., Zhu, X. <strong>LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1.</strong> Hum. Molec. Genet. 21: 1931-1944, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22228096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22228096</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22228096[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/dds003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22228096">Wang et al. (2012)</a> concluded that LRRK2 regulates mitochondrial dynamics by interacting with DLP1, and that LRRK2 kinase activity plays a critical role in this process. The findings supported a role for altered mitochondrial fission/fusion in the pathogenesis of PD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22228096" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Bonello, F., Hassoun, S.-M., Mouton-Liger, F., Shin, Y. S., Muscat, A., Tesson, C., Lesage, S., Beart, P. M., Brice, A., Krupp, J., Corvol, J.-C., Corti, O. <strong>LRRK2 impairs PNK1/parkin-dependent mitophagy via its kinase activity: pathologic insights into Parkinson's disease.</strong> Hum. Molec. Genet. 28: 1645-1660, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30629163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30629163</a>] [<a href="https://doi.org/10.1093/hmg/ddz004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30629163">Bonello et al. (2019)</a> found that LRRK2 attenuated parkin-dependent mitophagy induced by carbonylcyanide m-chlorophenylhydrazone (CCCP) in COS-7 cells. The attenuation of mitophagy was kinase dependent, as LRRK2 kinase activity disrupted protein-protein interactions involving parkin and DRP1 (DNM1L; <a href="/entry/603850">603850</a>) on mitochondria. The authors also developed a model for parkin-dependent mitophagy triggered by thermal stress in human fibroblasts. They found that parkin-dependent mitophagy was impaired in fibroblasts from patients with PD. Furthermore, in agreement with disruption of mitochondrial recruitment of DRP1 by LRRK2 activity, a pharmacologic LRRK2 kinase inhibitor rescued the mitophagy defect in fibroblasts from PD patients in a DRP1-dependent manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30629163" 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 immunoprecipitation and pull-down assays, <a href="#66" class="mim-tip-reference" title="Shani, V., Safory, H., Szargel, R., Wang, N., Cohen, T., Elghani, F. A., Hamza, H., Savyon, M., Radzishevsky, I., Shaulov, L., Rott, R., Lim, K. L., Ross, C. A., Bandopadhyay, R., Zhang, H., Engelender, S. <strong>Physiological and pathological roles of LRRK2 in the nuclear envelope integrity.</strong> Hum. Molec. Genet. 28: 3982-3996, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31626293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31626293</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31626293[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/ddz245" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31626293">Shani et al. (2019)</a> showed that LRRK2 interacted with lamin A/C in the nuclear cytoskeleton. LRRK2 also interacted with the ubiquitin ligases SIAH1 (<a href="/entry/602212">602212</a>) and SIAH2 (<a href="/entry/602213">602213</a>), both of which ubiquitinated LRRK2. Further analysis with SIAH1 confirmed that it facilitated nuclear translocation of LRRK2. In vitro and in vivo analyses demonstrated that LRRK2 helped maintain the nuclear lamina and the nuclear membrane integrity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31626293" 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 knockdown analysis in human and mouse primary monocyte-derived cells polarized to macrophages, <a href="#50" class="mim-tip-reference" title="Liu, Z., Xu, E., Zhao, H. T., Cole, T., West, A. B. <strong>LRRK2 and Rab10 coordinate macropinocytosis to mediate immunological responses in phagocytes.</strong> EMBO J. 39: e104862, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32853409/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32853409</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32853409[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/10.15252/embj.2020104862" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32853409">Liu et al. (2020)</a> showed that RAB10 (<a href="/entry/612672">612672</a>) expression regulated macropinocytosis. RAB10 was recruited to early stages of macropinocytosis and regulated macropinosome trafficking. GTP binding was required for localization of RAB10 to early macropinosomes, whereas GTP hydrolysis was required for dissociation of RAB10 from macropinosomes. LRRK2 transiently interacted with the GTP-bound form of RAB10 on early macropinosomes, where it phosphorylated RAB10 and thereby stalled RAB10 on early macropinosomes during vesicle maturation. A proteomic approach in mouse macrophages showed that Ehbp1l1 (<a href="/entry/619583">619583</a>) interacted with GTP-bound, vesicle-associated Rab10 to regulate recycling of macropinosomes. Lrrk2-mediated phosphorylation of GTP-bound Rab10 inhibited Ehbp1l1-dependent fast recycling of macropinosomes by directly competing with Ehbp1l1 for complex occupancy and blocking binding of Ehbp1l1 to Rab10. Further analysis demonstrated that, although Lrrk2 phosphorylation of GTP-bound Rab10 did not directly regulate fluid cargo uptake, it potentiated Ccl5 (<a href="/entry/187011">187011</a>)-stimulated Akt (<a href="/entry/164730">164730</a>) signaling and macrophage chemotaxis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32853409" 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="#62" class="mim-tip-reference" title="Pischedda, F., Cirnaru, M. D., Ponzoni, L., Sandre, M., Biosa, A., Carrion, M. P., Marin, O., Morari, M., Pan, L., Greggio, E., Bandopadhyay, R., Sala, M., Piccoli, G. <strong>LRRK2 G2019S kinase activity triggers neurotoxic NSF aggregation.</strong> Brain 144: 1509-1525, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33876242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33876242</a>] [<a href="https://doi.org/10.1093/brain/awab073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33876242">Pischedda et al. (2021)</a> studied dopaminergic neurons differentiated from iPSCs expressing LRRK2 with the G2019S mutation (<a href="#0006">609007.0006</a>) and identified the presence of high molecular weight complexes containing N-ethylmaleimide sensitive factor (NSF). These complexes were found to be dependent on phosphorylation of NSF at Thr645. <a href="#62" class="mim-tip-reference" title="Pischedda, F., Cirnaru, M. D., Ponzoni, L., Sandre, M., Biosa, A., Carrion, M. P., Marin, O., Morari, M., Pan, L., Greggio, E., Bandopadhyay, R., Sala, M., Piccoli, G. <strong>LRRK2 G2019S kinase activity triggers neurotoxic NSF aggregation.</strong> Brain 144: 1509-1525, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33876242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33876242</a>] [<a href="https://doi.org/10.1093/brain/awab073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33876242">Pischedda et al. (2021)</a> suggested that phosphorylation of NSF at Thr645 by LRRK2 with the G2019S mutation promotes oligomerization and precipitation into cytotoxic protein inclusions. <a href="#62" class="mim-tip-reference" title="Pischedda, F., Cirnaru, M. D., Ponzoni, L., Sandre, M., Biosa, A., Carrion, M. P., Marin, O., Morari, M., Pan, L., Greggio, E., Bandopadhyay, R., Sala, M., Piccoli, G. <strong>LRRK2 G2019S kinase activity triggers neurotoxic NSF aggregation.</strong> Brain 144: 1509-1525, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33876242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33876242</a>] [<a href="https://doi.org/10.1093/brain/awab073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33876242">Pischedda et al. (2021)</a> also studied postmortem brain tissue from patients with sporadic Parkinson disease and patients with Parkinson disease caused by the LRKK2 G2019S mutation and identified aggregates containing NSF in the basal ganglia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33876242" 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>LRRK2 contains a 'Ras of complex proteins' (ROC) domain that may act as a GTPase to regulate its kinase activity. <a href="#16" class="mim-tip-reference" title="Deng, J., Lewis, P. A., Greggio, E., Sluch, E., Beilina, A., Cookson, M. R. <strong>Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase.</strong> Proc. Nat. Acad. Sci. 105: 1499-1504, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18230735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18230735</a>] [<a href="https://doi.org/10.1073/pnas.0709098105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18230735">Deng et al. (2008)</a> reported the crystal structure of the LRRK2 ROC domain in complex with GDP-Mg(2+) at 2.0-angstrom resolution. The structure displayed a dimeric fold generated by extensive domain swapping, resulting in a pair of active sites with essential functional groups contributed from both monomers. Two residues mutated in PARK8, arg1331 and ile1371, were located at the interface of the 2 monomers and provided interactions to stabilize the ROC dimer. <a href="#16" class="mim-tip-reference" title="Deng, J., Lewis, P. A., Greggio, E., Sluch, E., Beilina, A., Cookson, M. R. <strong>Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase.</strong> Proc. Nat. Acad. Sci. 105: 1499-1504, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18230735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18230735</a>] [<a href="https://doi.org/10.1073/pnas.0709098105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18230735">Deng et al. (2008)</a> concluded that PARK8-associated mutations in the ROC domain disrupt dimer formation, resulting in decreased GTPase activity. They proposed that the ROC domain regulates LRRK2 kinase activity as a dimer, possibly via the COR domain acting as a molecular hinge. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18230735" 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="#14" class="mim-tip-reference" title="Dachsel, J. C., Farrer, M. J. <strong>LRRK2 and Parkinson disease.</strong> Arch. Neurol. 67: 542-547, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20457952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20457952</a>] [<a href="https://doi.org/10.1001/archneurol.2010.79" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20457952">Dachsel and Farrer (2010)</a> provided a review of the LRRK2 gene and its role in Parkinson disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20457952" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 5 families with autosomal dominant Parkinson disease-8 (PARK8; <a href="/entry/607060">607060</a>), <a href="#59" class="mim-tip-reference" title="Paisan-Ruiz, C., Jain, S., Evans, E. W., Gilks, W. P., Simon, J., van der Brug, M., Lopez de Munain, A., Aparicio, S., Martinez Gil, A., Khan, N., Johnson, J., Martinez, J. R., and 9 others. <strong>Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease.</strong> Neuron 44: 595-600, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15541308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15541308</a>] [<a href="https://doi.org/10.1016/j.neuron.2004.10.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15541308">Paisan-Ruiz et al. (2004)</a> identified 2 different heterozygous mutations in the LRRK2 gene (<a href="#0001">609007.0001</a>-<a href="#0002">609007.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15541308" 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="#88" class="mim-tip-reference" title="Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln, S., Kachergus, J., Hulihan, M., Uitti, R. J., Calne, D. B., Stoessl, A. J., Pfeiffer, R. F., Patenge, N., Carballo Carbajal, I., Vieregge, P., Asmus, F., Muller-Myhsok, B., Dickson, D. W., Meitinger, T., Strom, T. M., Wszolek, Z. K., Gasser, T. <strong>Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.</strong> Neuron 44: 601-607, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15541309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15541309</a>] [<a href="https://doi.org/10.1016/j.neuron.2004.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15541309">Zimprich et al. (2004)</a> identified 6 mutations in the LRRK2 gene in families with Parkinson disease-8 (see, e.g., <a href="#0003">609007.0003</a>-<a href="#0005">609007.0005</a>). Postmortem analysis of several affected persons demonstrated variable pathology, including Lewy bodies, nigral degeneration without Lewy bodies, and tau (MAPT; <a href="/entry/157140">157140</a>)-reactive neuronal and glial lesions. <a href="#88" class="mim-tip-reference" title="Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln, S., Kachergus, J., Hulihan, M., Uitti, R. J., Calne, D. B., Stoessl, A. J., Pfeiffer, R. F., Patenge, N., Carballo Carbajal, I., Vieregge, P., Asmus, F., Muller-Myhsok, B., Dickson, D. W., Meitinger, T., Strom, T. M., Wszolek, Z. K., Gasser, T. <strong>Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.</strong> Neuron 44: 601-607, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15541309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15541309</a>] [<a href="https://doi.org/10.1016/j.neuron.2004.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15541309">Zimprich et al. (2004)</a> suggested that LRRK2 may play a role in several neurodegenerative disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15541309" 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="#56" class="mim-tip-reference" title="Nichols, W. C., Pankratz, N., Hernandez, D., Paisan-Ruiz, C., Jain, S., Halter, C. A., Michaels, V. E., Reed, T., Rudolph, A., Shults, C. W., Singleton, A., Foroud, T. <strong>Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease.</strong> Lancet 365: 410-412, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15680455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15680455</a>] [<a href="https://doi.org/10.1016/S0140-6736(05)17828-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15680455">Nichols et al. (2005)</a> identified a heterozygous gly2019-to-ser substitution in the LRRK2 gene (G2019S; <a href="#0006">609007.0006</a>) in 6% of families with autosomal dominant PD and suggested genetic screening for this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15680455" 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 all 19 affected members of the original Japanese family with Parkinson disease-8 (<a href="#34" class="mim-tip-reference" title="Hasegawa, K., Kowa, H. <strong>Autosomal dominant familial Parkinson disease: older onset of age, and good response to levodopa therapy.</strong> Europ. Neurol. 38 (suppl. 1): 39-43, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9276200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9276200</a>] [<a href="https://doi.org/10.1159/000113460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9276200">Hasegawa and Kowa, 1997</a>), <a href="#20" class="mim-tip-reference" title="Funayama, M., Hasegawa, K., Ohta, E., Kawashima, N., Komiyama, M., Kowa, H., Tsuji, S., Obata, F. <strong>An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family.</strong> Ann. Neurol. 57: 918-921, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15880653/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15880653</a>] [<a href="https://doi.org/10.1002/ana.20484" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15880653">Funayama et al. (2005)</a> identified a heterozygous mutation in the LRRK2 gene (<a href="#0007">609007.0007</a>). The mutation was not identified in 188 patients with sporadic PD. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9276200+15880653" 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 allelic discrimination assays for 9 LRRK2 mutations, <a href="#19" class="mim-tip-reference" title="Farrer, M., Stone, J., Mata, I. F., Lincoln, S., Kachergus, J., Hulihan, M., Strain, K. J., Maraganore, D. M. <strong>LRRK2 mutations in Parkinson disease.</strong> Neurology 65: 738-740, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16157908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16157908</a>] [<a href="https://doi.org/10.1212/01.wnl.0000169023.51764.b0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16157908">Farrer et al. (2005)</a> identified pathogenic mutations in the LRRK2 gene in 5 (0.6%) of 786 probands with idiopathic PD. Four probands carried the common G2019S mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16157908" 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 screening LRRK2 exons 31, 35, and 41, <a href="#87" class="mim-tip-reference" title="Zabetian, C. P., Samii, A., Mosley, A. D., Roberts, J. W., Leis, B. C., Yearout, D., Raskind, W. H., Griffith, A. <strong>A clinic-based study of the LRRK2 gene in Parkinson disease yields new mutations.</strong> Neurology 65: 741-744, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16157909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16157909</a>] [<a href="https://doi.org/10.1212/01.wnl.0000172630.22804.73" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16157909">Zabetian et al. (2005)</a> identified LRRK2 mutations in 6 (1.6%) of 371 unrelated patients with PD. Four patients were sporadic, and 2 had a family history of the disorder. All 6 patients were of European ancestry. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16157909" 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="#60" class="mim-tip-reference" title="Paisan-Ruiz, C., Lang, A. E., Kawarai, T., Sato, C., Salehi-Rad, S., Fisman, G. K., Al-Khairallah, T., St George-Hyslop, P., Singleton, A., Rogaeva, E. <strong>LRRK2 gene in Parkinson disease: mutation analysis and case control association study.</strong> Neurology 65: 696-700, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16157901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16157901</a>] [<a href="https://doi.org/10.1212/01.wnl.0000167552.79769.b3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16157901">Paisan-Ruiz et al. (2005)</a> identified 2 different LRRK2 mutations in 3 of 23 unrelated probands with autosomal dominant Parkinson disease. Two probands had the common G2019S mutation. In a case-control study of 121 unrelated PD patients and 250 controls, <a href="#60" class="mim-tip-reference" title="Paisan-Ruiz, C., Lang, A. E., Kawarai, T., Sato, C., Salehi-Rad, S., Fisman, G. K., Al-Khairallah, T., St George-Hyslop, P., Singleton, A., Rogaeva, E. <strong>LRRK2 gene in Parkinson disease: mutation analysis and case control association study.</strong> Neurology 65: 696-700, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16157901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16157901</a>] [<a href="https://doi.org/10.1212/01.wnl.0000167552.79769.b3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16157901">Paisan-Ruiz et al. (2005)</a> found no association between PD and any of 4 LRRK2 polymorphisms examined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16157901" 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 7 of 100 unrelated families with Parkinson disease, <a href="#54" class="mim-tip-reference" title="Mata, I. F., Kachergus, J. M., Taylor, J. P., Lincoln, S., Aasly, J., Lynch, T., Hulihan, M. M., Cobb, S. A., Wu, R.-M., Lu, C.-S., Lahoz, C., Wszolek, Z. K., Farrer, M. J. <strong>Lrrk2 pathogenic substitutions in Parkinson's disease.</strong> Neurogenetics 6: 171-177, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16172858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16172858</a>] [<a href="https://doi.org/10.1007/s10048-005-0005-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16172858">Mata et al. (2005)</a> identified 7 different heterozygous mutations in the LRRK2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16172858" 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="Biskup, S., Mueller, J. C., Sharma, M., Lichtner, P., Zimprich, A., Berg, D., Wullner, U., Illig, T., Meitinger, T., Gasser, T. <strong>Common variants of LRRK2 are not associated with sporadic Parkinson's disease.</strong> Ann. Neurol. 58: 905-908, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16254973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16254973</a>] [<a href="https://doi.org/10.1002/ana.20664" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16254973">Biskup et al. (2005)</a> identified the G2019S mutation in 1 (0.29%) of 340 German patients with sporadic PD. In a case-control study of these 340 patients and 680 controls, they found no significant association between PD and any of 121 LRRK2 SNPs, covering the entire gene region. They replicated the finding in a second set of 322 German sporadic PD patients and 322 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16254973" 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 autophosphorylation and GTP-binding assay, <a href="#81" class="mim-tip-reference" title="West, A. B., Moore, D. J., Choi, C., Andrabi, S. A., Li, X., Dikeman, D., Biskup, S., Zhang, Z., Lim, K.-L, Dawson, V. L., Dawson, T. M. <strong>Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity.</strong> Hum. Molec. Genet. 16: 223-232, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17200152/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17200152</a>] [<a href="https://doi.org/10.1093/hmg/ddl471" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17200152">West et al. (2007)</a> showed that in the normal state, the GTPase activity of the LRRK2 protein is required for and modulates downstream kinase activity, but that kinase activity does not have a significant effect on GTP binding. Using site-directed mutagenesis constructs of specific PD-associated mutations, the authors showed that increased kinase activity was the most common biochemical feature of pathogenic missense mutations. Specific mutations examined included 2 in the kinase domain (G2019S; <a href="#0006">609007.0006</a> and I2020T; <a href="#0007">609007.0007</a>), 2 in the GTPase domain (R1441C; <a href="#0003">609007.0003</a> and R1441G; <a href="#0001">609007.0001</a>), 1 in the LRR domain (I1122V; <a href="#0005">609007.0005</a>), and 1 in the COR domain (Y1699C; <a href="#0002">609007.0002</a>). The G2385R (<a href="#0009">609007.0009</a>) polymorphism did not cause any change in kinase activity, consistent with it being a benign polymorphism. Studies in cultured mouse cells showed that the increased kinase activity of the mutants was toxic. Overall, the findings indicated that pathogenic LRRK2 mutations potentiate neurotoxicity in a kinase-dependent manner via gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17200152" 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="#61" class="mim-tip-reference" title="Paisan-Ruiz, C., Nath, P., Washecka, N., Gibbs, J. R., Singleton, A. B. <strong>Comprehensive analysis of LRRK2 in publicly available Parkinson's disease cases and neurologically normal controls.</strong> Hum. Mutat. 29: 485-490, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18213618/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18213618</a>] [<a href="https://doi.org/10.1002/humu.20668" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18213618">Paisan-Ruiz et al. (2008)</a> performed a comprehensive sequence-based analysis of the entire LRRK2 gene in 275 patients with PD and 275 controls. Six novel disease-associated mutations were identified, but there were no gene deletions or duplications. LRRK2 mutations were found in 3.6% of the PD patients. Multiple gene variants or SNPs were identified, none of which were associated with disease. Combined with previous reports, the data showed that the majority of disease-causing LRRK2 mutations lie in the C-terminal half of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18213618" 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="Garrido, A., Perez-Sisques, L., Simonet, C., Campoy-Campos, G., Solana-Balaguer, J., Martin-Flores, N., Fernandez, M., Soto, M., Obiang, D., Camara, A., Valldeoriola, F., Munoz, E., Compta, Y., Perez-Navarro, E., Alberch, J., Tolosa, E., Marti, M. J., Ezquerra, M., Malagelada, C., Fernandez-Santiago, R. <strong>Increased phospho-AKT in blood cells from LRRK2 G2019S mutation carriers.</strong> Ann. Neurol. 92: 888-894, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35929078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35929078</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35929078[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.26469" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35929078">Garrido et al. (2022)</a> studied AKT phosphorylation in PBMCs from 25 patients with PD and 25 individuals at risk for PD who were heterozygous for the G2019S mutation (<a href="#0006">609007.0006</a>) in the LRRK2 gene. Compared to controls and patients with idiopathic PD, heterozygotes for the G2019S mutation had increased phosphorylation at ser473 of the AKT (<a href="/entry/164730">164730</a>) protein. <a href="#25" class="mim-tip-reference" title="Garrido, A., Perez-Sisques, L., Simonet, C., Campoy-Campos, G., Solana-Balaguer, J., Martin-Flores, N., Fernandez, M., Soto, M., Obiang, D., Camara, A., Valldeoriola, F., Munoz, E., Compta, Y., Perez-Navarro, E., Alberch, J., Tolosa, E., Marti, M. J., Ezquerra, M., Malagelada, C., Fernandez-Santiago, R. <strong>Increased phospho-AKT in blood cells from LRRK2 G2019S mutation carriers.</strong> Ann. Neurol. 92: 888-894, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35929078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35929078</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35929078[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.26469" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35929078">Garrido et al. (2022)</a> concluded that AKT ser473 is a biomarker for the G2019 mutation in the LRRK2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35929078" 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>Susceptibility to Parkinson Disease</em></strong></p><p>
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<a href="#68" class="mim-tip-reference" title="Skipper, L., Li, Y., Bonnard, C., Pavanni, R., Yih, Y., Chua, E., Sung, W.-K., Tan, L., Wong, M.-C., Tan, E.-K., Liu, J. <strong>Comprehensive evaluation of common genetic variation within LRRK2 reveals evidence for association with sporadic Parkinson's disease.</strong> Hum. Molec. Genet. 14: 3549-3556, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16269443/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16269443</a>] [<a href="https://doi.org/10.1093/hmg/ddi376" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16269443">Skipper et al. (2005)</a> identified a subset of tagging-SNPs (tSNP) that captured the majority of common variation within LRRK2. Both single tSNP and tSNP haplotype analyses, using a large epidemiologically-matched sporadic case-control series comprising 932 Chinese individuals, yielded significant evidence for association with Parkinson disease. The authors identified a haplotype that dramatically increased disease risk when present in 2 copies (odds ratio = 5.5; P = 0.0001). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16269443" 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>Among Taiwanese and Chinese, <a href="#18" class="mim-tip-reference" title="Di Fonzo, A., Wu-Chou, Y.-H., Lu, C.-S., van Doeselaar, M., Simons, E. J., Rohe, C. F., Chang, H.-C., Chen, R.-S., Weng, Y.-H., Vanacore, N., Breedveld, G. J., Oostra, B. A., Bonifati, V. <strong>A common missense variant in the LRRK2 gene, gly2385-to-arg, associated with Parkinson's disease risk in Taiwan.</strong> Neurogenetics 7: 133-138, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16633828/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16633828</a>] [<a href="https://doi.org/10.1007/s10048-006-0041-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16633828">Di Fonzo et al. (2006)</a> and <a href="#72" class="mim-tip-reference" title="Tan, E. K., Zhao, Y., Skipper, L., Tan, M. G., Di Fonzo, A., Sun, L., Fook-Chong, S., Tang, S., Chua, E., Yuen, Y., Tan, L., Pavanni, R., Wong, M. C., Kolatkar, P., Lu, C. S., Bonifati, V., Liu, J. J. <strong>The LRRK2 gly2385-to-arg variant is associated with Parkinson's disease: genetic and functional evidence.</strong> Hum. Genet. 120: 857-863, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17019612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17019612</a>] [<a href="https://doi.org/10.1007/s00439-006-0268-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17019612">Tan et al. (2007)</a> found that a common polymorphism (G2385R; <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs34778348;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs34778348</a>; <a href="#0009">609007.0009</a>) was significantly more frequent among patients with Parkinson disease compared to controls. The findings suggested that the G2385R variant may be a common risk factor for later-onset PD among Asian populations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16633828+17019612" 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="#64" class="mim-tip-reference" title="Ross, O. A., Wu, Y.-R., Lee, M.-C., Funayama, M., Chen, M.-L., Soto, A. I., Mata, I. F., Lee-Chen, G.-J., Chen, C. M., Tang, M., Zhao, Y., Hattori, N., Farrer, M. J., Tan, E.-K., Wu, R.-M. <strong>Analysis of LRRK2 R1628P as a risk factor for Parkinson's disease.</strong> Ann. Neurol. 64: 88-96, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18412265/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18412265</a>] [<a href="https://doi.org/10.1002/ana.21405" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18412265">Ross et al. (2008)</a> found that a 4883G-C SNP in the LRRK2 gene, resulting in an arg1628-to-pro (R1628P; <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs33949390;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs33949390</a>) variant, was associated with increased risk for typical late-onset, dopa-responsive Parkinson disease in Chinese individuals. The carrier frequency was 6.1% among 1,079 Han Chinese PD patients and 3.4% among 907 controls (odds ratio of 1.84; p = 0.006) combined from 3 cohorts. Haplotype analysis indicated an ancestral founder for carriers about 2,500 years ago. <a href="#64" class="mim-tip-reference" title="Ross, O. A., Wu, Y.-R., Lee, M.-C., Funayama, M., Chen, M.-L., Soto, A. I., Mata, I. F., Lee-Chen, G.-J., Chen, C. M., Tang, M., Zhao, Y., Hattori, N., Farrer, M. J., Tan, E.-K., Wu, R.-M. <strong>Analysis of LRRK2 R1628P as a risk factor for Parkinson's disease.</strong> Ann. Neurol. 64: 88-96, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18412265/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18412265</a>] [<a href="https://doi.org/10.1002/ana.21405" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18412265">Ross et al. (2008)</a> noted that the R1628P SNP is highly conserved and located within the functionally important COR domain. Among 1,337 Han Chinese individuals, <a href="#51" class="mim-tip-reference" title="Lu, C.-S., Wu-Chou, Y.-H., van Doeselaar, M., Simons, E. J., Chang, H.-C., Breedveld, G. J., Di Fonzo, A., Chen, R.-S., Weng, Y.-H., Lai, S.-C., Oostra, B. A., Bonifati, V. <strong>The LRRK2 Arg1628Pro variant is a risk factor for Parkinson's disease in the Chinese population.</strong> Neurogenetics 9: 271-276, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18716801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18716801</a>] [<a href="https://doi.org/10.1007/s10048-008-0140-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18716801">Lu et al. (2008)</a> found that the R1628P SNP was more common among patients (3.8%) compared to controls (1.8%) (odds ratio of 2.13; p = 0.004). <a href="#51" class="mim-tip-reference" title="Lu, C.-S., Wu-Chou, Y.-H., van Doeselaar, M., Simons, E. J., Chang, H.-C., Breedveld, G. J., Di Fonzo, A., Chen, R.-S., Weng, Y.-H., Lai, S.-C., Oostra, B. A., Bonifati, V. <strong>The LRRK2 Arg1628Pro variant is a risk factor for Parkinson's disease in the Chinese population.</strong> Neurogenetics 9: 271-276, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18716801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18716801</a>] [<a href="https://doi.org/10.1007/s10048-008-0140-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18716801">Lu et al. (2008)</a> concluded that R1628P is a risk factor for Parkinson disease in the Han Chinese population. <a href="#71" class="mim-tip-reference" title="Tan, E. K., Tan, L. C., Lim, H. Q., Li, R., Tang, M., Yih, Y., Pavanni, R., Prakash, K. M., Fook-Chong, S., Zhao, Y. <strong>LRRK2 R1628P increases risk of Parkinson's disease: replication evidence.</strong> Hum. Genet. 124: 287-288, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18781329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18781329</a>] [<a href="https://doi.org/10.1007/s00439-008-0544-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18781329">Tan et al. (2008)</a> also concluded that R1628P is a risk factor for PD among Han Chinese individuals. The frequency of the heterozygous R1628P mutation was higher in 246 PD patients compared to 243 controls (8.4% vs 3.4%, OR of 2.5). Multivariant logistic regression analysis controlling for age, age at onset, and gender yielded an OR of 3.3. <a href="#74" class="mim-tip-reference" title="Tan, E.-K., Tang, M., Tan, L. C., Wu, Y.-R., Wu, R.-M., Ross, O. A., Zhao, Y. <strong>Lrrk2 R1628P in non-Chinese Asian races.</strong> Ann. Neurol. 64: 472-473, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18688798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18688798</a>] [<a href="https://doi.org/10.1002/ana.21467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18688798">Tan et al. (2008)</a> found no association between the R1628P variant and PD among 132 PD patients of Malay ancestry compared to 160 Malay controls. In addition, the R1628P variant was not identified in 165 Indian individuals, both PD patients and controls. The authors concluded that the R1628P variant is indeed specific to the Chinese population, and that it is a relatively recent mutation event, occurring about 2,500 years earlier. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18688798+18412265+18716801+18781329" 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 genomewide association studies in 1,713 individuals of European ancestry with PD and 3,978 controls, with replication in 3,361 cases and 4,573 controls, <a href="#67" class="mim-tip-reference" title="Simon-Sanchez, J., Schulte, C., Bras, J. M., Sharma, M., Gibbs, J. R., Berg, D., Paisan-Ruiz, C., Lichtner, P., Scholz, S. W., Hernandez, D. G., Kruger, R., Federoff, M., and 35 others. <strong>Genome-wide association study reveals genetic risk underlying Parkinson's disease. (Letter)</strong> Nature Genet. 41: 1308-1312, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19915575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19915575</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19915575[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.487" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19915575">Simon-Sanchez et al. (2009)</a> found supporting evidence that common variation around LRRK2 modulates risk for PD (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1491923;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1491923</a>, OR = 1.14, p = 1.55 x 10(-5)). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19915575" 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="#73" class="mim-tip-reference" title="Tan, E.-K., Peng, R., Teo, Y.-Y., Tan, L. C., Angeles, D., Ho, P., Chen, M.-L., Lin, C.-H., Mao, X.-Y., Chang, X.-L., Prakash, K. M., Liu, J.-J., Au, W.-L., Le, W.-D., Jankovic, J., Burgunder, J.-M., Zhao, Y., Wu, R.-M. <strong>Multiple LRRK2 variants modulate risk of Parkinson disease: a Chinese multicenter study.</strong> Hum. Mutat. 31: 561-568, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20186690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20186690</a>] [<a href="https://doi.org/10.1002/humu.21225" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20186690">Tan et al. (2010)</a> genotyped a total of 1,363 Han Chinese patients with PD and 1,251 Han Chinese controls for SNPs in the LRRK2 gene. There was a discovery set of 250 patients from Singapore and 3 replication cohorts including 192 patients from Singapore, 293 patients from Taiwan, and 628 patients from China, along with controls. The median age at onset for the entire patient group was 56 years. Significant disease associations were found with SNPs <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs7308720;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs7308720</a> (N551K), <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs7133914;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs7133914</a> (R1398H), and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11564148;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs11564148</a> (S1647T). A combined analysis showed that R1398H and N551K were associated with a decreased disease risk, and S1647T, R1628P, and G2385R were associated with an increased disease risk. Multivariate regression analysis showed that the effect of R1398H and N551K was independent of G2385R and R1628P. The estimated risk of PD for carriers of both R1628P and G2385R was 1.87, and the presence of a protective variant, R1398H or N551K, reduced this risk to 1.5 to 1.6. In vitro functional analysis showed that R1628P and G2385R had higher autophosphorylation and kinase activity compared to control and that R1398H had decreased autophosphorylation and compromised kinase activity. <a href="#73" class="mim-tip-reference" title="Tan, E.-K., Peng, R., Teo, Y.-Y., Tan, L. C., Angeles, D., Ho, P., Chen, M.-L., Lin, C.-H., Mao, X.-Y., Chang, X.-L., Prakash, K. M., Liu, J.-J., Au, W.-L., Le, W.-D., Jankovic, J., Burgunder, J.-M., Zhao, Y., Wu, R.-M. <strong>Multiple LRRK2 variants modulate risk of Parkinson disease: a Chinese multicenter study.</strong> Hum. Mutat. 31: 561-568, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20186690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20186690</a>] [<a href="https://doi.org/10.1002/humu.21225" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20186690">Tan et al. (2010)</a> concluded that multiple LRRK2 variants exert individual effects and together may modulate the risk of PD in the Han Chinese population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20186690" 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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In COS-7 cells, <a href="#52" class="mim-tip-reference" title="MacLeod, D., Dowman, J., Hammond, R., Leete, T., Inoue, K., Abeliovich, A. <strong>The familial parkinsonism gene LRRK2 regulates neurite process morphology.</strong> Neuron 52: 587-593, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17114044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17114044</a>] [<a href="https://doi.org/10.1016/j.neuron.2006.10.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17114044">MacLeod et al. (2006)</a> found that G2019S and I2020T (<a href="#0007">609007.0007</a>) mutant LRRK2 had significantly increased kinase activity compared to wildtype LRRK2. The G2019S-mutant protein was present in distinctive tau-positive spheroid-like axonal inclusions and at intracellular membranous structures. Overexpression of either of these mutants in rat cortical neurons resulted in a dramatic reduction in neurite length and branching, as well as decreased neuron survival. In contrast, cortical neurons transfected with LRRK2-shRNA vectors showed a prominent increase in neurite length and branching. Overall, the findings indicated that LRRK2 regulates neuronal process morphology in the central nervous system, suggesting a role for LRRK2 in the maintenance of neuronal process length and complexity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17114044" 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="Lin, X., Parisiadou, L., Gu, X.-L., Wang, L., Shim, H., Sun, L., Xie, C., Long, C.-X., Yang, W.-J., Ding, J., Chen, Z. Z., Gallant, P. E., Tao-Cheng, J.-H., Rudow, G., Troncoso, J. C., Liu, Z., Li, Z., Cai, H. <strong>Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein.</strong> Neuron 64: 807-827, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20064389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20064389</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20064389[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2009.11.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20064389">Lin et al. (2009)</a> found that overexpression of Lrrk2, either wildtype or mutant, in transgenic mice carrying an A53T Snca mutation (<a href="/entry/163890#0001">163890.0001</a>) accelerated the PD-related neuropathologic abnormalities by promoting aggregation and accumulation of cytotoxic Snca-containing protein inclusions in cell bodies of striatal neurons. However, the 2 proteins did not appear to interact directly. Degenerating neurons showed fragmentation of the Golgi apparatus, which correlated with the accumulation of Snca. Immunostaining studies showed evidence of impaired microtubule assembly within the cells as well as impairment of the ubiquitin-proteasome system. Mitochondrial function was also impaired. Inhibition of Lrrk2 in these mice suppressed these abnormalities and delayed the progression of neuropathology in A53T mutant mice. The findings suggested that Lrrk2 may regulate mutant Snca-mediated neuropathology by modulating the intracellular trafficking and microtubule-based axonal transport of Snca. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20064389" 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="Lee, B. D., Shin, J.-H., VanKampen, J., Petrucelli, L., West, A. B., Ko, H. S., Lee, Y.-I., Maguire-Zeiss, K. A., Bowers, W. J., Federoff, H. J., Dawson, V. L., Dawson, T. M. <strong>Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease.</strong> Nature Med. 16: 998-1000, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20729864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20729864</a>] [<a href="https://doi.org/10.1038/nm.2199" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20729864">Lee et al. (2010)</a> presented evidence demonstrating that pharmacologic inhibitors of LRRK2 kinase activity are protective in both in vitro and in vivo mouse models of LRRK2-induced neurodegeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20729864" 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="#9" class="mim-tip-reference" title="Boddu, R., Hull, T. D., Bolisetty, S., Hu, X., Moehle, M. S., Daher, J. P. L., Kamal, A. I., Joseph, R., George, J. F., Agarwal, A., Curtis, L. M., West, A. B. <strong>Leucine-rich repeat kinase 2 deficiency is protective in rhabdomyolysis-induced kidney injury.</strong> Hum. Molec. Genet. 24: 4078-4093, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25904107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25904107</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25904107[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/ddv147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25904107">Boddu et al. (2015)</a> stated that Lrrk2 -/- mice and rats have subtle multisystem abnormalities, but the most striking phenotype is development of profound kidney discoloration. In rats, <a href="#9" class="mim-tip-reference" title="Boddu, R., Hull, T. D., Bolisetty, S., Hu, X., Moehle, M. S., Daher, J. P. L., Kamal, A. I., Joseph, R., George, J. F., Agarwal, A., Curtis, L. M., West, A. B. <strong>Leucine-rich repeat kinase 2 deficiency is protective in rhabdomyolysis-induced kidney injury.</strong> Hum. Molec. Genet. 24: 4078-4093, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25904107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25904107</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25904107[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/ddv147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25904107">Boddu et al. (2015)</a> found that discoloration in Lrrk2 -/- kidney was due to accumulation of oxidized hemoglobin. Lrrk2 -/- rat kidney also showed mononuclear infiltration and accumulation of oxidized lipids and other blood products, but mutant kidney had overall normal architecture and function, and Lrrk2 -/- rats lived to normal ages. Mutant proximal tubules demonstrated upregulation of cytoprotective heme oxygenase (HMOX1; <a href="/entry/141250">141250</a>), which appeared to mitigate acute kidney injury, including glycerol-induced rhabdomyolysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25904107" 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="#40" class="mim-tip-reference" title="Kozina, E., Sadasivan, S., Jiao, Y., Dou, Y., Ma, Z., Tan, H., Kodali, K., Shaw, T., Peng, J., Smeyne, R. J. <strong>Mutant LRRK2 mediates peripheral and central immune responses leading to neurodegeneration in vivo.</strong> Brain 141: 1753-1769, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29800472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29800472</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29800472[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/awy077" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29800472">Kozina et al. (2018)</a> characterized transgenic mice overexpressing human LRRK2 with the R1441G or G2019S mutation and found that they did not develop an overt neurodegenerative phenotype up to 2 years of age. However, a systematic inflammatory response induced by administration of lipopolysaccharide (LPS) caused LRRK2 mutation-specific neuronal loss in substantia nigra pars compacta of transgenic mice. LPS-induced neurodegeneration in transgenic mice was accompanied by exacerbated neuroinflammation in brain. The increased immune response in brain of transgenic mice subsequently had an effect on neurons by inducing intraneuronal LRRK2 upregulation. Neuronal loss and neuroinflammation in transgenic mice were not due to dysfunctional microglia or infiltrated T cells and/or monocytes, but were likely initiated through circulating inflammatory mediators. By analyzing cytokine kinetics and inflammatory pathways in peripheral immune cells, the authors showed that mutant LRRK2 altered the type II interferon immune response, suggesting that the increased neuroinflammatory response may arise outside the central nervous system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29800472" 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="#62" class="mim-tip-reference" title="Pischedda, F., Cirnaru, M. D., Ponzoni, L., Sandre, M., Biosa, A., Carrion, M. P., Marin, O., Morari, M., Pan, L., Greggio, E., Bandopadhyay, R., Sala, M., Piccoli, G. <strong>LRRK2 G2019S kinase activity triggers neurotoxic NSF aggregation.</strong> Brain 144: 1509-1525, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33876242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33876242</a>] [<a href="https://doi.org/10.1093/brain/awab073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33876242">Pischedda et al. (2021)</a> characterized the histopathologic and functional phenotype of mice overexpressing the human LRRK2 gene with the G2019S mutation. The mutant mice displayed age-dependent motor and cognitive impairment, including worsening novel object recognition, compared to wildtype mice. Examination of brains from the mutant mice revealed protein aggregates containing N-ethylmaleimide sensitive factor (NSF), which localized with LC3 and p62-positive protein aggregates. The mouse brains further displayed signs of cell death in the substantia nigra, striatum, cortex, and hippocampus, including increased cleaved caspase-3 (<a href="/entry/600636">600636</a>). Studies in cortical neurons collected from embryonic mutant mice showed that the protein aggregations depended on phosphorylation of NSF at Thr645. <a href="#62" class="mim-tip-reference" title="Pischedda, F., Cirnaru, M. D., Ponzoni, L., Sandre, M., Biosa, A., Carrion, M. P., Marin, O., Morari, M., Pan, L., Greggio, E., Bandopadhyay, R., Sala, M., Piccoli, G. <strong>LRRK2 G2019S kinase activity triggers neurotoxic NSF aggregation.</strong> Brain 144: 1509-1525, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33876242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33876242</a>] [<a href="https://doi.org/10.1093/brain/awab073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33876242">Pischedda et al. (2021)</a> also found that induction of autophagy with trehalose resulted in clearance of NSF aggregates in 6-month-old mutant mice and improved cognitive performance in 12-month-old mutant mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33876242" 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="#49" class="mim-tip-reference" title="Liu, Z., Wang, X., Yu, Y., Li, X., Wang, T., Jiang, H., Ren, Q., Jiao, Y., Sawa, A., Moran, T., Ross, C. A., Montell, C., Smith, W. W. <strong>A Drosophila model for LRRK2-linked parkinsonism.</strong> Proc. Nat. Acad. Sci. 105: 2693-2698, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18258746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18258746</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18258746[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.0708452105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18258746">Liu et al. (2008)</a> found that Drosophila expressing the human LRRK2 G2019S mutation in neuronal cells showed adult-onset loss of dopaminergic neurons, locomotor dysfunction, and early mortality. Overexpression of LRRK2 resulted in a less severe form of parkinsonism. Treatment of mutant flies with L-DOPA improved locomotor impairment but did not prevent the loss of dopaminergic cells. Expression of mutant protein in photoreceptor cells resulted in retinal degeneration. The findings provided a gain-of-function animal model for human LRRK2-linked PD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18258746" 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="#77" class="mim-tip-reference" title="Venderova, K., Kabbach, G., Abdel-Messih, E., Zhang, Y., Parks, R. J., Imai, Y., Gehrke, S., Ngsee, J., LaVoie, M. J., Slack, R. S., Rao, Y., Zhang, Z., Lu, B., Haque, M. E., Park, D. S. <strong>Leucine-rich repeat kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease.</strong> Hum. Molec. Genet. 18: 4390-4404, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19692353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19692353</a>] [<a href="https://doi.org/10.1093/hmg/ddp394" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19692353">Venderova et al. (2009)</a> generated several independent Drosophila lines carrying wildtype or mutant human LRRK2 with mutations in the kinase (I2020T), COR (Y1699C) or LRR (I1122V) domains, respectively. Ectopic expression of wildtype or mutant LRRK2 in dopaminergic neurons caused their significant loss accompanied by complex age-dependent changes in locomotor activity. Overall, the ubiquitous expression of LRRK2 increased life span and fertility of the flies. However, these flies were more sensitive to rotenone. LRRK2 expression in the eye exacerbated retinal degeneration. Importantly, in double transgenic flies, various indices of the eye and dopaminergic survival were modified in a complex fashion by the concomitant expression of PINK1 (<a href="/entry/608309">608309</a>), PARK7 (<a href="/entry/602533">602533</a>) or parkin (<a href="/entry/602544">602544</a>). This evidence suggests a genetic interaction between these PD-relevant genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19692353" 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="Hindle, S., Afsari, F., Stark, M., Middleton, C. A., Evans, G. J. O., Sweeney, S. T., Elliott, C. J. H. <strong>Dopaminergic expression of the Parkinsonian gene LRRK2-G2019S leads to non-autonomous visual neurodegeneration, accelerated by increased neural demands for energy.</strong> Hum. Molec. Genet. 22: 2129-2140, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23396536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23396536</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23396536[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/ddt061" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23396536">Hindle et al. (2013)</a> found that expression of human LRRK2 with the G2019S mutation in fly dopaminergic neurons caused photoreceptor neurodegeneration. Further analysis showed degeneration throughout the fly visual system, including regions not directly innervated by dopaminergic neurons. Other PD-related mutations did not affect photoreceptor function. G2019S appeared to act in a gain-of-function manner rather than in a dominant-negative manner, and increased energy demand appeared to contribute to G2019S-induced neurodegeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23396536" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of 4 families from the Basque region of Spain who had Parkinson disease (PARK8; <a href="/entry/607060">607060</a>), <a href="#59" class="mim-tip-reference" title="Paisan-Ruiz, C., Jain, S., Evans, E. W., Gilks, W. P., Simon, J., van der Brug, M., Lopez de Munain, A., Aparicio, S., Martinez Gil, A., Khan, N., Johnson, J., Martinez, J. R., and 9 others. <strong>Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease.</strong> Neuron 44: 595-600, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15541308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15541308</a>] [<a href="https://doi.org/10.1016/j.neuron.2004.10.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15541308">Paisan-Ruiz et al. (2004)</a> identified a heterozygous mutation in the LRRK2 gene that predicts an arg1396-to-gly substitution in the RAS domain. The mutation was also identified in 11 of 137 (8%) additional Spanish PD patients. The mutation was not identified in 1,300 chromosomes from North American controls and 160 chromosomes from Basque controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15541308" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Gasser, T. <strong>Genetics of Parkinson's disease.</strong> Curr. Opin. Neurol. 18: 363-369, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16003110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16003110</a>] [<a href="https://doi.org/10.1097/01.wco.0000170951.08924.3d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16003110">Gasser (2005)</a> noted that the correct numbering of this mutation is arg1441-to-gly (R1441G). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16003110" 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="Gaig, C., Ezquerra, M., Marti, M. J., Munoz, E., Valldeoriola, F., Tolosa, E. <strong>LRRK2 mutations in Spanish patients with Parkinson disease: frequency, clinical features, and incomplete penetrance.</strong> Arch. Neurol. 63: 377-382, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16533964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16533964</a>] [<a href="https://doi.org/10.1001/archneur.63.3.377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16533964">Gaig et al. (2006)</a> identified the R1441G mutation in 2 (0.7%) of 302 patients with PD from the Catalonia region of northeast Spain. Both patients had a family history of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16533964" 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="Gorostidi, A., Ruiz-Martinez, J., Lopez de Munain, A., Alzualde, A., Marti Masso, J. F. <strong>LRRK2 G2019S and R1441G mutations associated with Parkinson's disease are common in the Basque country, but relative prevalence is determined by ethnicity.</strong> Neurogenetics 10: 157-159, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19020907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19020907</a>] [<a href="https://doi.org/10.1007/s10048-008-0162-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19020907">Gorostidi et al. (2009)</a> found that 13.15% of 418 PD patients from the Basque region were heterozygous for the R1441G mutation. The frequency rose to 22.4% when restricted to those patients of Basque origin, reinforcing the importance of ethnicity when establishing mutation prevalence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19020907" 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="#53" class="mim-tip-reference" title="Mata, I. F., Hutter, C. M., Gonzalez-Fernandez, M. C., de Pancorbo, M. M., Lezcano, E., Huerta, C., Blazquez, M., Ribacoba, R., Guisasola, L. M., Salvador, C., Gomez-Esteban, J. C., Zarranz, J. J., Infante, J., Jankovic, J., Deng, H., Edwards, K. L., Alvarez, V., Zabetian, C. P. <strong>Lrrk2 R1441G-related Parkinson's disease: evidence of a common founding event in the seventh century in Northern Spain.</strong> Neurogenetics 10: 347-353, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19308469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19308469</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19308469[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s10048-009-0187-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19308469">Mata et al. (2009)</a> performed haplotype analysis of 29 unrelated PD patients heterozygous for the R1441G mutation and 85 wildtype controls. Nine of the patients were of Basque origin and 20 were non-Basques. The authors estimated that the most recent common ancestor lived about 1,350 years ago in approximately the 7th century. The findings were consistent with the hypothesis that R1441G originated in the Basque population and that dispersion of the mutation occurred through short-range gene flow largely limited to nearby regions in Spain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19308469" 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">rs35801418 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs35801418;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=rs35801418" 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=rs35801418" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 7 affected members of an English family with Parkinson disease (PARK8; <a href="/entry/607060">607060</a>), <a href="#59" class="mim-tip-reference" title="Paisan-Ruiz, C., Jain, S., Evans, E. W., Gilks, W. P., Simon, J., van der Brug, M., Lopez de Munain, A., Aparicio, S., Martinez Gil, A., Khan, N., Johnson, J., Martinez, J. R., and 9 others. <strong>Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease.</strong> Neuron 44: 595-600, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15541308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15541308</a>] [<a href="https://doi.org/10.1016/j.neuron.2004.10.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15541308">Paisan-Ruiz et al. (2004)</a> identified a heterozygous mutation in the LRRK2 gene that predicts a tyr1654-to-cys substitution. Seven unaffected family members did not have the mutation. The mutation was not identified in 1,300 chromosomes from North American controls and 160 chromosomes from Basque controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15541308" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Gasser, T. <strong>Genetics of Parkinson's disease.</strong> Curr. Opin. Neurol. 18: 363-369, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16003110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16003110</a>] [<a href="https://doi.org/10.1097/01.wco.0000170951.08924.3d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16003110">Gasser (2005)</a> noted that the correct numbering of this mutation is tyr1699-to-cys (Y1699C). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16003110" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a family with autosomal dominant Parkinson disease originally reported by <a href="#83" class="mim-tip-reference" title="Wszolek, Z. K., Vieregge, P., Uitti, R. J., Gasser, T., Yasuhara, O., McGeer, P., Berry, K., Calne, D. B., Vingerhoets, F. J. G., Klein, C., Pfeiffer, R. F. <strong>German-Canadian family (family A) with parkinsonism, amyotrophy, and dementia--longitudinal observations.</strong> Parkinsonism Relat. Disord. 3: 125-139, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18591067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18591067</a>] [<a href="https://doi.org/10.1016/s1353-8020(97)00013-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18591067">Wszolek et al. (1997)</a>, <a href="#88" class="mim-tip-reference" title="Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln, S., Kachergus, J., Hulihan, M., Uitti, R. J., Calne, D. B., Stoessl, A. J., Pfeiffer, R. F., Patenge, N., Carballo Carbajal, I., Vieregge, P., Asmus, F., Muller-Myhsok, B., Dickson, D. W., Meitinger, T., Strom, T. M., Wszolek, Z. K., Gasser, T. <strong>Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.</strong> Neuron 44: 601-607, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15541309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15541309</a>] [<a href="https://doi.org/10.1016/j.neuron.2004.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15541309">Zimprich et al. (2004)</a> identified heterozygosity for the Y1699C mutation resulting from a 5096A-G transition in the LRRK2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18591067+15541309" 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> rs33939927 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs33939927;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/rs33939927?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=rs33939927" 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=rs33939927" 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=RCV000002015 OR RCV002472921" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002015, RCV002472921" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002015...</a>
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<p>In affected members of a family with autosomal dominant Parkinson disease (PARK8; <a href="/entry/607060">607060</a>) originally reported by <a href="#82" class="mim-tip-reference" title="Wszolek, Z. K., Pfeiffer, B., Fulgham, J. R., Parisi, J. E., Thompson, B. M., Uitti, R. J., Calne, D. B., Pfeiffer, R. F. <strong>Western Nebraska family (family D) with autosomal dominant parkinsonism.</strong> Neurology 45: 502-505, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7898705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7898705</a>] [<a href="https://doi.org/10.1212/wnl.45.3.502" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7898705">Wszolek et al. (1995)</a>, <a href="#88" class="mim-tip-reference" title="Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln, S., Kachergus, J., Hulihan, M., Uitti, R. J., Calne, D. B., Stoessl, A. J., Pfeiffer, R. F., Patenge, N., Carballo Carbajal, I., Vieregge, P., Asmus, F., Muller-Myhsok, B., Dickson, D. W., Meitinger, T., Strom, T. M., Wszolek, Z. K., Gasser, T. <strong>Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.</strong> Neuron 44: 601-607, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15541309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15541309</a>] [<a href="https://doi.org/10.1016/j.neuron.2004.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15541309">Zimprich et al. (2004)</a> identified a heterozygous 4321C-T transition in the LRRK2 gene, resulting in an arg1441-to-cys (R1441C) substitution in the ROC (GTPase) domain. Affected members of another unrelated family also had the R1441C mutation. The mutation was not identified in more than 1,000 control individuals or 300 patients with sporadic PD. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7898705+15541309" 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="#80" class="mim-tip-reference" title="West, A. B., Moore, D. J., Biskup, S., Bugayenko, A., Smith, W. W., Ross, C. A., Dawson, V. L., Dawson, T. M. <strong>Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity.</strong> Proc. Nat. Acad. Sci. 102: 16842-16847, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16269541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16269541</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16269541[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.0507360102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16269541">West et al. (2005)</a> determined that the R1441C mutation, which lies within the GTPase domain of LRRK2, did not alter the steady-state level, turnover, or intracellular localization of the LRRK2 protein, but that R1441C appeared to enhance protein kinase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16269541" 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="#76" class="mim-tip-reference" title="Tong, Y., Pisani, A., Martella, G., Karouani, M., Yamaguchi, H., Pothos, E. N., Shen, J. <strong>R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice.</strong> Proc. Nat. Acad. Sci. 106: 14622-14627, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19667187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19667187</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19667187[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.0906334106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19667187">Tong et al. (2009)</a> found that mutant knockin mice with expression of normal levels of the R1441C mutant protein appeared grossly normal and did not show any evidence of dopaminergic degeneration up to 2 years of age. However, knockin mice showed impaired augmentation of locomotor activity in response to amphetamine compared to wildtype, suggesting a defect in drug-induced dopamine release. Adrenal chromaffin cells derived from mutant mice showed a significant reduction in stimulus-induced catecholamine release compared to controls. Mutant mice also showed impaired dopamine D2 receptor (DRD2; <a href="/entry/126450">126450</a>)-mediated functions, such as reduced response to the locomotor inhibitory effect of a DRD2 agonist and decreased cellular sensitivity to suppression by DRD2 agonists. <a href="#76" class="mim-tip-reference" title="Tong, Y., Pisani, A., Martella, G., Karouani, M., Yamaguchi, H., Pothos, E. N., Shen, J. <strong>R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice.</strong> Proc. Nat. Acad. Sci. 106: 14622-14627, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19667187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19667187</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19667187[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.0906334106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19667187">Tong et al. (2009)</a> suggested that these changes may represent pathogenic precursors to dopaminergic degeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19667187" 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="#78" class="mim-tip-reference" title="Wallings, R., Connor-Robson, N., Wade-Martins, R. <strong>LRRK2 interacts with the vacuolar-type H(+)-ATPase pump a1 subunit to regulate lysosomal function.</strong> Hum. Molec. Genet. 28: 2696-2710, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31039583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31039583</a>] [<a href="https://doi.org/10.1093/hmg/ddz088" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31039583">Wallings et al. (2019)</a> analyzed primary cortical neuronal cultures from transgenic rats expressing human LRRK2 carrying the R1441C mutation The R1441C mutation altered basal autophagy levels in rat neurons. Assessing LC3 (MAP1LC3A; <a href="/entry/601242">601242</a>) expression changes in cortical and midbrain tissue of aged rats showed that the R1441C-dependent autophagy phenotype was also present in vivo in rat brain tissue. R1441C caused autophagosome-lysosome fusion deficiency in rat neurons, resulting in inhibition of autophagosome clearance and a deficit in autolysosome maturation, thereby leading to accumulation of autophagosomes. Lysosomal calcium dynamics were impaired in R1441C neurons, likely causing the decrease in fusion efficiency between autophagosomes and lysosomes. Decreased autolysosome maturation was coupled with decreased lysosomal protein degradation in transgenic rat neurons, but the autophagy phenotype was not dependent on LRRK2 kinase activity. Instead, R1441C impaired lysosomal pH, on which both lysosomal degradation and autophagosome/lysosome fusion were highly dependent, in neurons. The R1441C mutation also altered LRRK2 cellular localization by decreasing colocalization of LRRK2 with the trans-Golgi and increasing its colocalization with autophagic puncta. LRRK2 interacted with V-ATPase subunit A1 (ATP6V1A; <a href="/entry/607027">607027</a>), but the interaction was abolished by the R1441C mutation, causing a decrease in A1 protein and its cellular mislocalization, which led to alteration of LRRK2 cellular localization. Additionally, analysis with primary neuronal cultures prepared from Lrrk2 -/- rats showed that the autophagy phenotypes in R1441C transgenic neurons were likely caused by a gain of function, as Lrrk2 -/- rat neurons displayed increased autophagic flux and decreased lysosomal protein degradation. Clioquinol, a zinc/copper ionophore, rescued the LRRK2-R1441C cellular phenotype as clioquinol modulated lysosomal zinc levels and upregulated V-ATPase A1 protein in R1441C neuronal cultures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31039583" 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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LRRK2, ILE1122VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs34805604 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs34805604;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=rs34805604" 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=rs34805604" 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=RCV000002016" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002016" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002016</a>
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<p>In affected members of a family with autosomal dominant Parkinson disease (PARK8; <a href="/entry/607060">607060</a>), <a href="#88" class="mim-tip-reference" title="Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln, S., Kachergus, J., Hulihan, M., Uitti, R. J., Calne, D. B., Stoessl, A. J., Pfeiffer, R. F., Patenge, N., Carballo Carbajal, I., Vieregge, P., Asmus, F., Muller-Myhsok, B., Dickson, D. W., Meitinger, T., Strom, T. M., Wszolek, Z. K., Gasser, T. <strong>Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.</strong> Neuron 44: 601-607, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15541309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15541309</a>] [<a href="https://doi.org/10.1016/j.neuron.2004.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15541309">Zimprich et al. (2004)</a> identified a heterozygous 3364A-G transition in the LRRK2 gene, resulting in an ile1122-to-val (I1122V) substitution. The mutation occurred in a region that is highly conserved among species. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15541309" 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 8, AUTOSOMAL DOMINANT</strong>
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LRRK2, GLY2019SER
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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> rs34637584 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs34637584;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/rs34637584?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=rs34637584" 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=rs34637584" 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=RCV000002017 OR RCV000325492 OR RCV000622347 OR RCV001195216 OR RCV001836691 OR RCV003407254 OR RCV003993728" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002017, RCV000325492, RCV000622347, RCV001195216, RCV001836691, RCV003407254, RCV003993728" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002017...</a>
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<p>In affected members of 4 of 61 (6.6%) unrelated families with autosomal dominant Parkinson disease (PARK8; <a href="/entry/607060">607060</a>), <a href="#17" class="mim-tip-reference" title="Di Fonzo, A., Rohe, C. F., Ferreira, J., Chien, H. F., Vacca, L., Stocchi, F., Guedes, L., Fabrizio, E., Manfredi, M., Vanacore, N., Goldwurm, S., Breedveld, G., Sampaio, C., Meco, G., Barbosa, E., Oostra, B. A., Bonifati, V., Italian Parkinson Genetics Network. <strong>A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease.</strong> Lancet 365: 412-415, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15680456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15680456</a>] [<a href="https://doi.org/10.1016/S0140-6736(05)17829-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15680456">Di Fonzo et al. (2005)</a> identified a heterozygous 6055G-A transition in exon 41 of the LRRK2 gene, resulting in a gly2019-to-ser (G2019S) substitution. Two families were from Italy, and 1 each were from Portugal and Brazil. The gly2019 residue is highly conserved and is part of a 3-amino acid motif required by all human kinase proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15680456" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Gilks, W. P., Abou-Sleiman, P. M., Gandhi, S., Jain, S., Singleton, A., Lees, A. J., Shaw, K., Bhatia, K. P., Bonifati, V., Quinn, N. P., Lynch, J., Healy, D. G., Holton, J. L., Revesz, T., Wood, N. W. <strong>A common LRRK2 mutation in idiopathic Parkinson's disease.</strong> Lancet 365: 415-416, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15680457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15680457</a>] [<a href="https://doi.org/10.1016/S0140-6736(05)17830-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15680457">Gilks et al. (2005)</a> identified the G2019S mutation in 8 of 482 (1.6%) unrelated patients with Parkinson disease. Five of the patients had no family history of the disorder, suggesting either a de novo occurrence or reduced penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15680457" 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="#56" class="mim-tip-reference" title="Nichols, W. C., Pankratz, N., Hernandez, D., Paisan-Ruiz, C., Jain, S., Halter, C. A., Michaels, V. E., Reed, T., Rudolph, A., Shults, C. W., Singleton, A., Foroud, T. <strong>Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease.</strong> Lancet 365: 410-412, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15680455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15680455</a>] [<a href="https://doi.org/10.1016/S0140-6736(05)17828-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15680455">Nichols et al. (2005)</a> identified the G2019S mutation in 20 of 358 (6%) families with PD. In 1 family, 1 sib was heterozygous for the mutation and another was homozygous; the homozygous individual did not differ in clinical presentation from the sib and did not have early disease onset or more rapid progression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15680455" 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 sequencing the LRRK2 gene in multiplex families showing linkage to the PARK8 region, <a href="#38" class="mim-tip-reference" title="Kachergus, J., Mata, I. F., Hulihan, M., Taylor, J. P., Lincoln, S., Aasly, J., Gibson, J. M., Ross, O. A., Lynch, T., Wiley, J., Payami, H., Nutt, J., Maraganore, D. M., Czyzewski, K., Styczynska, M., Wszolek, Z. K., Farrer, M. J., Toft, M. <strong>Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations.</strong> Am. J. Hum. Genet. 76: 672-680, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15726496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15726496</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15726496[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/10.1086/429256" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15726496">Kachergus et al. (2005)</a> identified the G2019S mutation. The families in which the mutation was found originated from the United States, Norway, Ireland, and Poland. In patients with idiopathic Parkinson disease from the same population, further screening identified 6 more patients with the LRRK2 G2019S mutation; no mutations were found in matched control individuals. Subsequently, 42 family members of the 13 probands were examined; 22 had an LRRK2 G2019S substitution, 7 with a diagnosis of PD. All patients shared an ancestral haplotype indicative of a common founder, and, within families, LRRK2 G2019S segregated with disease (multipoint lod score 2.41). Penetrance was age dependent, increasing from 17% at age 50 to 85% at age 70 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15726496" 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="#35" class="mim-tip-reference" title="Hernandez, D. G., Paisan-Ruiz, C., McInerney-Leo, A., Jain, S., Meyer-Lindenberg, A., Evans, E. W., Berman, K. F., Johnson, J., Auburger, G., Schaffer, A. A., Lopez, G. J., Nussbaum, R. L., Singleton, A. B. <strong>Clinical and positron emission tomography of Parkinson's disease caused by LRRK2.</strong> Ann. Neurol. 57: 453-456, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15732108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15732108</a>] [<a href="https://doi.org/10.1002/ana.20401" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15732108">Hernandez et al. (2005)</a> identified the G2019S mutation in affected members of 2 unrelated families with PARK8. One family was North American with English ancestry, and the other family was of Ashkenazi Jewish origin and had migrated from Russia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15732108" 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="Lesage, S., Leutenegger, A.-L., Ibanez, P., Janin, S., Lohmann, E., Durr, A., Brice, A. <strong>LRRK2 haplotype analysis in European and North African families with Parkinson disease: a common founder for the G2019S mutation dating from the 13th century (Letter)</strong> Am. J. Hum. Genet. 77: 330-332, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16145815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16145815</a>] [<a href="https://doi.org/10.1086/432422" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16145815">Lesage et al. (2005)</a> identified a common haplotype containing the G2019S mutation in PD patients from several European countries (France, Belgium, Portugal, and the Netherlands) and from 3 countries in North Africa (Algeria, Morocco, and Tunisia). The minimal common region spans approximately 60 kb within the LRRK2 gene, although many patients shared larger regions. <a href="#46" class="mim-tip-reference" title="Lesage, S., Leutenegger, A.-L., Ibanez, P., Janin, S., Lohmann, E., Durr, A., Brice, A. <strong>LRRK2 haplotype analysis in European and North African families with Parkinson disease: a common founder for the G2019S mutation dating from the 13th century (Letter)</strong> Am. J. Hum. Genet. 77: 330-332, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16145815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16145815</a>] [<a href="https://doi.org/10.1086/432422" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16145815">Lesage et al. (2005)</a> estimated that the G2019S mutation occurred approximately 725 years ago, in the 13th century. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16145815" 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="Aasly, J. O., Toft, M., Fernandez-Mata, I., Kachergus, J., Hulihan, M., White, L. R., Farrer, M. <strong>Clinical features of LRRK2-associated Parkinson's disease in central Norway.</strong> Ann. Neurol. 57: 762-765, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15852371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15852371</a>] [<a href="https://doi.org/10.1002/ana.20456" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15852371">Aasly et al. (2005)</a> identified the G2019S mutation in 9 Norwegian patients from 7 families with PARK8. Eleven unaffected first-degree relatives also carried the mutation, suggesting age-related penetrance. The clinical features of affected members were typical for idiopathic Parkinson disease, including resting tremor, bradykinesia, and rigidity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15852371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Deng, H., Le, W., Guo, Y., Hunter, C. B., Xie, W., Jankovic, J. <strong>Genetic and clinical identification of Parkinson's disease patients with LRRK2 G2019S mutation.</strong> Ann. Neurol. 57: 933-934, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15929036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15929036</a>] [<a href="https://doi.org/10.1002/ana.20510" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15929036">Deng et al. (2005)</a> identified the G2019S mutation in 4 (1.2%) of 326 Parkinson disease patients from North America. One of the patients had no family history of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15929036" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Albrecht, M. <strong>LRRK2 mutations and parkinsonism. (Letter)</strong> Lancet 365: 1230 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15811455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15811455</a>] [<a href="https://doi.org/10.1016/S0140-6736(05)74810-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15811455">Albrecht (2005)</a> stated that the gly2019 residue is part of a highly conserved DFG-like motif (DYG in LRRK2) at the N terminus of the kinase activation segment of the protein. As residues in and around the DFG-like motif are important for proper positioning of magnesium and phosphates, mutations in this area may impair kinase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15811455" 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="#80" class="mim-tip-reference" title="West, A. B., Moore, D. J., Biskup, S., Bugayenko, A., Smith, W. W., Ross, C. A., Dawson, V. L., Dawson, T. M. <strong>Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity.</strong> Proc. Nat. Acad. Sci. 102: 16842-16847, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16269541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16269541</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16269541[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.0507360102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16269541">West et al. (2005)</a> determined that the G2019S mutation, which lies within the mixed-lineage kinase-like domain, did not alter the steady-state level, turnover, or intracellular localization of the LRRK2 protein, but that G2019S appeared to enhance protein kinase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16269541" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Brice, A. <strong>Genetics of Parkinson's disease: LRRK2 on the rise.</strong> Brain 128: 2760-2762, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16311269/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16311269</a>] [<a href="https://doi.org/10.1093/brain/awh676" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16311269">Brice (2005)</a> estimated that the G2019S mutation in exon 41 of the LRRK2 gene accounts for 2 to 6% of familial and 1 to 2% of sporadic cases of Parkinson disease. The mutation is less common in Asian populations but prevalent in patients from North Africa, as observed by <a href="#43" class="mim-tip-reference" title="Lesage, S., Durr, A., Tazir, M., Lohmann, E., Leutenegger, A.-L., Janin, S., Pollak, P., Brice, A. <strong>LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs. (Letter)</strong> New Eng. J. Med. 354: 422-423, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16436781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16436781</a>] [<a href="https://doi.org/10.1056/NEJMc055540" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16436781">Lesage et al. (2006)</a>. In a newly ascertained series of North African Arabs, 23 of 59 patients with Parkinson disease were carriers of the G2019S mutation (39%), as compared with only 2 of 69 controls (3%; P less than 0.001). <a href="#58" class="mim-tip-reference" title="Ozelius, L. J., Senthil, G., Saunders-Pullman, R., Ohmann, E., Deligtisch, A., Tagliati, M., Hunt, A. L., Klein, C., Henick, B., Hailpern, S. M., Lipton, R. B., Soto-Valencia, J., Risch, N., Bressman, S. B. <strong>LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. (Letter)</strong> New Eng. J. Med. 354: 424-425, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16436782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16436782</a>] [<a href="https://doi.org/10.1056/NEJMc055509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16436782">Ozelius et al. (2006)</a> observed that the G2019S mutation appeared to be an important cause of both familial and sporadic Parkinson disease in a group of 120 unrelated Ashkenazi Jewish patients with Parkinson disease. The prevalence of the G2019S mutation among this group reached 29.7% in familial cases and 13.3% in sporadic cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16436782+16311269+16436781" 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="Lesage, S., Ibanez, P., Lohmann, E., Pollak, P., Tison, F., Tazir, M., Leutenegger, A.-L., Guimaraes, J., Bonnet, A.-M., Agid, Y., Durr, A., Brice, A., French Parkinson's Disease Genetics Study Group. <strong>G2019S LRRK2 mutation in French and North African families with Parkinson's disease.</strong> Ann. Neurol. 58: 784-787, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16240353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16240353</a>] [<a href="https://doi.org/10.1002/ana.20636" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16240353">Lesage et al. (2005)</a> identified the G2019S mutation in 7 (41%) of 17 North African PD families and 5 (2.9%) of 174 European PD families. One patient from Algeria was homozygous for the mutation, likely due to consanguinity. His age at onset was 56 years, similar to that of heterozygotes, suggesting that gene dosage had no effect. The G2019S mutation was also identified in 1 of 256 control individuals, a 60-year-old male of European descent with no family history of the PD. Age-dependent penetrance, estimated within 2 large affected families, increased from 33% at age 55 to 100% at older than age 76. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16240353" 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="#85" class="mim-tip-reference" title="Zabetian, C. P., Lauricella, C. J., Tsuang, D. W., Leverenz, J. B., Schellenberg, G. D., Payami, H. <strong>Analysis of the LRRK2 G2019S mutation in Alzheimer disease. (Letter)</strong> Arch. Neurol. 63: 156-157, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16401756/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16401756</a>] [<a href="https://doi.org/10.1001/archneur.63.1.156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16401756">Zabetian et al. (2006)</a> did not identify the G2019S mutation in any of 754 patients with Alzheimer disease (AD; <a href="/entry/104300">104300</a>), suggesting that it is not a cause of AD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16401756" 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="#84" class="mim-tip-reference" title="Zabetian, C. P., Hutter, C. M., Yearout, D., Lopez, A. N., Factor, S. A., Griffith, A., Leis, B. C., Bird, T. D., Nutt, J. G., Higgins, D. S., Roberts, J. W., Kay, D. M., Edwards, K. L., Samii, A., Payami, H. <strong>LRRK2 G2019S in families with Parkinson disease who originated from Europe and the Middle East: evidence of two distinct founding events beginning two millennia ago.</strong> Am. J. Hum. Genet. 79: 752-758, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16960813/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16960813</a>] [<a href="https://doi.org/10.1086/508025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16960813">Zabetian et al. (2006)</a> stated that the G2019S mutation accounts for 1 to 7% of Parkinson disease in patients of European origin and 20 to 40% in Ashkenazi Jews and North African Arabs with PD. Previous studies had concluded that patients from these populations share a common Middle Eastern founder who lived in the 13th century. <a href="#84" class="mim-tip-reference" title="Zabetian, C. P., Hutter, C. M., Yearout, D., Lopez, A. N., Factor, S. A., Griffith, A., Leis, B. C., Bird, T. D., Nutt, J. G., Higgins, D. S., Roberts, J. W., Kay, D. M., Edwards, K. L., Samii, A., Payami, H. <strong>LRRK2 G2019S in families with Parkinson disease who originated from Europe and the Middle East: evidence of two distinct founding events beginning two millennia ago.</strong> Am. J. Hum. Genet. 79: 752-758, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16960813/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16960813</a>] [<a href="https://doi.org/10.1086/508025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16960813">Zabetian et al. (2006)</a> tested this hypothesis by genotyping 25 microsatellite and single-nucleotide polymorphism (SNP) markers in 22 families with G2019S and observed 2 distinct haplotypes. Haplotype 1 was present in 19 families of Ashkenazi Jewish and European ancestry, whereas haplotype 2 occurred in 3 European American families. Using a maximum likelihood method, the authors estimated that the families with haplotype 1 shared a common ancestor 2,250 (95% confidence interval 1,650-3,120) years ago, whereas those with haplotype 2 appeared to share a more recent founder. Their data suggested 2 separate founding events for G2019S in these populations, beginning at a time that coincided with the Jewish Diasporas. <a href="#86" class="mim-tip-reference" title="Zabetian, C. P., Morino, H., Ujike, H., Yamamoto, M., Oda, M., Maruyama, H., Izumi, Y., Kaji, R., Griffith, A. Leis, B. C., Roberts, J. W., Yearout, D., Samii, A., Kawakami, H. <strong>Identification and haplotype analysis of LRRK2 G2019S in Japanese patients with Parkinson disease.</strong> Neurology 67: 697-699, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16728648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16728648</a>] [<a href="https://doi.org/10.1212/01.wnl.0000227732.37801.d4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16728648">Zabetian et al. (2006)</a> identified the G2019S mutation in Japanese patients with Parkinson disease on a haplotype background clearly distinct from the 2 others, which indicated that at least 3 founding events had occurred. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16960813+16728648" 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="#37" class="mim-tip-reference" title="Ishihara, L., Warren, L., Gibson, R., Amouri, R., Lesage, S., Durr, A., Tazir, M., Wszolek, Z. K., Uitti, R. J., Nichols, W. C., Griffith, A., Hattori, N., Leppert, D., Watts, R., Zabetian, C. P., Foroud, T. M., Farrer, M. J., Brice, A., Middleton, L., Hentati, F. <strong>Clinical features of Parkinson disease patients with homozygous leucine-rich repeat kinase 2 G2019S mutations.</strong> Arch. Neurol. 63: 1250-1254, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16966502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16966502</a>] [<a href="https://doi.org/10.1001/archneur.63.9.1250" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16966502">Ishihara et al. (2006)</a> found no observable phenotypic differences between 26 patients with Parkinson disease who were homozygous for the G2019S mutation, including 20 patients of Tunisian origin, and reports of patients who were heterozygous for the mutation. In addition, 3 clinically unaffected Tunisian individuals were homozygous for the mutation at ages 42, 45, and 70 years. The findings did not support a gene dosage effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16966502" 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>Among 302 PD patients from the Catalonia region of northeast Spain, <a href="#21" class="mim-tip-reference" title="Gaig, C., Ezquerra, M., Marti, M. J., Munoz, E., Valldeoriola, F., Tolosa, E. <strong>LRRK2 mutations in Spanish patients with Parkinson disease: frequency, clinical features, and incomplete penetrance.</strong> Arch. Neurol. 63: 377-382, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16533964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16533964</a>] [<a href="https://doi.org/10.1001/archneur.63.3.377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16533964">Gaig et al. (2006)</a> identified the G2019S mutation in 6.4% of familial and 3.4% of sporadic cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16533964" 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="#70" class="mim-tip-reference" title="Spanaki, C., Latsoudis, H., Plaitakis, A. <strong>LRRK2 mutations on Crete: R1441H associated with PD evolving to PSP.</strong> Neurology 67: 1518-1519, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17060595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17060595</a>] [<a href="https://doi.org/10.1212/01.wnl.0000239829.33936.73" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17060595">Spanaki et al. (2006)</a> identified the G2019S mutation in 1 (1.1%) of 92 familial PD probands on the island of Crete, thus showing a decreased frequency of the mutation compared to other Mediterranean regions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17060595" 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="Clark, L. N., Wang, Y., Karlins, E., Saito, L., Mejia-Santana, H., Harris, J., Louis, E. D., Cote, L. J., Andrews, H., Fahn, S., Waters, C., Ford, B., Frucht, S., Ottman, R., Marder, K. <strong>Frequency of LRRK2 mutations in early- and late-onset Parkinson disease.</strong> Neurology 67: 1786-1791, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17050822/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17050822</a>] [<a href="https://doi.org/10.1212/01.wnl.0000244345.49809.36" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17050822">Clark et al. (2006)</a> identified the G2019S mutation in 4.9% of 245 PD patients with onset before age 50 years and 6.2% of 259 PD patients with onset after age 50 years, a nonsignificant difference. All patients with the G2019S mutation had the same 45-kb disease-associated haplotype. The frequency of the mutation was higher in the subset of 181 cases reporting 4 Jewish grandparents (9.9%) compared to other cases (3.1%). Age-specific penetrance to age 80 was 24%, suggesting that other factors must be involved. The G2019S mutation was identified in 2 (0.6%) controls of Jewish origin who showed mild signs suggestive of the disorder on further examination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17050822" 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="#45" class="mim-tip-reference" title="Lesage, S., Janin, S., Lohmann, E., Leutenegger, A.-L., Leclere, L., Viallet, F., Pollak, P., Durif, F., Thobois, S., Layet, V., Vidailhet, M., Agid, Y., Durr, A., Brice, A., French Parkinson's Disease Genetics Study Group. <strong>LRRK2 exon 41 mutations in sporadic Parkinson disease in Europeans.</strong> Arch. Neurol. 64: 425-430, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17353388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17353388</a>] [<a href="https://doi.org/10.1001/archneur.64.3.425" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17353388">Lesage et al. (2007)</a> identified the G2019S mutation in 6 (1.9%) of 320 European patients with sporadic PD. Five patients were of French origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17353388" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 19 Italian PD families with the G2019S mutation, <a href="#32" class="mim-tip-reference" title="Goldwurm, S., Zini, M., Mariani, L., Tesei, S., Miceli, R., Sironi, F., Clementi, M., Bonifati, V., Pezzoli, G. <strong>Evaluation of LRRK2 G2019S penetrance: relevance for genetic counseling in Parkinson disease.</strong> Neurology 68: 1141-1143, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17215492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17215492</a>] [<a href="https://doi.org/10.1212/01.wnl.0000254483.19854.ef" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17215492">Goldwurm et al. (2007)</a> estimated the cumulative incidence of the disease to be 15% at 60 years, 21% at 70 years, and 32% at 80 years, confirming reduced penetrance. Among 33 mutation carriers, 5 over age 75 years had no sign of disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17215492" 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="#57" class="mim-tip-reference" title="Orr-Urtreger, A., Shifrin, C., Rozovski, U., Rosner, S., Bercovich, D., Gurevich, T., Yagev-More, H., Bar-Shira, A., Giladi, N. <strong>The LRRK2 G2019S mutation in Ashkenazi Jews with Parkinson disease: is there a gender effect?</strong> Neurology 69: 1595-1602, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17938369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17938369</a>] [<a href="https://doi.org/10.1212/01.wnl.0000277637.33328.d8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17938369">Orr-Urtreger et al. (2007)</a> identified a heterozygous G2019S mutation in 12.3% of 472 Jewish PD patients, and in 14.8% of the 344 patients in this group who were specifically of Ashkenazi Jewish origin. The mutation was also detected in 2.4% of Ashkenazi Jewish controls. A common shared haplotype identified by <a href="#46" class="mim-tip-reference" title="Lesage, S., Leutenegger, A.-L., Ibanez, P., Janin, S., Lohmann, E., Durr, A., Brice, A. <strong>LRRK2 haplotype analysis in European and North African families with Parkinson disease: a common founder for the G2019S mutation dating from the 13th century (Letter)</strong> Am. J. Hum. Genet. 77: 330-332, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16145815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16145815</a>] [<a href="https://doi.org/10.1086/432422" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16145815">Lesage et al. (2005)</a> was found in 97% of mutation carriers. None of 42 Jewish patients from Iraq or Morocco carried the G2019S mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16145815+17938369" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="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> did not identify the G2019S mutation among 72 unrelated Korean patients with early-onset PD before age 50, suggesting that it is not a common cause of PD in the Korean population. <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="#42" class="mim-tip-reference" title="Lesage, S., Belarbi, S., Troiano, A., Condroyer, C., Hecham, N., Pollak, P., Lohman, E., Benhassine, T., Ysmail-Dahlouk, F., Durr, A., Tazir, M., Brice, A. <strong>Is the common LRRK2 G2019S mutation related to dyskinesias in North African Parkinson disease?</strong> Neurology 71: 1550-1552, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18981379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18981379</a>] [<a href="https://doi.org/10.1212/01.wnl.0000338460.89796.06" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18981379">Lesage et al. (2008)</a> identified the G2019S mutation in 7 (41%) of 17 North African patients with familial PD and 40 (34%) of 119 North African patients with sporadic PD. All were heterozygous for the mutation except 3 patients, who were homozygous. One (1.5%) of 66 Algerian controls was homozygous for the mutation, but showed no evidence of disease at age 41 years, which is younger than the average age of disease onset. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18981379" 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="Gorostidi, A., Ruiz-Martinez, J., Lopez de Munain, A., Alzualde, A., Marti Masso, J. F. <strong>LRRK2 G2019S and R1441G mutations associated with Parkinson's disease are common in the Basque country, but relative prevalence is determined by ethnicity.</strong> Neurogenetics 10: 157-159, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19020907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19020907</a>] [<a href="https://doi.org/10.1007/s10048-008-0162-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19020907">Gorostidi et al. (2009)</a> identified a heterozygous G2019S mutation in 3.82% of 418 PD patients from the Basque country in Spain. The frequency increased to 6% when only those who were not of Basque origin were considered. The R1441G mutation (<a href="#0001">609007.0001</a>) was more common among those of Basque descent. The findings reinforced the importance of ethnicity when establishing mutation prevalence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19020907" 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="Bar-Shira, A., Hutter, C. M., Giladi, N., Zabetian, C. P., Orr-Urtreger, A. <strong>Ashkenazi Parkinson's disease patients with the LRRK2 G2019S mutation share a common founder dating from the second to fifth centuries.</strong> Neurogenetics 10: 355-358, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19283415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19283415</a>] [<a href="https://doi.org/10.1007/s10048-009-0186-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19283415">Bar-Shira et al. (2009)</a> analyzed LRRK2 haplotypes in 77 G2019S carriers, mostly Ashkenazi Jews, and in 50 noncarrier Ashkenazi PD patients. A single 243-kb haplotype was detected in all mutation carriers, indicating a common founder. The authors estimated that Ashkenazi Jews with G2019S share a common ancestor who lived approximately 1,830 years ago, around the 2nd century, after the second Jewish Diaspora. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19283415" 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="Alcalay, R. N., Mejia-Santana, H., Tang, M. X., Rosado, L., Verbitsky, M., Kisselev, S., Ross, B. M., Louis, E. D., Comella, C. L., Colcher, A., Jennings, D., Nance, M. A., and 21 others. <strong>Motor phenotype of LRRK2 G2019S carriers in early-onset Parkinson disease.</strong> Arch. Neurol. 66: 1517-1522, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20008657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20008657</a>] [<a href="https://doi.org/10.1001/archneurol.2009.267" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20008657">Alcalay et al. (2009)</a> found that 34 (3.7%) of 925 patients with early-onset PD, defined as age at onset before age 51 years, carried the G2019S mutation. Compared to noncarriers, carriers of the G2019S mutation were more likely to be of Ashkenazi Jewish descent (55.9% vs 11.9%), to have a lower tremor score (p = 0.03), and to have a higher score of postural instability and gait difficulty (PIGD; 92.3% vs 58.9%, p = 0.003). The PIGD phenotype in general is associated with a more severe phenotype and a faster rate of cognitive decline compared to the tremor dominant phenotype, so the findings of this study suggested implications for disease course in G2019S mutation carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20008657" 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="#55" class="mim-tip-reference" title="Mortiboys, H., Johansen, K. K., Aasly, J. O., Bandmann, O. <strong>Mitochondrial impairment in patients with Parkinson disease with the G2019S mutation in LRRK2.</strong> Neurology 75: 2017-2020, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21115957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21115957</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181ff9685" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21115957">Mortiboys et al. (2010)</a> found that skin fibroblasts from 5 PD patients with the G2019S mutation showed evidence of mitochondrial dysfunction, both decreased membrane potential and decreased total intracellular ATP levels. There also appeared to be increased mitochondrial elongation and interconnectivity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21115957" 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="#48" class="mim-tip-reference" title="Liu, G.-H., Qu, J., Suzuki, K., Nivet, E., Li, M., Montserrat, N., Yi, F., Xu, X., Ruiz, S., Zhang, W., Wagner, U., Kim, A., and 11 others. <strong>Progressive degeneration of human neural stem cells caused by pathogenic LRRK2.</strong> Nature 491: 603-607, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23075850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23075850</a>] [<a href="https://doi.org/10.1038/nature11557" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23075850">Liu et al. (2012)</a> reported on the generation of induced pluripotent stem cells (iPSCs) derived from Parkinson disease patients and the implications of the LRRK2 G2019S mutation in human neural stem cell populations. Mutant neural stem cells showed increased susceptibility to proteasomal stress as well as passage-dependent deficiencies in nuclear envelope organization, clonal expansion, and neuronal differentiation. Disease phenotypes were rescued by targeted correction of the LRRK2 G2019S mutation with its wildtype counterpart in Parkinson disease iPSCs and were recapitulated after targeted knockin of the LRRK2 G2019S mutation in human embryonic stem cells. Analysis of human brain tissue showed nuclear envelope impairment in clinically diagnosed Parkinson disease patients. <a href="#48" class="mim-tip-reference" title="Liu, G.-H., Qu, J., Suzuki, K., Nivet, E., Li, M., Montserrat, N., Yi, F., Xu, X., Ruiz, S., Zhang, W., Wagner, U., Kim, A., and 11 others. <strong>Progressive degeneration of human neural stem cells caused by pathogenic LRRK2.</strong> Nature 491: 603-607, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23075850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23075850</a>] [<a href="https://doi.org/10.1038/nature11557" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23075850">Liu et al. (2012)</a> concluded that their results identified the nucleus as a previously unknown cellular organelle in Parkinson disease pathology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23075850" 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="#66" class="mim-tip-reference" title="Shani, V., Safory, H., Szargel, R., Wang, N., Cohen, T., Elghani, F. A., Hamza, H., Savyon, M., Radzishevsky, I., Shaulov, L., Rott, R., Lim, K. L., Ross, C. A., Bandopadhyay, R., Zhang, H., Engelender, S. <strong>Physiological and pathological roles of LRRK2 in the nuclear envelope integrity.</strong> Hum. Molec. Genet. 28: 3982-3996, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31626293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31626293</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31626293[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/ddz245" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31626293">Shani et al. (2019)</a> found that the interation of LRRK2 with lamin A/C (LMNA; <a href="/entry/150330">150330</a>) in the nuclear cytoskeleton was diminished for PD-associated LRRK2 mutations, including G2019S. G2019S did not alter LRRK2 interaction with SIAH1 (<a href="/entry/602212">602212</a>) or LRRK2 translocation to the nucleus, but nuclear accumulation of the G2019S mutant appeared to be harmful to neurons. In vitro and in vivo analyses demonstrated that G2019S interfered with the ability of LRRK2 to maintain nuclear lamina and nuclear membrane integrity, disrupting the nuclear membrane and altering its permeability. Dopaminergic neurons of PD patients with the LRRK2 G2019S mutation contained widespread alterations of nuclear lamina structure, supporting nuclear envelope disruption as a hallmark of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31626293" 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 8, AUTOSOMAL DOMINANT</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">rs35870237 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs35870237;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=rs35870237" 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=rs35870237" 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=RCV000002018 OR RCV001311806" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002018, RCV001311806" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002018...</a>
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<p>In all 19 affected members of the original Japanese family with Parkinson disease-8 (PARK8; <a href="/entry/607060">607060</a>) (<a href="#34" class="mim-tip-reference" title="Hasegawa, K., Kowa, H. <strong>Autosomal dominant familial Parkinson disease: older onset of age, and good response to levodopa therapy.</strong> Europ. Neurol. 38 (suppl. 1): 39-43, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9276200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9276200</a>] [<a href="https://doi.org/10.1159/000113460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9276200">Hasegawa and Kowa, 1997</a>), <a href="#20" class="mim-tip-reference" title="Funayama, M., Hasegawa, K., Ohta, E., Kawashima, N., Komiyama, M., Kowa, H., Tsuji, S., Obata, F. <strong>An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family.</strong> Ann. Neurol. 57: 918-921, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15880653/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15880653</a>] [<a href="https://doi.org/10.1002/ana.20484" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15880653">Funayama et al. (2005)</a> identified a heterozygous 6059T-C transition in exon 41 of the LRRK2 gene, resulting in an ile2020-to-thr (I2020T) substitution in a conserved region of the kinase motif domain. The neuropathologic features in this family were notable for absence of Lewy bodies. The mutation was also detected in 2 affected members of another family with PARK8. In the second family, 3 unaffected members also carried the mutation, but their ages (73, 58, and 56) were within the variation of age at onset in that family (39 to 76 years). The I2020T substitution was not identified in 368 control individuals or in 188 patients with sporadic Parkinson disease. The mutation had previously been reported by <a href="#88" class="mim-tip-reference" title="Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln, S., Kachergus, J., Hulihan, M., Uitti, R. J., Calne, D. B., Stoessl, A. J., Pfeiffer, R. F., Patenge, N., Carballo Carbajal, I., Vieregge, P., Asmus, F., Muller-Myhsok, B., Dickson, D. W., Meitinger, T., Strom, T. M., Wszolek, Z. K., Gasser, T. <strong>Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.</strong> Neuron 44: 601-607, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15541309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15541309</a>] [<a href="https://doi.org/10.1016/j.neuron.2004.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15541309">Zimprich et al. (2004)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9276200+15541309+15880653" 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 HEK293 cells, <a href="#31" class="mim-tip-reference" title="Gloeckner, C. J., Kinkl, N., Schumacher, A., Braun, R. J., O'Neill. E., Meitinger, T., Kolch, W., Prokisch, H., Ueffing, M. <strong>The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity.</strong> Hum. Molec. Genet. 15: 223-232, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16321986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16321986</a>] [<a href="https://doi.org/10.1093/hmg/ddi439" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16321986">Gloeckner et al. (2006)</a> demonstrated that the I2020T-mutant protein shows significantly increased (about 40%) autophosphorylation activity compared to wildtype LRRK2, consistent with a gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16321986" 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 purified in vitro translated N-terminally truncated wildtype and mutant proteins, <a href="#63" class="mim-tip-reference" title="Ray, S., Bender, S., Kang, S., Lin, R., Glicksman, M. A., Liu, M. <strong>The Parkinson disease-linked LRRK2 protein mutation I2020T stabilizes an active state conformation leading to increased kinase activity.</strong> J. Biol. Chem. 289: 13042-13053, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24695735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24695735</a>] [<a href="https://doi.org/10.1074/jbc.M113.537811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24695735">Ray et al. (2014)</a> found that wildtype and I2020T mutant LRRK2 had essentially the same activity against a synthetic peptide containing a phosphorylatable threonine residue. However, the I2020T mutant had significantly enhanced activity against the identical peptide with a phosphorylatable serine residue. <a href="#63" class="mim-tip-reference" title="Ray, S., Bender, S., Kang, S., Lin, R., Glicksman, M. A., Liu, M. <strong>The Parkinson disease-linked LRRK2 protein mutation I2020T stabilizes an active state conformation leading to increased kinase activity.</strong> J. Biol. Chem. 289: 13042-13053, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24695735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24695735</a>] [<a href="https://doi.org/10.1074/jbc.M113.537811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24695735">Ray et al. (2014)</a> observed that I2020 lies next to a critical regulatory DYG motif in the ATP-binding pocket of LRRK2 that flips between the active DYG-in conformation to inactive DYG-out conformation. Using molecular modeling and simulations, <a href="#63" class="mim-tip-reference" title="Ray, S., Bender, S., Kang, S., Lin, R., Glicksman, M. A., Liu, M. <strong>The Parkinson disease-linked LRRK2 protein mutation I2020T stabilizes an active state conformation leading to increased kinase activity.</strong> J. Biol. Chem. 289: 13042-13053, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24695735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24695735</a>] [<a href="https://doi.org/10.1074/jbc.M113.537811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24695735">Ray et al. (2014)</a> found that the threonine side chain of the mutant makes a hydrogen bond with the backbone carbonyl of asp2017 in the DYG motif, which then stabilizes a hydrogen bond between DYG and a phosphate group of ATP. This increased stability of the DYG-in active conformation significantly prolongs residence time of ATP and elevates the kinase activity of the I2020T mutant LRRK2 compared with wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24695735" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a Taiwanese father and daughter with Parkinson disease-8 (PARK8; <a href="/entry/607060">607060</a>), <a href="#54" class="mim-tip-reference" title="Mata, I. F., Kachergus, J. M., Taylor, J. P., Lincoln, S., Aasly, J., Lynch, T., Hulihan, M. M., Cobb, S. A., Wu, R.-M., Lu, C.-S., Lahoz, C., Wszolek, Z. K., Farrer, M. J. <strong>Lrrk2 pathogenic substitutions in Parkinson's disease.</strong> Neurogenetics 6: 171-177, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16172858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16172858</a>] [<a href="https://doi.org/10.1007/s10048-005-0005-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16172858">Mata et al. (2005)</a> identified a heterozygous 4322G-A transition in exon 31 of the LRRK2 gene, resulting in an arg1441-to-his (R1441H) substitution in the ROC (GTPase) domain. <a href="#87" class="mim-tip-reference" title="Zabetian, C. P., Samii, A., Mosley, A. D., Roberts, J. W., Leis, B. C., Yearout, D., Raskind, W. H., Griffith, A. <strong>A clinic-based study of the LRRK2 gene in Parkinson disease yields new mutations.</strong> Neurology 65: 741-744, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16157909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16157909</a>] [<a href="https://doi.org/10.1212/01.wnl.0000172630.22804.73" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16157909">Zabetian et al. (2005)</a> also identified the R1441H mutation in affected members of a family with Parkinson disease-8. Two other pathogenic LRRK2 mutations have been identified in this same codon (R1441G; <a href="#0001">609007.0001</a> and R1441C; <a href="#0003">609007.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16172858+16157909" 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="#70" class="mim-tip-reference" title="Spanaki, C., Latsoudis, H., Plaitakis, A. <strong>LRRK2 mutations on Crete: R1441H associated with PD evolving to PSP.</strong> Neurology 67: 1518-1519, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17060595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17060595</a>] [<a href="https://doi.org/10.1212/01.wnl.0000239829.33936.73" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17060595">Spanaki et al. (2006)</a> identified the R1441H substitution in 1 of 92 familial PD probands on the island of Crete. The proband had an affected brother who developed parkinsonism at age 61 years and responded well to L-DOPA therapy, but showed a clear clinical transition to a degenerative phenotype consistent with progressive supranuclear palsy (PSP; <a href="/entry/601104">601104</a>) after 8 years. The brother deteriorated rapidly, showing postural instability, supranuclear vertical gaze palsy, bulbar dysfunction, and moderate dementia. None of 13 additional unrelated patients with a clinical diagnosis of PSP had any of the 5 LRRK2 mutations investigated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17060595" 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> rs34778348 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs34778348;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/rs34778348?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=rs34778348" 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=rs34778348" 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=RCV000032508 OR RCV001449818 OR RCV003488320" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032508, RCV001449818, RCV003488320" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032508...</a>
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<p><a href="#54" class="mim-tip-reference" title="Mata, I. F., Kachergus, J. M., Taylor, J. P., Lincoln, S., Aasly, J., Lynch, T., Hulihan, M. M., Cobb, S. A., Wu, R.-M., Lu, C.-S., Lahoz, C., Wszolek, Z. K., Farrer, M. J. <strong>Lrrk2 pathogenic substitutions in Parkinson's disease.</strong> Neurogenetics 6: 171-177, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16172858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16172858</a>] [<a href="https://doi.org/10.1007/s10048-005-0005-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16172858">Mata et al. (2005)</a> reported the LRRK2 gly2385-to-arg (G2385R) variant in a Taiwanese family with Parkinson disease (PARK8; <a href="/entry/607060">607060</a>). <a href="#18" class="mim-tip-reference" title="Di Fonzo, A., Wu-Chou, Y.-H., Lu, C.-S., van Doeselaar, M., Simons, E. J., Rohe, C. F., Chang, H.-C., Chen, R.-S., Weng, Y.-H., Vanacore, N., Breedveld, G. J., Oostra, B. A., Bonifati, V. <strong>A common missense variant in the LRRK2 gene, gly2385-to-arg, associated with Parkinson's disease risk in Taiwan.</strong> Neurogenetics 7: 133-138, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16633828/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16633828</a>] [<a href="https://doi.org/10.1007/s10048-006-0041-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16633828">Di Fonzo et al. (2006)</a> showed, in a large case-control sample of Taiwanese individuals, that this variant is a common polymorphism that was significantly more frequent among PD patients than controls. <a href="#18" class="mim-tip-reference" title="Di Fonzo, A., Wu-Chou, Y.-H., Lu, C.-S., van Doeselaar, M., Simons, E. J., Rohe, C. F., Chang, H.-C., Chen, R.-S., Weng, Y.-H., Vanacore, N., Breedveld, G. J., Oostra, B. A., Bonifati, V. <strong>A common missense variant in the LRRK2 gene, gly2385-to-arg, associated with Parkinson's disease risk in Taiwan.</strong> Neurogenetics 7: 133-138, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16633828/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16633828</a>] [<a href="https://doi.org/10.1007/s10048-006-0041-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16633828">Di Fonzo et al. (2006)</a> failed to find this variant in Caucasians. On the other hand, the gly2019-to-ser mutation (<a href="#0006">609007.0006</a>), which is commonly associated with PD in other ethnic groups, has not been found in Chinese. In ethnic Chinese in Singapore, <a href="#72" class="mim-tip-reference" title="Tan, E. K., Zhao, Y., Skipper, L., Tan, M. G., Di Fonzo, A., Sun, L., Fook-Chong, S., Tang, S., Chua, E., Yuen, Y., Tan, L., Pavanni, R., Wong, M. C., Kolatkar, P., Lu, C. S., Bonifati, V., Liu, J. J. <strong>The LRRK2 gly2385-to-arg variant is associated with Parkinson's disease: genetic and functional evidence.</strong> Hum. Genet. 120: 857-863, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17019612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17019612</a>] [<a href="https://doi.org/10.1007/s00439-006-0268-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17019612">Tan et al. (2007)</a> found that the heterozygous G2385R genotype was higher in PD patients compared to controls (7.3 vs 3.6%, odds ratio = 2.1). These values yielded an estimated population-attributable risk of approximately 4%. In transfection studies, <a href="#72" class="mim-tip-reference" title="Tan, E. K., Zhao, Y., Skipper, L., Tan, M. G., Di Fonzo, A., Sun, L., Fook-Chong, S., Tang, S., Chua, E., Yuen, Y., Tan, L., Pavanni, R., Wong, M. C., Kolatkar, P., Lu, C. S., Bonifati, V., Liu, J. J. <strong>The LRRK2 gly2385-to-arg variant is associated with Parkinson's disease: genetic and functional evidence.</strong> Hum. Genet. 120: 857-863, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17019612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17019612</a>] [<a href="https://doi.org/10.1007/s00439-006-0268-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17019612">Tan et al. (2007)</a> demonstrated that both the wildtype and the G2385R variant LRRK2 protein localize to the cytoplasm and form aggregates. However, under conditions of oxidative stress, the G2385R variant was more toxic and was associated with a higher rate of apoptosis. <a href="#72" class="mim-tip-reference" title="Tan, E. K., Zhao, Y., Skipper, L., Tan, M. G., Di Fonzo, A., Sun, L., Fook-Chong, S., Tang, S., Chua, E., Yuen, Y., Tan, L., Pavanni, R., Wong, M. C., Kolatkar, P., Lu, C. S., Bonifati, V., Liu, J. J. <strong>The LRRK2 gly2385-to-arg variant is associated with Parkinson's disease: genetic and functional evidence.</strong> Hum. Genet. 120: 857-863, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17019612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17019612</a>] [<a href="https://doi.org/10.1007/s00439-006-0268-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17019612">Tan et al. (2007)</a> concluded that the G2385R variant appears to be a common risk factor for PD in Chinese and may act through proapoptotic mechanisms. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16633828+16172858+17019612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="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 G2385R variant in 9 (12.5%) of 72 unrelated Korean patients with onset of PD before age 50 and in 5% of controls. This yielded an odds ratio of 2.71 for carriers of G2385R, but the results were not significant. <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="#75" class="mim-tip-reference" title="Tan, E.-K., Zhao, Y., Tan, L., Lim, H.-Q., Lee, J., Yuen, Y., Pavanni, R., Wong, M.-C., Fook-Chong, S., Liu, J. J. <strong>Analysis of LRRK2 gly2385arg genetic variant in non-Chinese Asians.</strong> Mov. Disord. 22: 1816-1818, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17659642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17659642</a>] [<a href="https://doi.org/10.1002/mds.21658" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17659642">Tan et al. (2007)</a> found no association between the G2385R allele and PD among 472 non-Chinese Asian subjects in Singapore, including 166 PD and 306 controls of Malay or Indian ethnicity. Stratification by Malay and Indian ethnicity showed that no Indian individuals carried the allele (66 PD patients and 133 controls), and the frequency in Malay individuals was about 2% in both groups, which is much lower than the 8 to 10% prevalence reported in the Chinese population. The age of the G2385R mutation was estimated to be approximately 4,000 years ago (<a href="#74" class="mim-tip-reference" title="Tan, E.-K., Tang, M., Tan, L. C., Wu, Y.-R., Wu, R.-M., Ross, O. A., Zhao, Y. <strong>Lrrk2 R1628P in non-Chinese Asian races.</strong> Ann. Neurol. 64: 472-473, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18688798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18688798</a>] [<a href="https://doi.org/10.1002/ana.21467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18688798">Tan et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18688798+17659642" 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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Aasly, J. O., Toft, M., Fernandez-Mata, I., Kachergus, J., Hulihan, M., White, L. R., Farrer, M.
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<strong>Clinical features of LRRK2-associated Parkinson's disease in central Norway.</strong>
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Ann. Neurol. 57: 762-765, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15852371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15852371</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15852371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>LRRK2 mutations and parkinsonism. (Letter)</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15811455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15811455</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15811455" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Alcalay, R. N., Mejia-Santana, H., Tang, M. X., Rosado, L., Verbitsky, M., Kisselev, S., Ross, B. M., Louis, E. D., Comella, C. L., Colcher, A., Jennings, D., Nance, M. A., and 21 others.
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<strong>Motor phenotype of LRRK2 G2019S carriers in early-onset Parkinson disease.</strong>
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Arch. Neurol. 66: 1517-1522, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20008657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20008657</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20008657" 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/archneurol.2009.267" target="_blank">Full Text</a>]
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<strong>LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model.</strong>
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[<a href="https://doi.org/10.1093/hmg/ddp346" target="_blank">Full Text</a>]
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Angeles, D. C., Gan, B.-H., Onstead, L., Zhao, Y., Lim, K.-L., Dachsel, J., Melrose, H., Farrer, M., Wszolek, Z. K., Dickson, D. W., Tan, E.-K.
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[<a href="https://doi.org/10.1002/humu.21582" target="_blank">Full Text</a>]
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<strong>Ashkenazi Parkinson's disease patients with the LRRK2 G2019S mutation share a common founder dating from the second to fifth centuries.</strong>
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[<a href="https://doi.org/10.1007/s10048-009-0186-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.21019" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.20664" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddv147" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddz004" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/brain/awh676" 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/10.1212/01.wnl.0000244345.49809.36" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneurol.2010.79" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.20510" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/S0140-6736(05)17829-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10048-006-0041-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000169023.51764.b0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.20484" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.63.3.377" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.20401" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddt061" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.63.9.1250" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/429256" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddq289" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/brain/awy077" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nm.2199" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000338460.89796.06" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMc055540" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.20636" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.64.3.425" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/432422" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.neuron.2009.11.006" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0708452105" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.15252/embj.2020104862" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10048-008-0140-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.neuron.2006.10.008" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10048-009-0187-z" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10048-005-0005-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e3181ff9685" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/S0140-6736(05)17828-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000277637.33328.d8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMc055509" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.neuron.2004.10.023" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000167552.79769.b3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.20668" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/brain/awab073" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M113.537811" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.21405" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp337" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31626293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31626293</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31626293[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=31626293" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddz245" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng.487" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddi376" target="_blank">Full Text</a>]
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<strong>Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin and mutant LRRK2 induces neuronal degeneration.</strong>
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[<a href="https://doi.org/10.1073/pnas.0508052102" target="_blank">Full Text</a>]
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<strong>LRRK2 mutations on Crete: R1441H associated with PD evolving to PSP.</strong>
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[<a href="https://doi.org/10.1212/01.wnl.0000239829.33936.73" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-008-0544-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-006-0268-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.21225" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.21467" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/mds.21658" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0906334106" target="_blank">Full Text</a>]
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<strong>Leucine-rich repeat kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease.</strong>
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[<a href="https://doi.org/10.1093/hmg/ddp394" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddz088" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/dds003" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0507360102" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddl471" target="_blank">Full Text</a>]
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<a id="82" class="mim-anchor"></a>
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<a id="Wszolek1995" class="mim-anchor"></a>
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<p class="mim-text-font">
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Wszolek, Z. K., Pfeiffer, B., Fulgham, J. R., Parisi, J. E., Thompson, B. M., Uitti, R. J., Calne, D. B., Pfeiffer, R. F.
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<strong>Western Nebraska family (family D) with autosomal dominant parkinsonism.</strong>
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Neurology 45: 502-505, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7898705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7898705</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7898705" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/wnl.45.3.502" target="_blank">Full Text</a>]
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<a id="83" class="mim-anchor"></a>
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<a id="Wszolek1997" class="mim-anchor"></a>
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Wszolek, Z. K., Vieregge, P., Uitti, R. J., Gasser, T., Yasuhara, O., McGeer, P., Berry, K., Calne, D. B., Vingerhoets, F. J. G., Klein, C., Pfeiffer, R. F.
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<strong>German-Canadian family (family A) with parkinsonism, amyotrophy, and dementia--longitudinal observations.</strong>
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Parkinsonism Relat. Disord. 3: 125-139, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18591067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18591067</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18591067" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s1353-8020(97)00013-8" target="_blank">Full Text</a>]
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<a id="84" class="mim-anchor"></a>
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<a id="Zabetian2006" class="mim-anchor"></a>
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Zabetian, C. P., Hutter, C. M., Yearout, D., Lopez, A. N., Factor, S. A., Griffith, A., Leis, B. C., Bird, T. D., Nutt, J. G., Higgins, D. S., Roberts, J. W., Kay, D. M., Edwards, K. L., Samii, A., Payami, H.
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<strong>LRRK2 G2019S in families with Parkinson disease who originated from Europe and the Middle East: evidence of two distinct founding events beginning two millennia ago.</strong>
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Am. J. Hum. Genet. 79: 752-758, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16960813/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16960813</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16960813" 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/10.1086/508025" target="_blank">Full Text</a>]
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<a id="85" class="mim-anchor"></a>
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Zabetian, C. P., Lauricella, C. J., Tsuang, D. W., Leverenz, J. B., Schellenberg, G. D., Payami, H.
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<strong>Analysis of the LRRK2 G2019S mutation in Alzheimer disease. (Letter)</strong>
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Arch. Neurol. 63: 156-157, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16401756/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16401756</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16401756" 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.63.1.156" target="_blank">Full Text</a>]
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Zabetian, C. P., Morino, H., Ujike, H., Yamamoto, M., Oda, M., Maruyama, H., Izumi, Y., Kaji, R., Griffith, A. Leis, B. C., Roberts, J. W., Yearout, D., Samii, A., Kawakami, H.
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<strong>Identification and haplotype analysis of LRRK2 G2019S in Japanese patients with Parkinson disease.</strong>
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Neurology 67: 697-699, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16728648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16728648</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16728648" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000227732.37801.d4" target="_blank">Full Text</a>]
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<a id="87" class="mim-anchor"></a>
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<a id="Zabetian2005" class="mim-anchor"></a>
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Zabetian, C. P., Samii, A., Mosley, A. D., Roberts, J. W., Leis, B. C., Yearout, D., Raskind, W. H., Griffith, A.
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<strong>A clinic-based study of the LRRK2 gene in Parkinson disease yields new mutations.</strong>
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Neurology 65: 741-744, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16157909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16157909</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16157909" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000172630.22804.73" target="_blank">Full Text</a>]
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<a id="88" class="mim-anchor"></a>
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<a id="Zimprich2004" class="mim-anchor"></a>
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<div class="">
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Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln, S., Kachergus, J., Hulihan, M., Uitti, R. J., Calne, D. B., Stoessl, A. J., Pfeiffer, R. F., Patenge, N., Carballo Carbajal, I., Vieregge, P., Asmus, F., Muller-Myhsok, B., Dickson, D. W., Meitinger, T., Strom, T. M., Wszolek, Z. K., Gasser, T.
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<strong>Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.</strong>
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Neuron 44: 601-607, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15541309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15541309</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15541309" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.neuron.2004.11.005" target="_blank">Full Text</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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Bao Lige - updated : 01/10/2023
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 12/09/2022<br>Bao Lige - updated : 03/02/2022<br>Bao Lige - updated : 10/21/2021<br>Hilary J. Vernon - updated : 08/13/2021<br>Bao Lige - updated : 01/22/2020<br>Bao Lige - updated : 07/03/2018<br>Patricia A. Hartz - updated : 11/09/2017<br>Patricia A. Hartz - updated : 05/08/2017<br>Patricia A. Hartz - updated : 10/10/2013<br>Cassandra L. Kniffin - updated : 7/15/2013<br>Ada Hamosh - updated : 12/13/2012<br>Patricia A. Hartz - updated : 8/3/2012<br>Cassandra L. Kniffin - updated : 4/2/2012<br>Paul J. Converse - updated : 2/7/2011<br>Cassandra L. Kniffin - updated : 12/3/2010<br>George E. Tiller - updated : 10/22/2010<br>George E. Tiller - updated : 9/30/2010<br>Cassandra L. Kniffin - updated : 8/30/2010<br>Ada Hamosh - updated : 8/24/2010<br>George E. Tiller - updated : 8/6/2010<br>Cassandra L. Kniffin - updated : 7/13/2010<br>Cassandra L. Kniffin - updated : 6/25/2010<br>Cassandra L. Kniffin - updated : 1/4/2010<br>Cassandra L. Kniffin - updated : 12/14/2009<br>Cassandra L. Kniffin - updated : 10/15/2009<br>Cassandra L. Kniffin - updated : 5/14/2009<br>George E. Tiller - updated : 4/23/2009<br>Cassandra L. Kniffin - updated : 4/6/2009<br>Cassandra L. Kniffin - updated : 10/28/2008<br>Cassandra L. Kniffin - updated : 7/22/2008<br>Patricia A. Hartz - updated : 4/15/2008<br>Cassandra L. Kniffin - updated : 4/2/2008<br>Cassandra L. Kniffin - updated : 3/12/2008<br>Cassandra L. Kniffin - updated : 12/27/2007<br>Cassandra L. Kniffin - updated : 11/7/2007<br>Victor A. McKusick - updated : 9/24/2007<br>Cassandra L. Kniffin - updated : 9/12/2007<br>Cassandra L. Kniffin - updated : 2/19/2007<br>Cassandra L. Kniffin - updated : 11/6/2006<br>Victor A. McKusick - updated : 9/22/2006<br>Cassandra L. Kniffin - updated : 7/17/2006<br>Cassandra L. Kniffin - updated : 4/21/2006<br>Cassandra L. Kniffin - updated : 3/15/2006<br>Cassandra L. Kniffin - updated : 3/2/2006<br>Victor A. McKusick - updated : 2/9/2006<br>Cassandra L. Kniffin - updated : 1/4/2006<br>Patricia A. Hartz - updated : 12/22/2005<br>Cassandra L. Kniffin - updated : 11/7/2005<br>Cassandra L. Kniffin - updated : 8/26/2005<br>Cassandra L. Kniffin - updated : 8/9/2005<br>Cassandra L. Kniffin - updated : 6/10/2005<br>Cassandra L. Kniffin - updated : 5/11/2005<br>Victor A. McKusick - updated : 3/11/2005<br>Cassandra L. Kniffin - updated : 2/9/2005
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Cassandra L. Kniffin : 11/2/2004
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carol : 01/23/2024
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carol : 12/14/2023<br>mgross : 01/10/2023<br>carol : 12/09/2022<br>mgross : 03/02/2022<br>mgross : 10/21/2021<br>carol : 08/13/2021<br>mgross : 01/22/2020<br>mgross : 07/03/2018<br>alopez : 11/09/2017<br>carol : 10/25/2017<br>alopez : 10/23/2017<br>alopez : 05/08/2017<br>alopez : 10/04/2016<br>alopez : 03/11/2016<br>mcolton : 2/24/2014<br>mgross : 10/10/2013<br>carol : 7/16/2013<br>ckniffin : 7/15/2013<br>alopez : 12/21/2012<br>terry : 12/13/2012<br>terry : 12/13/2012<br>mgross : 8/8/2012<br>terry : 8/3/2012<br>terry : 5/24/2012<br>carol : 4/4/2012<br>ckniffin : 4/2/2012<br>carol : 11/22/2011<br>carol : 11/16/2011<br>ckniffin : 11/14/2011<br>wwang : 3/8/2011<br>ckniffin : 2/15/2011<br>mgross : 2/8/2011<br>terry : 2/7/2011<br>wwang : 12/6/2010<br>ckniffin : 12/3/2010<br>ckniffin : 11/17/2010<br>ckniffin : 11/17/2010<br>wwang : 10/22/2010<br>wwang : 10/12/2010<br>terry : 9/30/2010<br>terry : 9/9/2010<br>wwang : 9/3/2010<br>ckniffin : 8/30/2010<br>ckniffin : 8/27/2010<br>mgross : 8/25/2010<br>terry : 8/24/2010<br>wwang : 8/11/2010<br>terry : 8/6/2010<br>wwang : 7/14/2010<br>ckniffin : 7/13/2010<br>wwang : 6/29/2010<br>ckniffin : 6/25/2010<br>alopez : 1/4/2010<br>wwang : 12/28/2009<br>ckniffin : 12/14/2009<br>terry : 12/1/2009<br>wwang : 11/9/2009<br>ckniffin : 11/9/2009<br>ckniffin : 10/15/2009<br>wwang : 5/27/2009<br>ckniffin : 5/14/2009<br>wwang : 5/13/2009<br>wwang : 4/28/2009<br>terry : 4/23/2009<br>wwang : 4/10/2009<br>ckniffin : 4/6/2009<br>wwang : 11/7/2008<br>wwang : 11/7/2008<br>ckniffin : 10/28/2008<br>ckniffin : 10/28/2008<br>wwang : 7/28/2008<br>ckniffin : 7/22/2008<br>mgross : 4/15/2008<br>wwang : 4/10/2008<br>ckniffin : 4/2/2008<br>wwang : 4/1/2008<br>ckniffin : 3/12/2008<br>wwang : 1/14/2008<br>ckniffin : 12/27/2007<br>wwang : 11/27/2007<br>wwang : 11/26/2007<br>ckniffin : 11/7/2007<br>alopez : 11/7/2007<br>terry : 9/24/2007<br>wwang : 9/21/2007<br>ckniffin : 9/12/2007<br>wwang : 2/22/2007<br>ckniffin : 2/19/2007<br>wwang : 11/9/2006<br>ckniffin : 11/6/2006<br>alopez : 9/27/2006<br>terry : 9/22/2006<br>wwang : 8/10/2006<br>carol : 7/19/2006<br>ckniffin : 7/17/2006<br>wwang : 4/25/2006<br>ckniffin : 4/21/2006<br>ckniffin : 4/19/2006<br>carol : 4/18/2006<br>wwang : 4/5/2006<br>ckniffin : 3/15/2006<br>wwang : 3/14/2006<br>ckniffin : 3/2/2006<br>alopez : 2/14/2006<br>terry : 2/9/2006<br>wwang : 2/1/2006<br>ckniffin : 1/4/2006<br>wwang : 12/22/2005<br>wwang : 11/15/2005<br>ckniffin : 11/7/2005<br>terry : 9/23/2005<br>wwang : 9/6/2005<br>ckniffin : 8/26/2005<br>ckniffin : 8/9/2005<br>wwang : 6/16/2005<br>ckniffin : 6/10/2005<br>ckniffin : 5/11/2005<br>wwang : 3/14/2005<br>terry : 3/11/2005<br>tkritzer : 2/22/2005<br>ckniffin : 2/9/2005<br>terry : 1/4/2005<br>carol : 11/2/2004<br>ckniffin : 11/2/2004
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<strong>*</strong> 609007
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<h3>
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LEUCINE-RICH REPEAT KINASE 2; LRRK2
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DARDARIN
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<strong>
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<em>
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Cytogenetic location: 12q12
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Genomic coordinates <span class="small">(GRCh38)</span> : 12:40,224,997-40,369,285 </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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</p>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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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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</thead>
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<tbody>
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<td rowspan="1">
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<span class="mim-font">
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12q12
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</td>
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<td>
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<span class="mim-font">
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{Parkinson disease 8}
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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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607060
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</span>
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<span class="mim-font">
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Autosomal dominant
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<td>
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<span class="mim-font">
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3
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</table>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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<span class="mim-font">
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<strong>Description</strong>
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</h4>
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<span class="mim-text-font">
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<p>The LRRK2 gene encodes a protein with 5 putative functional domains: an N-terminal leucine-rich repeat (LRR) domain, a Roc (Ras of complex protein) domain that shares sequence homology to the Ras-related GTPase superfamily, a COR (C-terminal of Roc) domain, a mitogen-activated protein kinase kinase kinase (MAPKKK) domain, and a C-terminal WD40 repeat domain. Mutation in this gene is one of the most common causes of inherited Parkinson disease (PARK8; 607060) (summary by Gandhi et al., 2008). </p>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</h4>
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<p>Paisan-Ruiz et al. (2004) identified a putative disease-causing transcript (DKFZp434H2111) within a 2.6-Mb region encompassing a locus for Parkinson disease-8 (PARK8; 607060). The predicted transcript encodes a deduced 2,482-amino acid protein with a leucine-rich repeat, a kinase domain, a RAS domain, and a WD40 domain. Northern blot analysis detected a 9-kb mRNA transcript in all tissues tested, including brain. The authors named the protein product dardarin, derived from the Basque word dardara, meaning tremor. </p><p>Zimprich et al. (2004) cloned LRRK2 from a human brain cDNA library and found that it encodes a 2,527-amino acid protein with a molecular mass of approximately 250-kD. Northern blot analysis detected a major 9-kb transcript at low levels in most brain regions. Highest transcript levels were obtained in the putamen, substantia nigra, and lung. The appearance of smaller bands suggested alternative splicing. </p><p>By 5-prime RACE of human brain cDNA, West et al. (2005) found LRRK2 transcripts with at least 6 transcription start sites upstream of the predicted Kozak sequence. They also identified a splice variant, resulting from utilization of a cryptic splice site within intron 50, that encodes a protein lacking 6 amino acids near the C-terminal WD40 domain. In transfected human embryonic kidney cells, LRRK2 was largely excluded from the nucleus and localized to the cytosol, but about 10% of LRRK2 was associated with the outer mitochondrial membrane. LRRK2 migrated at an apparent molecular mass of 280 kD. </p><p>By fractionation analysis of rat brain, Shani et al. (2019) showed that endogenous Lrrk2 was present in cytosol and nucleus. Immunofluorescence and immunocytochemical analyses confirmed the nuclear presence of LRRK2 transfected HEK293 cells and transfected rat primary cortical neurons. Nuclear subfractionation further revealed that LRRK2 was present in the nuclear cytoskeleton fraction, which contains lamin A/C (LMNA; 150330). LRRK2 contains 3 putative nuclear translocation signals, but mutation analysis showed that they were not relevant to nuclear localization of LRRK2. </p>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</h4>
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<span class="mim-text-font">
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<p>Zimprich et al. (2004) determined that the LRRK2 gene contains 51 exons spanning 144 kb. </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By genomic sequence analysis, Zimprich et al. (2004) mapped the LRRK2 gene to chromosome 12q12. </p>
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</span>
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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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</h4>
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<p>By measuring the activity of LRRK2 against myelin basic protein (159430) as a test substrate, West et al. (2005) determined that LRRK2 possesses mixed-lineage kinase activity. LRRK2 also showed autophosphorylation activity. </p><p>Smith et al. (2005) demonstrated that LRRK2 is primarily cytoplasmic and interacts with parkin (PARK2; 602544). LRRK2 interacted preferentially with the C-terminal R2 RING finger domain of parkin, and parkin interacted with the COR domain of LRRK2. Coexpression of LRRK2 and parkin increased cytoplasmic protein aggregates that contained LRRK2 and enhanced the ubiquitination of these aggregates. Expression of mutant LRRK2 induced apoptotic cell death in human SH-SY5Y neuroblastoma cells and in mouse cortical neurons in vitro. </p><p>Using oligonucleotide probes, Galter et al. (2006) detected LRRK2 expression in medium-sized spiny neurons of the caudate and putamen. Larger, presumably cholinergic neurons and dopamine neurons were devoid of LRRK2 signal. No differences were observed between normal brains and those from individuals with Parkinson disease. Similar studies on rodent brain showed Lrrk2 expression in the striatum and absence of Lrrk2 expression in the midbrain. The findings demonstrated LRRK2 expression in brain dopaminoceptive areas, suggesting to the authors that LRRK2 dysfunction in these areas may diminish trophic support of dopamine neurons. </p><p>Using immunohistochemistry and Western blot analysis, Biskup et al. (2006) detected Lrrk2 in multiple areas throughout rat brain. Lrrk2 localization was neuron-specific, detected in microsomal, synaptic vesicle-enriched and synaptosomal cytosolic fractions, as well as the mitochondrial outer membrane. Lrrk2 was also detected in the kidney. Further studies in human and rat brain showed LRRK2 in punctate structures within neuronal perikarya, dendrites, and axons. LRRK2 immunoreactivity was associated with membranous and vesicular intracellular structures, including lysosomes, endosomes, transport vesicles, and mitochondria. Biskup et al. (2006) concluded that LRRK2 has an affinity for lipids or lipid-associated proteins and may play a role in the biogenesis or regulation of membranous intracellular structures in the brain. </p><p>In HEK293 cells, Gloeckner et al. (2006) demonstrated that LRRK2 was associated with particulate membrane structures within the cytoplasm, such as mitochondria, microsomal membranes, endoplasmic reticulum, and the Golgi apparatus. However, LRRK2 did not appear to be integrated into membranes. Further studies showed that LRRK2 dimerizes, shows kinase activity, and is able to phosphorylate itself. </p><p>Using a combination of protein pull-down assays, mass spectrometry, Western blotting, and immunofluorescence microscopy, Gandhi et al. (2008) found that the ROC, or GTPase-like, domain of LRRK2 interacted with alpha (see TUBA1A; 602529)/beta (see TUBB2B; 612850)-tubulin heterodimers that form microtubules. The interaction was guanine-nucleotide independent. Endogenous LRRK2 protein was found to colocalize with alpha/beta-tubulin in the cell body and neuronal processes of rat primary hippocampal neurons. These findings linked LRRK2 with microtubules, a structural component of the cell critically involved in the pathogenesis of several neurodegenerative diseases, including Parkinson disease. However, the pathogenic R1441C LRRK2 mutation (609007.0003), located within the ROC domain, retained interaction with alpha/beta-tubulin heterodimers, suggesting that disruption of this interaction is not the pathogenic mechanism. </p><p>Gillardon (2009) showed that recombinant human LRRK2 preferentially phosphorylated bovine brain beta-tubulin at the highly conserved residue thr107. Tubulin becomes phosphorylated during neurite outgrowth, and phosphorylation may stabilize the microtubule cytoskeleton. Gillardon (2009) found that LRRK2 coimmunoprecipitated with tubulin-beta in both wildtype mouse brain and nonneuronal HEK293 cells, and in vitro coincubation of brain tubulins with LRRK2 increased microtubule stability in the presence of microtubule-associated proteins. Lrrk2-deficient murine neuron cultures showed a significant decrease in neurite length compared to wildtype neurons. The findings suggested that stabilization of microtubules by tubulin-beta phosphorylation may represent a physiologic function of LRRK2 in neurons. Phosphorylation of tubulin was enhanced 3-fold by the LRRK2 G2019S mutation (609007.0006), which suggested that mutant LRRK2-induced neurodegeneration in PD may be partly mediated by increased phosphorylation of tubulin-beta, which may interfere with neurite outgrowth, axonal transport, and synapse formation. </p><p>Sancho et al. (2009) reported interaction of LRRK2 with the dishevelled family of phosphoproteins, DVL1 (601365), DVL2 (602151), and DVL3 (601368), key regulators of Wnt (Wingless/Int; 164820) signaling pathways important for axon guidance, synapse formation, and neuronal maintenance. The LRRK2 Roc-COR domain and the DVL1 (601365) DEP domain were necessary and sufficient for LRRK2-DVL1 interaction. Coexpression of DVL1 increased LRRK2 steady-state protein levels, an effect that was dependent on the DEP domain. LRRK2-DVL1-3 interactions were disrupted by the LRRK2 Y1699C mutation (609007.0002), whereas pathogenic mutations at residues arg1441 (see, e.g., 609007.0001) and arg1728 strengthened LRRK2-DVL1 interactions. Coexpression of DVL1 with LRRK2 in mammalian cells resulted in the redistribution of LRRK2 to typical cytoplasmic DVL1 aggregates in HEK293 and SH-SY5Y cells and colocalization in neurites and growth cones of differentiated dopaminergic SH-SY5Y cells. Since the DVL1 DEP domain is known to be involved in the regulation of small GTPases, Sancho et al. (2009) proposed that DVLs may influence LRRK2 GTPase activity, and that Roc-COR domain mutations modulating LRRK2-DVL interactions indirectly influence kinase activity. </p><p>Gehrke et al. (2010) found that LRRK2 interacted with the microRNA (miRNA) pathway to regulate protein synthesis. They showed that mRNAs for Drosophila E2f1 (189971) and Dp (TFDP1; 189902), which had previously been implicated in cell cycle and survival control (Girling et al., 1993), were translationally repressed by the miRNAs Let7 (MIRLET7A1; 605386) and miR184* (613146), respectively. Pathogenic human LRRK2 antagonized Let7 and miR184*, leading to overproduction of E2f1 and Dp, which was critical for LRRK2 pathogenesis. In Drosophila, genetic deletion of Let7, antagomir-mediated blockage of Let7 and miR184* action, transgenic expression of Dp target protector, or replacement of endogenous Dp with a Dp transgene nonresponsive to Let7 each had toxic effects similar to those of pathogenic LRRK2. Conversely, increasing the level of Let7 or miR184* attenuated pathogenic LRRK2 effects. Human LRRK2 associated with Drosophila Argonaute-1 (EIF2C1, or AGO1; 606228) or human Argonaute-2 (EIF2C2, or AGO2; 606229) of the RNA-induced silencing complex (RISC). In aged fly brain, Ago1 protein level was negatively regulated by human LRRK2. Furthermore, pathogenic LRRK2 promoted the association of phosphorylated 4EBP1 (EIF4EPB1; 602223) with human AGO2. Gehrke et al. (2010) concluded that deregulated synthesis of E2F1 and DP caused by miRNA pathway impairment is a key event in LRRK2 pathogenesis, suggesting that novel miRNA-based therapeutic strategies may be useful for Parkinson disease. </p><p>Using a human LRRK2-Ypet genomic reporter system, immunofluorescence microscopy, and immunoelectron microscopy, Alegre-Abarrategui et al. (2009) found that LRRK2 was located to membrane microdomains such as the neck of caveolae, microvilli/filopodia and intraluminal vesicles of multivesicular bodies (MVBs). In human brain and in cultured human cells, LRRK2 was present in cytoplasmic puncta corresponding to MVBs and autophagic vacuoles (AVs). Expression of the common R1441C mutation (609007.0003) from a genomic DNA construct caused impaired autophagic balance evident by the accumulation of MVBs and large AVs containing incompletely degraded material and increased levels of p62 (SQSTM1; 601530). The R1441C mutation induced the formation of skein-like abnormal MVBs. Conversely, LRRK2 siRNA knockdown increased autophagic activity and prevented cell death caused by inhibition of autophagy in starvation conditions. Alegre-Abarrategui et al. (2009) proposed a functional involvement of LRRK2 in the endosomal-autophagic pathway. </p><p>Using microarray and RT-PCR analyses, Gardet et al. (2010) detected increased LRRK2 expression in monocytes and B cells and upregulation of LRRK2 after IFNG (147570) stimulation. Analysis of the LRRK2 promoter region revealed a conserved binding site for IFN response factors. Examination of lamina propria tissue from Crohn disease (CD; 266600) patient specimens revealed upregulated LRRK2 expression in inflamed tissue compared with noninflamed tissue. Reporter assays showed that LRRK2 activated NFKB (see 164011) in an IKK (see 603258)-dependent manner. Confocal microscopy demonstrated colocalization of Lrrk2 with Salmonella typhimurium in infected murine macrophages. Lrrk2 knockdown interfered with the production of reactive oxygen species. Gardet et al. (2010) proposed that LRRK2 is an IFNG target gene that may be involved in signaling pathways relevant to Crohn disease. </p><p>Using mutant flies and fly cell lines and the human SH-SY5Y neuroblastoma cell line, Kanao et al. (2010) showed that the apoptotic effect of LRRK2 involved LRRK2-mediated phosphorylation of FOXO1 (FOXO1A; 136533) and downstream FOXO signaling through the proapoptotic protein BIM (BCL2L11; 603827). </p><p>Using a yeast 2-hybrid assay to screen a human cDNA library, Angeles et al. (2011) found that LRRK2 interacts with PRDX3 (604769), an important antioxidant scavenger of hydrogen peroxide in the mitochondria. Mutations in the kinase domain of LRRK2, particularly G2019S, significantly increased the phosphorylation of PRDX3 compared to wildtype LRRK2, resulting in decreased peroxidase activity and increased death in LRRK2-expressing cells, but not in LRRK2-depleted cells. This resulted in dysregulation of mitochondrial function and increased oxidative damage. These damaging effects were exacerbated in PRDX3-depleted cells, suggesting that PRDX3 normally can rescue LRRK2-induced oxidative stress. The findings suggested that loss of endogenous antioxidant function may contribute to neurodegeneration induced by mutant LRRK2, as seen in Parkinson disease. </p><p>Wang et al. (2012) found that overexpression of wildtype LRRK2 in human neuronal cell lines caused mitochondrial fragmentation associated with increased levels of DLP1 (603850), a mitochondrial fission protein, and that these processes were exacerbated by expression of PD-associated mutants R1441C (609007.0003) or G2019S (609007.0006). LRRK2 directly interacted with DLP1, and this interaction was enhanced by LRRK2 PD-associated mutations. Increased mitochondrial fragmentation was associated with mitochondrial dysfunction and enhanced susceptibility to oxidative stress, which was inhibited with coexpression of a dominant-negative DLP1 mutant. These mitochondrial features were not apparent with LRRK2 mutants that had lost kinase activity. Wang et al. (2012) concluded that LRRK2 regulates mitochondrial dynamics by interacting with DLP1, and that LRRK2 kinase activity plays a critical role in this process. The findings supported a role for altered mitochondrial fission/fusion in the pathogenesis of PD. </p><p>Bonello et al. (2019) found that LRRK2 attenuated parkin-dependent mitophagy induced by carbonylcyanide m-chlorophenylhydrazone (CCCP) in COS-7 cells. The attenuation of mitophagy was kinase dependent, as LRRK2 kinase activity disrupted protein-protein interactions involving parkin and DRP1 (DNM1L; 603850) on mitochondria. The authors also developed a model for parkin-dependent mitophagy triggered by thermal stress in human fibroblasts. They found that parkin-dependent mitophagy was impaired in fibroblasts from patients with PD. Furthermore, in agreement with disruption of mitochondrial recruitment of DRP1 by LRRK2 activity, a pharmacologic LRRK2 kinase inhibitor rescued the mitophagy defect in fibroblasts from PD patients in a DRP1-dependent manner. </p><p>By immunoprecipitation and pull-down assays, Shani et al. (2019) showed that LRRK2 interacted with lamin A/C in the nuclear cytoskeleton. LRRK2 also interacted with the ubiquitin ligases SIAH1 (602212) and SIAH2 (602213), both of which ubiquitinated LRRK2. Further analysis with SIAH1 confirmed that it facilitated nuclear translocation of LRRK2. In vitro and in vivo analyses demonstrated that LRRK2 helped maintain the nuclear lamina and the nuclear membrane integrity. </p><p>Using knockdown analysis in human and mouse primary monocyte-derived cells polarized to macrophages, Liu et al. (2020) showed that RAB10 (612672) expression regulated macropinocytosis. RAB10 was recruited to early stages of macropinocytosis and regulated macropinosome trafficking. GTP binding was required for localization of RAB10 to early macropinosomes, whereas GTP hydrolysis was required for dissociation of RAB10 from macropinosomes. LRRK2 transiently interacted with the GTP-bound form of RAB10 on early macropinosomes, where it phosphorylated RAB10 and thereby stalled RAB10 on early macropinosomes during vesicle maturation. A proteomic approach in mouse macrophages showed that Ehbp1l1 (619583) interacted with GTP-bound, vesicle-associated Rab10 to regulate recycling of macropinosomes. Lrrk2-mediated phosphorylation of GTP-bound Rab10 inhibited Ehbp1l1-dependent fast recycling of macropinosomes by directly competing with Ehbp1l1 for complex occupancy and blocking binding of Ehbp1l1 to Rab10. Further analysis demonstrated that, although Lrrk2 phosphorylation of GTP-bound Rab10 did not directly regulate fluid cargo uptake, it potentiated Ccl5 (187011)-stimulated Akt (164730) signaling and macrophage chemotaxis. </p><p>Pischedda et al. (2021) studied dopaminergic neurons differentiated from iPSCs expressing LRRK2 with the G2019S mutation (609007.0006) and identified the presence of high molecular weight complexes containing N-ethylmaleimide sensitive factor (NSF). These complexes were found to be dependent on phosphorylation of NSF at Thr645. Pischedda et al. (2021) suggested that phosphorylation of NSF at Thr645 by LRRK2 with the G2019S mutation promotes oligomerization and precipitation into cytotoxic protein inclusions. Pischedda et al. (2021) also studied postmortem brain tissue from patients with sporadic Parkinson disease and patients with Parkinson disease caused by the LRKK2 G2019S mutation and identified aggregates containing NSF in the basal ganglia. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>LRRK2 contains a 'Ras of complex proteins' (ROC) domain that may act as a GTPase to regulate its kinase activity. Deng et al. (2008) reported the crystal structure of the LRRK2 ROC domain in complex with GDP-Mg(2+) at 2.0-angstrom resolution. The structure displayed a dimeric fold generated by extensive domain swapping, resulting in a pair of active sites with essential functional groups contributed from both monomers. Two residues mutated in PARK8, arg1331 and ile1371, were located at the interface of the 2 monomers and provided interactions to stabilize the ROC dimer. Deng et al. (2008) concluded that PARK8-associated mutations in the ROC domain disrupt dimer formation, resulting in decreased GTPase activity. They proposed that the ROC domain regulates LRRK2 kinase activity as a dimer, possibly via the COR domain acting as a molecular hinge. </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>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Parkinson Disease 8, Autosomal Dominant</em></strong></p><p>
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Dachsel and Farrer (2010) provided a review of the LRRK2 gene and its role in Parkinson disease. </p><p>In affected members of 5 families with autosomal dominant Parkinson disease-8 (PARK8; 607060), Paisan-Ruiz et al. (2004) identified 2 different heterozygous mutations in the LRRK2 gene (609007.0001-609007.0002). </p><p>Zimprich et al. (2004) identified 6 mutations in the LRRK2 gene in families with Parkinson disease-8 (see, e.g., 609007.0003-609007.0005). Postmortem analysis of several affected persons demonstrated variable pathology, including Lewy bodies, nigral degeneration without Lewy bodies, and tau (MAPT; 157140)-reactive neuronal and glial lesions. Zimprich et al. (2004) suggested that LRRK2 may play a role in several neurodegenerative disorders. </p><p>Nichols et al. (2005) identified a heterozygous gly2019-to-ser substitution in the LRRK2 gene (G2019S; 609007.0006) in 6% of families with autosomal dominant PD and suggested genetic screening for this mutation. </p><p>In all 19 affected members of the original Japanese family with Parkinson disease-8 (Hasegawa and Kowa, 1997), Funayama et al. (2005) identified a heterozygous mutation in the LRRK2 gene (609007.0007). The mutation was not identified in 188 patients with sporadic PD. </p><p>Using allelic discrimination assays for 9 LRRK2 mutations, Farrer et al. (2005) identified pathogenic mutations in the LRRK2 gene in 5 (0.6%) of 786 probands with idiopathic PD. Four probands carried the common G2019S mutation. </p><p>By screening LRRK2 exons 31, 35, and 41, Zabetian et al. (2005) identified LRRK2 mutations in 6 (1.6%) of 371 unrelated patients with PD. Four patients were sporadic, and 2 had a family history of the disorder. All 6 patients were of European ancestry. </p><p>Paisan-Ruiz et al. (2005) identified 2 different LRRK2 mutations in 3 of 23 unrelated probands with autosomal dominant Parkinson disease. Two probands had the common G2019S mutation. In a case-control study of 121 unrelated PD patients and 250 controls, Paisan-Ruiz et al. (2005) found no association between PD and any of 4 LRRK2 polymorphisms examined. </p><p>In 7 of 100 unrelated families with Parkinson disease, Mata et al. (2005) identified 7 different heterozygous mutations in the LRRK2 gene. </p><p>Biskup et al. (2005) identified the G2019S mutation in 1 (0.29%) of 340 German patients with sporadic PD. In a case-control study of these 340 patients and 680 controls, they found no significant association between PD and any of 121 LRRK2 SNPs, covering the entire gene region. They replicated the finding in a second set of 322 German sporadic PD patients and 322 controls. </p><p>By autophosphorylation and GTP-binding assay, West et al. (2007) showed that in the normal state, the GTPase activity of the LRRK2 protein is required for and modulates downstream kinase activity, but that kinase activity does not have a significant effect on GTP binding. Using site-directed mutagenesis constructs of specific PD-associated mutations, the authors showed that increased kinase activity was the most common biochemical feature of pathogenic missense mutations. Specific mutations examined included 2 in the kinase domain (G2019S; 609007.0006 and I2020T; 609007.0007), 2 in the GTPase domain (R1441C; 609007.0003 and R1441G; 609007.0001), 1 in the LRR domain (I1122V; 609007.0005), and 1 in the COR domain (Y1699C; 609007.0002). The G2385R (609007.0009) polymorphism did not cause any change in kinase activity, consistent with it being a benign polymorphism. Studies in cultured mouse cells showed that the increased kinase activity of the mutants was toxic. Overall, the findings indicated that pathogenic LRRK2 mutations potentiate neurotoxicity in a kinase-dependent manner via gain of function. </p><p>Paisan-Ruiz et al. (2008) performed a comprehensive sequence-based analysis of the entire LRRK2 gene in 275 patients with PD and 275 controls. Six novel disease-associated mutations were identified, but there were no gene deletions or duplications. LRRK2 mutations were found in 3.6% of the PD patients. Multiple gene variants or SNPs were identified, none of which were associated with disease. Combined with previous reports, the data showed that the majority of disease-causing LRRK2 mutations lie in the C-terminal half of the protein. </p><p>Garrido et al. (2022) studied AKT phosphorylation in PBMCs from 25 patients with PD and 25 individuals at risk for PD who were heterozygous for the G2019S mutation (609007.0006) in the LRRK2 gene. Compared to controls and patients with idiopathic PD, heterozygotes for the G2019S mutation had increased phosphorylation at ser473 of the AKT (164730) protein. Garrido et al. (2022) concluded that AKT ser473 is a biomarker for the G2019 mutation in the LRRK2 gene. </p><p><strong><em>Susceptibility to Parkinson Disease</em></strong></p><p>
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Skipper et al. (2005) identified a subset of tagging-SNPs (tSNP) that captured the majority of common variation within LRRK2. Both single tSNP and tSNP haplotype analyses, using a large epidemiologically-matched sporadic case-control series comprising 932 Chinese individuals, yielded significant evidence for association with Parkinson disease. The authors identified a haplotype that dramatically increased disease risk when present in 2 copies (odds ratio = 5.5; P = 0.0001). </p><p>Among Taiwanese and Chinese, Di Fonzo et al. (2006) and Tan et al. (2007) found that a common polymorphism (G2385R; rs34778348; 609007.0009) was significantly more frequent among patients with Parkinson disease compared to controls. The findings suggested that the G2385R variant may be a common risk factor for later-onset PD among Asian populations. </p><p>Ross et al. (2008) found that a 4883G-C SNP in the LRRK2 gene, resulting in an arg1628-to-pro (R1628P; rs33949390) variant, was associated with increased risk for typical late-onset, dopa-responsive Parkinson disease in Chinese individuals. The carrier frequency was 6.1% among 1,079 Han Chinese PD patients and 3.4% among 907 controls (odds ratio of 1.84; p = 0.006) combined from 3 cohorts. Haplotype analysis indicated an ancestral founder for carriers about 2,500 years ago. Ross et al. (2008) noted that the R1628P SNP is highly conserved and located within the functionally important COR domain. Among 1,337 Han Chinese individuals, Lu et al. (2008) found that the R1628P SNP was more common among patients (3.8%) compared to controls (1.8%) (odds ratio of 2.13; p = 0.004). Lu et al. (2008) concluded that R1628P is a risk factor for Parkinson disease in the Han Chinese population. Tan et al. (2008) also concluded that R1628P is a risk factor for PD among Han Chinese individuals. The frequency of the heterozygous R1628P mutation was higher in 246 PD patients compared to 243 controls (8.4% vs 3.4%, OR of 2.5). Multivariant logistic regression analysis controlling for age, age at onset, and gender yielded an OR of 3.3. Tan et al. (2008) found no association between the R1628P variant and PD among 132 PD patients of Malay ancestry compared to 160 Malay controls. In addition, the R1628P variant was not identified in 165 Indian individuals, both PD patients and controls. The authors concluded that the R1628P variant is indeed specific to the Chinese population, and that it is a relatively recent mutation event, occurring about 2,500 years earlier. </p><p>In genomewide association studies in 1,713 individuals of European ancestry with PD and 3,978 controls, with replication in 3,361 cases and 4,573 controls, Simon-Sanchez et al. (2009) found supporting evidence that common variation around LRRK2 modulates risk for PD (rs1491923, OR = 1.14, p = 1.55 x 10(-5)). </p><p>Tan et al. (2010) genotyped a total of 1,363 Han Chinese patients with PD and 1,251 Han Chinese controls for SNPs in the LRRK2 gene. There was a discovery set of 250 patients from Singapore and 3 replication cohorts including 192 patients from Singapore, 293 patients from Taiwan, and 628 patients from China, along with controls. The median age at onset for the entire patient group was 56 years. Significant disease associations were found with SNPs rs7308720 (N551K), rs7133914 (R1398H), and rs11564148 (S1647T). A combined analysis showed that R1398H and N551K were associated with a decreased disease risk, and S1647T, R1628P, and G2385R were associated with an increased disease risk. Multivariate regression analysis showed that the effect of R1398H and N551K was independent of G2385R and R1628P. The estimated risk of PD for carriers of both R1628P and G2385R was 1.87, and the presence of a protective variant, R1398H or N551K, reduced this risk to 1.5 to 1.6. In vitro functional analysis showed that R1628P and G2385R had higher autophosphorylation and kinase activity compared to control and that R1398H had decreased autophosphorylation and compromised kinase activity. Tan et al. (2010) concluded that multiple LRRK2 variants exert individual effects and together may modulate the risk of PD in the Han Chinese population. </p>
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<strong>Animal Model</strong>
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<p><strong><em>Rodent Models</em></strong></p><p>
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In COS-7 cells, MacLeod et al. (2006) found that G2019S and I2020T (609007.0007) mutant LRRK2 had significantly increased kinase activity compared to wildtype LRRK2. The G2019S-mutant protein was present in distinctive tau-positive spheroid-like axonal inclusions and at intracellular membranous structures. Overexpression of either of these mutants in rat cortical neurons resulted in a dramatic reduction in neurite length and branching, as well as decreased neuron survival. In contrast, cortical neurons transfected with LRRK2-shRNA vectors showed a prominent increase in neurite length and branching. Overall, the findings indicated that LRRK2 regulates neuronal process morphology in the central nervous system, suggesting a role for LRRK2 in the maintenance of neuronal process length and complexity. </p><p>Lin et al. (2009) found that overexpression of Lrrk2, either wildtype or mutant, in transgenic mice carrying an A53T Snca mutation (163890.0001) accelerated the PD-related neuropathologic abnormalities by promoting aggregation and accumulation of cytotoxic Snca-containing protein inclusions in cell bodies of striatal neurons. However, the 2 proteins did not appear to interact directly. Degenerating neurons showed fragmentation of the Golgi apparatus, which correlated with the accumulation of Snca. Immunostaining studies showed evidence of impaired microtubule assembly within the cells as well as impairment of the ubiquitin-proteasome system. Mitochondrial function was also impaired. Inhibition of Lrrk2 in these mice suppressed these abnormalities and delayed the progression of neuropathology in A53T mutant mice. The findings suggested that Lrrk2 may regulate mutant Snca-mediated neuropathology by modulating the intracellular trafficking and microtubule-based axonal transport of Snca. </p><p>Lee et al. (2010) presented evidence demonstrating that pharmacologic inhibitors of LRRK2 kinase activity are protective in both in vitro and in vivo mouse models of LRRK2-induced neurodegeneration. </p><p>Boddu et al. (2015) stated that Lrrk2 -/- mice and rats have subtle multisystem abnormalities, but the most striking phenotype is development of profound kidney discoloration. In rats, Boddu et al. (2015) found that discoloration in Lrrk2 -/- kidney was due to accumulation of oxidized hemoglobin. Lrrk2 -/- rat kidney also showed mononuclear infiltration and accumulation of oxidized lipids and other blood products, but mutant kidney had overall normal architecture and function, and Lrrk2 -/- rats lived to normal ages. Mutant proximal tubules demonstrated upregulation of cytoprotective heme oxygenase (HMOX1; 141250), which appeared to mitigate acute kidney injury, including glycerol-induced rhabdomyolysis. </p><p>Kozina et al. (2018) characterized transgenic mice overexpressing human LRRK2 with the R1441G or G2019S mutation and found that they did not develop an overt neurodegenerative phenotype up to 2 years of age. However, a systematic inflammatory response induced by administration of lipopolysaccharide (LPS) caused LRRK2 mutation-specific neuronal loss in substantia nigra pars compacta of transgenic mice. LPS-induced neurodegeneration in transgenic mice was accompanied by exacerbated neuroinflammation in brain. The increased immune response in brain of transgenic mice subsequently had an effect on neurons by inducing intraneuronal LRRK2 upregulation. Neuronal loss and neuroinflammation in transgenic mice were not due to dysfunctional microglia or infiltrated T cells and/or monocytes, but were likely initiated through circulating inflammatory mediators. By analyzing cytokine kinetics and inflammatory pathways in peripheral immune cells, the authors showed that mutant LRRK2 altered the type II interferon immune response, suggesting that the increased neuroinflammatory response may arise outside the central nervous system. </p><p>Pischedda et al. (2021) characterized the histopathologic and functional phenotype of mice overexpressing the human LRRK2 gene with the G2019S mutation. The mutant mice displayed age-dependent motor and cognitive impairment, including worsening novel object recognition, compared to wildtype mice. Examination of brains from the mutant mice revealed protein aggregates containing N-ethylmaleimide sensitive factor (NSF), which localized with LC3 and p62-positive protein aggregates. The mouse brains further displayed signs of cell death in the substantia nigra, striatum, cortex, and hippocampus, including increased cleaved caspase-3 (600636). Studies in cortical neurons collected from embryonic mutant mice showed that the protein aggregations depended on phosphorylation of NSF at Thr645. Pischedda et al. (2021) also found that induction of autophagy with trehalose resulted in clearance of NSF aggregates in 6-month-old mutant mice and improved cognitive performance in 12-month-old mutant mice. </p><p><strong><em>Drosophila Models</em></strong></p><p>
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Liu et al. (2008) found that Drosophila expressing the human LRRK2 G2019S mutation in neuronal cells showed adult-onset loss of dopaminergic neurons, locomotor dysfunction, and early mortality. Overexpression of LRRK2 resulted in a less severe form of parkinsonism. Treatment of mutant flies with L-DOPA improved locomotor impairment but did not prevent the loss of dopaminergic cells. Expression of mutant protein in photoreceptor cells resulted in retinal degeneration. The findings provided a gain-of-function animal model for human LRRK2-linked PD. </p><p>Venderova et al. (2009) generated several independent Drosophila lines carrying wildtype or mutant human LRRK2 with mutations in the kinase (I2020T), COR (Y1699C) or LRR (I1122V) domains, respectively. Ectopic expression of wildtype or mutant LRRK2 in dopaminergic neurons caused their significant loss accompanied by complex age-dependent changes in locomotor activity. Overall, the ubiquitous expression of LRRK2 increased life span and fertility of the flies. However, these flies were more sensitive to rotenone. LRRK2 expression in the eye exacerbated retinal degeneration. Importantly, in double transgenic flies, various indices of the eye and dopaminergic survival were modified in a complex fashion by the concomitant expression of PINK1 (608309), PARK7 (602533) or parkin (602544). This evidence suggests a genetic interaction between these PD-relevant genes. </p><p>Hindle et al. (2013) found that expression of human LRRK2 with the G2019S mutation in fly dopaminergic neurons caused photoreceptor neurodegeneration. Further analysis showed degeneration throughout the fly visual system, including regions not directly innervated by dopaminergic neurons. Other PD-related mutations did not affect photoreceptor function. G2019S appeared to act in a gain-of-function manner rather than in a dominant-negative manner, and increased energy demand appeared to contribute to G2019S-induced neurodegeneration. </p>
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>9 Selected Examples):</strong>
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<span class="mim-font">
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<strong>.0001 PARKINSON DISEASE 8, AUTOSOMAL DOMINANT</strong>
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LRRK2, ARG1441GLY
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SNP: rs33939927,
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gnomAD: rs33939927,
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ClinVar: RCV000002013, RCV001659678
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<span class="mim-text-font">
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<p>In affected members of 4 families from the Basque region of Spain who had Parkinson disease (PARK8; 607060), Paisan-Ruiz et al. (2004) identified a heterozygous mutation in the LRRK2 gene that predicts an arg1396-to-gly substitution in the RAS domain. The mutation was also identified in 11 of 137 (8%) additional Spanish PD patients. The mutation was not identified in 1,300 chromosomes from North American controls and 160 chromosomes from Basque controls. </p><p>Gasser (2005) noted that the correct numbering of this mutation is arg1441-to-gly (R1441G). </p><p>Gaig et al. (2006) identified the R1441G mutation in 2 (0.7%) of 302 patients with PD from the Catalonia region of northeast Spain. Both patients had a family history of the disorder. </p><p>Gorostidi et al. (2009) found that 13.15% of 418 PD patients from the Basque region were heterozygous for the R1441G mutation. The frequency rose to 22.4% when restricted to those patients of Basque origin, reinforcing the importance of ethnicity when establishing mutation prevalence. </p><p>Mata et al. (2009) performed haplotype analysis of 29 unrelated PD patients heterozygous for the R1441G mutation and 85 wildtype controls. Nine of the patients were of Basque origin and 20 were non-Basques. The authors estimated that the most recent common ancestor lived about 1,350 years ago in approximately the 7th century. The findings were consistent with the hypothesis that R1441G originated in the Basque population and that dispersion of the mutation occurred through short-range gene flow largely limited to nearby regions in Spain. </p>
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<h4>
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<span class="mim-font">
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<strong>.0002 PARKINSON DISEASE 8, AUTOSOMAL DOMINANT</strong>
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LRRK2, TYR1699CYS
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SNP: rs35801418,
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ClinVar: RCV000002014
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<span class="mim-text-font">
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<p>In 7 affected members of an English family with Parkinson disease (PARK8; 607060), Paisan-Ruiz et al. (2004) identified a heterozygous mutation in the LRRK2 gene that predicts a tyr1654-to-cys substitution. Seven unaffected family members did not have the mutation. The mutation was not identified in 1,300 chromosomes from North American controls and 160 chromosomes from Basque controls. </p><p>Gasser (2005) noted that the correct numbering of this mutation is tyr1699-to-cys (Y1699C). </p><p>In affected members of a family with autosomal dominant Parkinson disease originally reported by Wszolek et al. (1997), Zimprich et al. (2004) identified heterozygosity for the Y1699C mutation resulting from a 5096A-G transition in the LRRK2 gene. </p>
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<h4>
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<span class="mim-font">
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<strong>.0003 PARKINSON DISEASE 8, AUTOSOMAL DOMINANT</strong>
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</span>
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<span class="mim-text-font">
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LRRK2, ARG1441CYS
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SNP: rs33939927,
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gnomAD: rs33939927,
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ClinVar: RCV000002015, RCV002472921
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<span class="mim-text-font">
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<p>In affected members of a family with autosomal dominant Parkinson disease (PARK8; 607060) originally reported by Wszolek et al. (1995), Zimprich et al. (2004) identified a heterozygous 4321C-T transition in the LRRK2 gene, resulting in an arg1441-to-cys (R1441C) substitution in the ROC (GTPase) domain. Affected members of another unrelated family also had the R1441C mutation. The mutation was not identified in more than 1,000 control individuals or 300 patients with sporadic PD. </p><p>West et al. (2005) determined that the R1441C mutation, which lies within the GTPase domain of LRRK2, did not alter the steady-state level, turnover, or intracellular localization of the LRRK2 protein, but that R1441C appeared to enhance protein kinase activity. </p><p>Tong et al. (2009) found that mutant knockin mice with expression of normal levels of the R1441C mutant protein appeared grossly normal and did not show any evidence of dopaminergic degeneration up to 2 years of age. However, knockin mice showed impaired augmentation of locomotor activity in response to amphetamine compared to wildtype, suggesting a defect in drug-induced dopamine release. Adrenal chromaffin cells derived from mutant mice showed a significant reduction in stimulus-induced catecholamine release compared to controls. Mutant mice also showed impaired dopamine D2 receptor (DRD2; 126450)-mediated functions, such as reduced response to the locomotor inhibitory effect of a DRD2 agonist and decreased cellular sensitivity to suppression by DRD2 agonists. Tong et al. (2009) suggested that these changes may represent pathogenic precursors to dopaminergic degeneration. </p><p>Wallings et al. (2019) analyzed primary cortical neuronal cultures from transgenic rats expressing human LRRK2 carrying the R1441C mutation The R1441C mutation altered basal autophagy levels in rat neurons. Assessing LC3 (MAP1LC3A; 601242) expression changes in cortical and midbrain tissue of aged rats showed that the R1441C-dependent autophagy phenotype was also present in vivo in rat brain tissue. R1441C caused autophagosome-lysosome fusion deficiency in rat neurons, resulting in inhibition of autophagosome clearance and a deficit in autolysosome maturation, thereby leading to accumulation of autophagosomes. Lysosomal calcium dynamics were impaired in R1441C neurons, likely causing the decrease in fusion efficiency between autophagosomes and lysosomes. Decreased autolysosome maturation was coupled with decreased lysosomal protein degradation in transgenic rat neurons, but the autophagy phenotype was not dependent on LRRK2 kinase activity. Instead, R1441C impaired lysosomal pH, on which both lysosomal degradation and autophagosome/lysosome fusion were highly dependent, in neurons. The R1441C mutation also altered LRRK2 cellular localization by decreasing colocalization of LRRK2 with the trans-Golgi and increasing its colocalization with autophagic puncta. LRRK2 interacted with V-ATPase subunit A1 (ATP6V1A; 607027), but the interaction was abolished by the R1441C mutation, causing a decrease in A1 protein and its cellular mislocalization, which led to alteration of LRRK2 cellular localization. Additionally, analysis with primary neuronal cultures prepared from Lrrk2 -/- rats showed that the autophagy phenotypes in R1441C transgenic neurons were likely caused by a gain of function, as Lrrk2 -/- rat neurons displayed increased autophagic flux and decreased lysosomal protein degradation. Clioquinol, a zinc/copper ionophore, rescued the LRRK2-R1441C cellular phenotype as clioquinol modulated lysosomal zinc levels and upregulated V-ATPase A1 protein in R1441C neuronal cultures. </p>
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</span>
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<div>
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<h4>
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<span class="mim-text-font">
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<strong>.0004 MOVED TO 609007.0002</strong>
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</span>
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</h4>
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</div>
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<div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 PARKINSON DISEASE 8, AUTOSOMAL DOMINANT</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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LRRK2, ILE1122VAL
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<br />
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SNP: rs34805604,
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ClinVar: RCV000002016
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<span class="mim-text-font">
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<p>In affected members of a family with autosomal dominant Parkinson disease (PARK8; 607060), Zimprich et al. (2004) identified a heterozygous 3364A-G transition in the LRRK2 gene, resulting in an ile1122-to-val (I1122V) substitution. The mutation occurred in a region that is highly conserved among species. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 PARKINSON DISEASE 8, AUTOSOMAL DOMINANT</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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LRRK2, GLY2019SER
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<br />
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SNP: rs34637584,
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gnomAD: rs34637584,
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ClinVar: RCV000002017, RCV000325492, RCV000622347, RCV001195216, RCV001836691, RCV003407254, RCV003993728
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</span>
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<p>In affected members of 4 of 61 (6.6%) unrelated families with autosomal dominant Parkinson disease (PARK8; 607060), Di Fonzo et al. (2005) identified a heterozygous 6055G-A transition in exon 41 of the LRRK2 gene, resulting in a gly2019-to-ser (G2019S) substitution. Two families were from Italy, and 1 each were from Portugal and Brazil. The gly2019 residue is highly conserved and is part of a 3-amino acid motif required by all human kinase proteins. </p><p>Gilks et al. (2005) identified the G2019S mutation in 8 of 482 (1.6%) unrelated patients with Parkinson disease. Five of the patients had no family history of the disorder, suggesting either a de novo occurrence or reduced penetrance. </p><p>Nichols et al. (2005) identified the G2019S mutation in 20 of 358 (6%) families with PD. In 1 family, 1 sib was heterozygous for the mutation and another was homozygous; the homozygous individual did not differ in clinical presentation from the sib and did not have early disease onset or more rapid progression. </p><p>By sequencing the LRRK2 gene in multiplex families showing linkage to the PARK8 region, Kachergus et al. (2005) identified the G2019S mutation. The families in which the mutation was found originated from the United States, Norway, Ireland, and Poland. In patients with idiopathic Parkinson disease from the same population, further screening identified 6 more patients with the LRRK2 G2019S mutation; no mutations were found in matched control individuals. Subsequently, 42 family members of the 13 probands were examined; 22 had an LRRK2 G2019S substitution, 7 with a diagnosis of PD. All patients shared an ancestral haplotype indicative of a common founder, and, within families, LRRK2 G2019S segregated with disease (multipoint lod score 2.41). Penetrance was age dependent, increasing from 17% at age 50 to 85% at age 70 years. </p><p>Hernandez et al. (2005) identified the G2019S mutation in affected members of 2 unrelated families with PARK8. One family was North American with English ancestry, and the other family was of Ashkenazi Jewish origin and had migrated from Russia. </p><p>Lesage et al. (2005) identified a common haplotype containing the G2019S mutation in PD patients from several European countries (France, Belgium, Portugal, and the Netherlands) and from 3 countries in North Africa (Algeria, Morocco, and Tunisia). The minimal common region spans approximately 60 kb within the LRRK2 gene, although many patients shared larger regions. Lesage et al. (2005) estimated that the G2019S mutation occurred approximately 725 years ago, in the 13th century. </p><p>Aasly et al. (2005) identified the G2019S mutation in 9 Norwegian patients from 7 families with PARK8. Eleven unaffected first-degree relatives also carried the mutation, suggesting age-related penetrance. The clinical features of affected members were typical for idiopathic Parkinson disease, including resting tremor, bradykinesia, and rigidity. </p><p>Deng et al. (2005) identified the G2019S mutation in 4 (1.2%) of 326 Parkinson disease patients from North America. One of the patients had no family history of the disorder. </p><p>Albrecht (2005) stated that the gly2019 residue is part of a highly conserved DFG-like motif (DYG in LRRK2) at the N terminus of the kinase activation segment of the protein. As residues in and around the DFG-like motif are important for proper positioning of magnesium and phosphates, mutations in this area may impair kinase activity. </p><p>West et al. (2005) determined that the G2019S mutation, which lies within the mixed-lineage kinase-like domain, did not alter the steady-state level, turnover, or intracellular localization of the LRRK2 protein, but that G2019S appeared to enhance protein kinase activity. </p><p>Brice (2005) estimated that the G2019S mutation in exon 41 of the LRRK2 gene accounts for 2 to 6% of familial and 1 to 2% of sporadic cases of Parkinson disease. The mutation is less common in Asian populations but prevalent in patients from North Africa, as observed by Lesage et al. (2006). In a newly ascertained series of North African Arabs, 23 of 59 patients with Parkinson disease were carriers of the G2019S mutation (39%), as compared with only 2 of 69 controls (3%; P less than 0.001). Ozelius et al. (2006) observed that the G2019S mutation appeared to be an important cause of both familial and sporadic Parkinson disease in a group of 120 unrelated Ashkenazi Jewish patients with Parkinson disease. The prevalence of the G2019S mutation among this group reached 29.7% in familial cases and 13.3% in sporadic cases. </p><p>Lesage et al. (2005) identified the G2019S mutation in 7 (41%) of 17 North African PD families and 5 (2.9%) of 174 European PD families. One patient from Algeria was homozygous for the mutation, likely due to consanguinity. His age at onset was 56 years, similar to that of heterozygotes, suggesting that gene dosage had no effect. The G2019S mutation was also identified in 1 of 256 control individuals, a 60-year-old male of European descent with no family history of the PD. Age-dependent penetrance, estimated within 2 large affected families, increased from 33% at age 55 to 100% at older than age 76. </p><p>Zabetian et al. (2006) did not identify the G2019S mutation in any of 754 patients with Alzheimer disease (AD; 104300), suggesting that it is not a cause of AD. </p><p>Zabetian et al. (2006) stated that the G2019S mutation accounts for 1 to 7% of Parkinson disease in patients of European origin and 20 to 40% in Ashkenazi Jews and North African Arabs with PD. Previous studies had concluded that patients from these populations share a common Middle Eastern founder who lived in the 13th century. Zabetian et al. (2006) tested this hypothesis by genotyping 25 microsatellite and single-nucleotide polymorphism (SNP) markers in 22 families with G2019S and observed 2 distinct haplotypes. Haplotype 1 was present in 19 families of Ashkenazi Jewish and European ancestry, whereas haplotype 2 occurred in 3 European American families. Using a maximum likelihood method, the authors estimated that the families with haplotype 1 shared a common ancestor 2,250 (95% confidence interval 1,650-3,120) years ago, whereas those with haplotype 2 appeared to share a more recent founder. Their data suggested 2 separate founding events for G2019S in these populations, beginning at a time that coincided with the Jewish Diasporas. Zabetian et al. (2006) identified the G2019S mutation in Japanese patients with Parkinson disease on a haplotype background clearly distinct from the 2 others, which indicated that at least 3 founding events had occurred. </p><p>Ishihara et al. (2006) found no observable phenotypic differences between 26 patients with Parkinson disease who were homozygous for the G2019S mutation, including 20 patients of Tunisian origin, and reports of patients who were heterozygous for the mutation. In addition, 3 clinically unaffected Tunisian individuals were homozygous for the mutation at ages 42, 45, and 70 years. The findings did not support a gene dosage effect. </p><p>Among 302 PD patients from the Catalonia region of northeast Spain, Gaig et al. (2006) identified the G2019S mutation in 6.4% of familial and 3.4% of sporadic cases. </p><p>Spanaki et al. (2006) identified the G2019S mutation in 1 (1.1%) of 92 familial PD probands on the island of Crete, thus showing a decreased frequency of the mutation compared to other Mediterranean regions. </p><p>Clark et al. (2006) identified the G2019S mutation in 4.9% of 245 PD patients with onset before age 50 years and 6.2% of 259 PD patients with onset after age 50 years, a nonsignificant difference. All patients with the G2019S mutation had the same 45-kb disease-associated haplotype. The frequency of the mutation was higher in the subset of 181 cases reporting 4 Jewish grandparents (9.9%) compared to other cases (3.1%). Age-specific penetrance to age 80 was 24%, suggesting that other factors must be involved. The G2019S mutation was identified in 2 (0.6%) controls of Jewish origin who showed mild signs suggestive of the disorder on further examination. </p><p>Lesage et al. (2007) identified the G2019S mutation in 6 (1.9%) of 320 European patients with sporadic PD. Five patients were of French origin. </p><p>In a study of 19 Italian PD families with the G2019S mutation, Goldwurm et al. (2007) estimated the cumulative incidence of the disease to be 15% at 60 years, 21% at 70 years, and 32% at 80 years, confirming reduced penetrance. Among 33 mutation carriers, 5 over age 75 years had no sign of disease. </p><p>Orr-Urtreger et al. (2007) identified a heterozygous G2019S mutation in 12.3% of 472 Jewish PD patients, and in 14.8% of the 344 patients in this group who were specifically of Ashkenazi Jewish origin. The mutation was also detected in 2.4% of Ashkenazi Jewish controls. A common shared haplotype identified by Lesage et al. (2005) was found in 97% of mutation carriers. None of 42 Jewish patients from Iraq or Morocco carried the G2019S mutation. </p><p>Choi et al. (2008) did not identify the G2019S mutation among 72 unrelated Korean patients with early-onset PD before age 50, suggesting that it is not a common cause of PD in the Korean population. </p><p>Lesage et al. (2008) identified the G2019S mutation in 7 (41%) of 17 North African patients with familial PD and 40 (34%) of 119 North African patients with sporadic PD. All were heterozygous for the mutation except 3 patients, who were homozygous. One (1.5%) of 66 Algerian controls was homozygous for the mutation, but showed no evidence of disease at age 41 years, which is younger than the average age of disease onset. </p><p>Gorostidi et al. (2009) identified a heterozygous G2019S mutation in 3.82% of 418 PD patients from the Basque country in Spain. The frequency increased to 6% when only those who were not of Basque origin were considered. The R1441G mutation (609007.0001) was more common among those of Basque descent. The findings reinforced the importance of ethnicity when establishing mutation prevalence. </p><p>Bar-Shira et al. (2009) analyzed LRRK2 haplotypes in 77 G2019S carriers, mostly Ashkenazi Jews, and in 50 noncarrier Ashkenazi PD patients. A single 243-kb haplotype was detected in all mutation carriers, indicating a common founder. The authors estimated that Ashkenazi Jews with G2019S share a common ancestor who lived approximately 1,830 years ago, around the 2nd century, after the second Jewish Diaspora. </p><p>Alcalay et al. (2009) found that 34 (3.7%) of 925 patients with early-onset PD, defined as age at onset before age 51 years, carried the G2019S mutation. Compared to noncarriers, carriers of the G2019S mutation were more likely to be of Ashkenazi Jewish descent (55.9% vs 11.9%), to have a lower tremor score (p = 0.03), and to have a higher score of postural instability and gait difficulty (PIGD; 92.3% vs 58.9%, p = 0.003). The PIGD phenotype in general is associated with a more severe phenotype and a faster rate of cognitive decline compared to the tremor dominant phenotype, so the findings of this study suggested implications for disease course in G2019S mutation carriers. </p><p>Mortiboys et al. (2010) found that skin fibroblasts from 5 PD patients with the G2019S mutation showed evidence of mitochondrial dysfunction, both decreased membrane potential and decreased total intracellular ATP levels. There also appeared to be increased mitochondrial elongation and interconnectivity. </p><p>Liu et al. (2012) reported on the generation of induced pluripotent stem cells (iPSCs) derived from Parkinson disease patients and the implications of the LRRK2 G2019S mutation in human neural stem cell populations. Mutant neural stem cells showed increased susceptibility to proteasomal stress as well as passage-dependent deficiencies in nuclear envelope organization, clonal expansion, and neuronal differentiation. Disease phenotypes were rescued by targeted correction of the LRRK2 G2019S mutation with its wildtype counterpart in Parkinson disease iPSCs and were recapitulated after targeted knockin of the LRRK2 G2019S mutation in human embryonic stem cells. Analysis of human brain tissue showed nuclear envelope impairment in clinically diagnosed Parkinson disease patients. Liu et al. (2012) concluded that their results identified the nucleus as a previously unknown cellular organelle in Parkinson disease pathology. </p><p>Shani et al. (2019) found that the interation of LRRK2 with lamin A/C (LMNA; 150330) in the nuclear cytoskeleton was diminished for PD-associated LRRK2 mutations, including G2019S. G2019S did not alter LRRK2 interaction with SIAH1 (602212) or LRRK2 translocation to the nucleus, but nuclear accumulation of the G2019S mutant appeared to be harmful to neurons. In vitro and in vivo analyses demonstrated that G2019S interfered with the ability of LRRK2 to maintain nuclear lamina and nuclear membrane integrity, disrupting the nuclear membrane and altering its permeability. Dopaminergic neurons of PD patients with the LRRK2 G2019S mutation contained widespread alterations of nuclear lamina structure, supporting nuclear envelope disruption as a hallmark of the disease. </p>
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<h4>
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<span class="mim-font">
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<strong>.0007 PARKINSON DISEASE 8, AUTOSOMAL DOMINANT</strong>
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</span>
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</h4>
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LRRK2, ILE2020THR
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<br />
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SNP: rs35870237,
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ClinVar: RCV000002018, RCV001311806
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<p>In all 19 affected members of the original Japanese family with Parkinson disease-8 (PARK8; 607060) (Hasegawa and Kowa, 1997), Funayama et al. (2005) identified a heterozygous 6059T-C transition in exon 41 of the LRRK2 gene, resulting in an ile2020-to-thr (I2020T) substitution in a conserved region of the kinase motif domain. The neuropathologic features in this family were notable for absence of Lewy bodies. The mutation was also detected in 2 affected members of another family with PARK8. In the second family, 3 unaffected members also carried the mutation, but their ages (73, 58, and 56) were within the variation of age at onset in that family (39 to 76 years). The I2020T substitution was not identified in 368 control individuals or in 188 patients with sporadic Parkinson disease. The mutation had previously been reported by Zimprich et al. (2004). </p><p>In HEK293 cells, Gloeckner et al. (2006) demonstrated that the I2020T-mutant protein shows significantly increased (about 40%) autophosphorylation activity compared to wildtype LRRK2, consistent with a gain of function. </p><p>Using purified in vitro translated N-terminally truncated wildtype and mutant proteins, Ray et al. (2014) found that wildtype and I2020T mutant LRRK2 had essentially the same activity against a synthetic peptide containing a phosphorylatable threonine residue. However, the I2020T mutant had significantly enhanced activity against the identical peptide with a phosphorylatable serine residue. Ray et al. (2014) observed that I2020 lies next to a critical regulatory DYG motif in the ATP-binding pocket of LRRK2 that flips between the active DYG-in conformation to inactive DYG-out conformation. Using molecular modeling and simulations, Ray et al. (2014) found that the threonine side chain of the mutant makes a hydrogen bond with the backbone carbonyl of asp2017 in the DYG motif, which then stabilizes a hydrogen bond between DYG and a phosphate group of ATP. This increased stability of the DYG-in active conformation significantly prolongs residence time of ATP and elevates the kinase activity of the I2020T mutant LRRK2 compared with wildtype. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0008 PARKINSON DISEASE 8, AUTOSOMAL DOMINANT</strong>
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</span>
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</h4>
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LRRK2, ARG1441HIS
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SNP: rs34995376,
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gnomAD: rs34995376,
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ClinVar: RCV000002019
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<p>In a Taiwanese father and daughter with Parkinson disease-8 (PARK8; 607060), Mata et al. (2005) identified a heterozygous 4322G-A transition in exon 31 of the LRRK2 gene, resulting in an arg1441-to-his (R1441H) substitution in the ROC (GTPase) domain. Zabetian et al. (2005) also identified the R1441H mutation in affected members of a family with Parkinson disease-8. Two other pathogenic LRRK2 mutations have been identified in this same codon (R1441G; 609007.0001 and R1441C; 609007.0003). </p><p>Spanaki et al. (2006) identified the R1441H substitution in 1 of 92 familial PD probands on the island of Crete. The proband had an affected brother who developed parkinsonism at age 61 years and responded well to L-DOPA therapy, but showed a clear clinical transition to a degenerative phenotype consistent with progressive supranuclear palsy (PSP; 601104) after 8 years. The brother deteriorated rapidly, showing postural instability, supranuclear vertical gaze palsy, bulbar dysfunction, and moderate dementia. None of 13 additional unrelated patients with a clinical diagnosis of PSP had any of the 5 LRRK2 mutations investigated. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>.0009 PARKINSON DISEASE 8, SUSCEPTIBILITY TO</strong>
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</span>
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</h4>
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LRRK2, GLY2385ARG ({dbSNP rs34778348})
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SNP: rs34778348,
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gnomAD: rs34778348,
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ClinVar: RCV000032508, RCV001449818, RCV003488320
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<span class="mim-text-font">
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<p>Mata et al. (2005) reported the LRRK2 gly2385-to-arg (G2385R) variant in a Taiwanese family with Parkinson disease (PARK8; 607060). Di Fonzo et al. (2006) showed, in a large case-control sample of Taiwanese individuals, that this variant is a common polymorphism that was significantly more frequent among PD patients than controls. Di Fonzo et al. (2006) failed to find this variant in Caucasians. On the other hand, the gly2019-to-ser mutation (609007.0006), which is commonly associated with PD in other ethnic groups, has not been found in Chinese. In ethnic Chinese in Singapore, Tan et al. (2007) found that the heterozygous G2385R genotype was higher in PD patients compared to controls (7.3 vs 3.6%, odds ratio = 2.1). These values yielded an estimated population-attributable risk of approximately 4%. In transfection studies, Tan et al. (2007) demonstrated that both the wildtype and the G2385R variant LRRK2 protein localize to the cytoplasm and form aggregates. However, under conditions of oxidative stress, the G2385R variant was more toxic and was associated with a higher rate of apoptosis. Tan et al. (2007) concluded that the G2385R variant appears to be a common risk factor for PD in Chinese and may act through proapoptotic mechanisms. </p><p>Choi et al. (2008) identified a heterozygous G2385R variant in 9 (12.5%) of 72 unrelated Korean patients with onset of PD before age 50 and in 5% of controls. This yielded an odds ratio of 2.71 for carriers of G2385R, but the results were not significant. </p><p>Tan et al. (2007) found no association between the G2385R allele and PD among 472 non-Chinese Asian subjects in Singapore, including 166 PD and 306 controls of Malay or Indian ethnicity. Stratification by Malay and Indian ethnicity showed that no Indian individuals carried the allele (66 PD patients and 133 controls), and the frequency in Malay individuals was about 2% in both groups, which is much lower than the 8 to 10% prevalence reported in the Chinese population. The age of the G2385R mutation was estimated to be approximately 4,000 years ago (Tan et al., 2008). </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<p class="mim-text-font">
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Aasly, J. O., Toft, M., Fernandez-Mata, I., Kachergus, J., Hulihan, M., White, L. R., Farrer, M.
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<strong>Clinical features of LRRK2-associated Parkinson's disease in central Norway.</strong>
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Ann. Neurol. 57: 762-765, 2005.
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[PubMed: 15852371]
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[Full Text: https://doi.org/10.1002/ana.20456]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Albrecht, M.
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<strong>LRRK2 mutations and parkinsonism. (Letter)</strong>
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Lancet 365: 1230 only, 2005.
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[PubMed: 15811455]
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[Full Text: https://doi.org/10.1016/S0140-6736(05)74810-8]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Alcalay, R. N., Mejia-Santana, H., Tang, M. X., Rosado, L., Verbitsky, M., Kisselev, S., Ross, B. M., Louis, E. D., Comella, C. L., Colcher, A., Jennings, D., Nance, M. A., and 21 others.
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<strong>Motor phenotype of LRRK2 G2019S carriers in early-onset Parkinson disease.</strong>
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Arch. Neurol. 66: 1517-1522, 2009.
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[PubMed: 20008657]
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[Full Text: https://doi.org/10.1001/archneurol.2009.267]
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</li>
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<p class="mim-text-font">
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Alegre-Abarrategui, J., Christian, H., Lufino, M. M. P., Mutihac, R., Venda, L. L., Ansorge, O., Wade-Martins, R.
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<strong>LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model.</strong>
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Hum. Molec. Genet. 18: 4022-4034, 2009.
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[PubMed: 19640926]
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[Full Text: https://doi.org/10.1093/hmg/ddp346]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Angeles, D. C., Gan, B.-H., Onstead, L., Zhao, Y., Lim, K.-L., Dachsel, J., Melrose, H., Farrer, M., Wszolek, Z. K., Dickson, D. W., Tan, E.-K.
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<strong>Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death.</strong>
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Hum. Mutat. 32: 1390-1397, 2011.
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[PubMed: 21850687]
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[Full Text: https://doi.org/10.1002/humu.21582]
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</li>
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<li>
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<p class="mim-text-font">
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Bar-Shira, A., Hutter, C. M., Giladi, N., Zabetian, C. P., Orr-Urtreger, A.
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<strong>Ashkenazi Parkinson's disease patients with the LRRK2 G2019S mutation share a common founder dating from the second to fifth centuries.</strong>
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Neurogenetics 10: 355-358, 2009.
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[PubMed: 19283415]
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[Full Text: https://doi.org/10.1007/s10048-009-0186-0]
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</li>
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<li>
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Biskup, S., Moore, D. J., Celsi, F., Higashi, S. West, A. B., Andrabi, S. A., Kurkinen, K., Yu, S.-W., Savitt, J. M., Waldvogel, H. J., Faull, R. L. M., Emson, P. C., Torp, R., Ottersen, O. P., Dawson, T. M., Dawson, V. L.
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<strong>Localization of LRRK2 to membranous and vesicular structures in mammalian brain.</strong>
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Ann. Neurol. 60: 557-569, 2006.
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[PubMed: 17120249]
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[Full Text: https://doi.org/10.1002/ana.21019]
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<p class="mim-text-font">
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Biskup, S., Mueller, J. C., Sharma, M., Lichtner, P., Zimprich, A., Berg, D., Wullner, U., Illig, T., Meitinger, T., Gasser, T.
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<strong>Common variants of LRRK2 are not associated with sporadic Parkinson's disease.</strong>
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Ann. Neurol. 58: 905-908, 2005.
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[PubMed: 16254973]
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Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln, S., Kachergus, J., Hulihan, M., Uitti, R. J., Calne, D. B., Stoessl, A. J., Pfeiffer, R. F., Patenge, N., Carballo Carbajal, I., Vieregge, P., Asmus, F., Muller-Myhsok, B., Dickson, D. W., Meitinger, T., Strom, T. M., Wszolek, Z. K., Gasser, T.
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Bao Lige - updated : 01/10/2023<br>Hilary J. Vernon - updated : 12/09/2022<br>Bao Lige - updated : 03/02/2022<br>Bao Lige - updated : 10/21/2021<br>Hilary J. Vernon - updated : 08/13/2021<br>Bao Lige - updated : 01/22/2020<br>Bao Lige - updated : 07/03/2018<br>Patricia A. Hartz - updated : 11/09/2017<br>Patricia A. Hartz - updated : 05/08/2017<br>Patricia A. Hartz - updated : 10/10/2013<br>Cassandra L. Kniffin - updated : 7/15/2013<br>Ada Hamosh - updated : 12/13/2012<br>Patricia A. Hartz - updated : 8/3/2012<br>Cassandra L. Kniffin - updated : 4/2/2012<br>Paul J. Converse - updated : 2/7/2011<br>Cassandra L. Kniffin - updated : 12/3/2010<br>George E. Tiller - updated : 10/22/2010<br>George E. Tiller - updated : 9/30/2010<br>Cassandra L. Kniffin - updated : 8/30/2010<br>Ada Hamosh - updated : 8/24/2010<br>George E. Tiller - updated : 8/6/2010<br>Cassandra L. Kniffin - updated : 7/13/2010<br>Cassandra L. Kniffin - updated : 6/25/2010<br>Cassandra L. Kniffin - updated : 1/4/2010<br>Cassandra L. Kniffin - updated : 12/14/2009<br>Cassandra L. Kniffin - updated : 10/15/2009<br>Cassandra L. Kniffin - updated : 5/14/2009<br>George E. Tiller - updated : 4/23/2009<br>Cassandra L. Kniffin - updated : 4/6/2009<br>Cassandra L. Kniffin - updated : 10/28/2008<br>Cassandra L. Kniffin - updated : 7/22/2008<br>Patricia A. Hartz - updated : 4/15/2008<br>Cassandra L. Kniffin - updated : 4/2/2008<br>Cassandra L. Kniffin - updated : 3/12/2008<br>Cassandra L. Kniffin - updated : 12/27/2007<br>Cassandra L. Kniffin - updated : 11/7/2007<br>Victor A. McKusick - updated : 9/24/2007<br>Cassandra L. Kniffin - updated : 9/12/2007<br>Cassandra L. Kniffin - updated : 2/19/2007<br>Cassandra L. Kniffin - updated : 11/6/2006<br>Victor A. McKusick - updated : 9/22/2006<br>Cassandra L. Kniffin - updated : 7/17/2006<br>Cassandra L. Kniffin - updated : 4/21/2006<br>Cassandra L. Kniffin - updated : 3/15/2006<br>Cassandra L. Kniffin - updated : 3/2/2006<br>Victor A. McKusick - updated : 2/9/2006<br>Cassandra L. Kniffin - updated : 1/4/2006<br>Patricia A. Hartz - updated : 12/22/2005<br>Cassandra L. Kniffin - updated : 11/7/2005<br>Cassandra L. Kniffin - updated : 8/26/2005<br>Cassandra L. Kniffin - updated : 8/9/2005<br>Cassandra L. Kniffin - updated : 6/10/2005<br>Cassandra L. Kniffin - updated : 5/11/2005<br>Victor A. McKusick - updated : 3/11/2005<br>Cassandra L. Kniffin - updated : 2/9/2005
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Cassandra L. Kniffin : 11/2/2004
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carol : 01/23/2024<br>carol : 12/14/2023<br>mgross : 01/10/2023<br>carol : 12/09/2022<br>mgross : 03/02/2022<br>mgross : 10/21/2021<br>carol : 08/13/2021<br>mgross : 01/22/2020<br>mgross : 07/03/2018<br>alopez : 11/09/2017<br>carol : 10/25/2017<br>alopez : 10/23/2017<br>alopez : 05/08/2017<br>alopez : 10/04/2016<br>alopez : 03/11/2016<br>mcolton : 2/24/2014<br>mgross : 10/10/2013<br>carol : 7/16/2013<br>ckniffin : 7/15/2013<br>alopez : 12/21/2012<br>terry : 12/13/2012<br>terry : 12/13/2012<br>mgross : 8/8/2012<br>terry : 8/3/2012<br>terry : 5/24/2012<br>carol : 4/4/2012<br>ckniffin : 4/2/2012<br>carol : 11/22/2011<br>carol : 11/16/2011<br>ckniffin : 11/14/2011<br>wwang : 3/8/2011<br>ckniffin : 2/15/2011<br>mgross : 2/8/2011<br>terry : 2/7/2011<br>wwang : 12/6/2010<br>ckniffin : 12/3/2010<br>ckniffin : 11/17/2010<br>ckniffin : 11/17/2010<br>wwang : 10/22/2010<br>wwang : 10/12/2010<br>terry : 9/30/2010<br>terry : 9/9/2010<br>wwang : 9/3/2010<br>ckniffin : 8/30/2010<br>ckniffin : 8/27/2010<br>mgross : 8/25/2010<br>terry : 8/24/2010<br>wwang : 8/11/2010<br>terry : 8/6/2010<br>wwang : 7/14/2010<br>ckniffin : 7/13/2010<br>wwang : 6/29/2010<br>ckniffin : 6/25/2010<br>alopez : 1/4/2010<br>wwang : 12/28/2009<br>ckniffin : 12/14/2009<br>terry : 12/1/2009<br>wwang : 11/9/2009<br>ckniffin : 11/9/2009<br>ckniffin : 10/15/2009<br>wwang : 5/27/2009<br>ckniffin : 5/14/2009<br>wwang : 5/13/2009<br>wwang : 4/28/2009<br>terry : 4/23/2009<br>wwang : 4/10/2009<br>ckniffin : 4/6/2009<br>wwang : 11/7/2008<br>wwang : 11/7/2008<br>ckniffin : 10/28/2008<br>ckniffin : 10/28/2008<br>wwang : 7/28/2008<br>ckniffin : 7/22/2008<br>mgross : 4/15/2008<br>wwang : 4/10/2008<br>ckniffin : 4/2/2008<br>wwang : 4/1/2008<br>ckniffin : 3/12/2008<br>wwang : 1/14/2008<br>ckniffin : 12/27/2007<br>wwang : 11/27/2007<br>wwang : 11/26/2007<br>ckniffin : 11/7/2007<br>alopez : 11/7/2007<br>terry : 9/24/2007<br>wwang : 9/21/2007<br>ckniffin : 9/12/2007<br>wwang : 2/22/2007<br>ckniffin : 2/19/2007<br>wwang : 11/9/2006<br>ckniffin : 11/6/2006<br>alopez : 9/27/2006<br>terry : 9/22/2006<br>wwang : 8/10/2006<br>carol : 7/19/2006<br>ckniffin : 7/17/2006<br>wwang : 4/25/2006<br>ckniffin : 4/21/2006<br>ckniffin : 4/19/2006<br>carol : 4/18/2006<br>wwang : 4/5/2006<br>ckniffin : 3/15/2006<br>wwang : 3/14/2006<br>ckniffin : 3/2/2006<br>alopez : 2/14/2006<br>terry : 2/9/2006<br>wwang : 2/1/2006<br>ckniffin : 1/4/2006<br>wwang : 12/22/2005<br>wwang : 11/15/2005<br>ckniffin : 11/7/2005<br>terry : 9/23/2005<br>wwang : 9/6/2005<br>ckniffin : 8/26/2005<br>ckniffin : 8/9/2005<br>wwang : 6/16/2005<br>ckniffin : 6/10/2005<br>ckniffin : 5/11/2005<br>wwang : 3/14/2005<br>terry : 3/11/2005<br>tkritzer : 2/22/2005<br>ckniffin : 2/9/2005<br>terry : 1/4/2005<br>carol : 11/2/2004<br>ckniffin : 11/2/2004
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