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<title>
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Entry
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- *191342 - UBIQUITIN CARBOXYL-TERMINAL ESTERASE L1; UCHL1
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- OMIM
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<div id="mimSearch" class="hidden-print">
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<div class="container">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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<li class="dropdown-header">
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Advanced Search
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<a href="/search/advanced/entry"> OMIM </a>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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</form>
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<p />
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<div class="row">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*191342</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/191342">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</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=ENSG00000154277;t=ENST00000284440" 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=7345" 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=191342" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000154277;t=ENST00000284440" 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_004181" 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_004181" 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=191342" 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=01877&isoform_id=01877_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/UCHL1" 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/35440,136681,296799,4185720,12653131,13477287,13623417,21361091,62087656,63991162,119613384,119613385,119613386,119613387,119613388,119613389,189067502,193786110,209402848,258676359,268308675" 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/P09936" 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=7345" 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=ENSG00000154277;t=ENST00000284440" 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=UCHL1" 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=UCHL1" 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+7345" 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/UCHL1" 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:7345" 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/7345" 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=chr4&hgg_gene=ENST00000284440.9&hgg_start=41256928&hgg_end=41268455&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://medlineplus.gov/genetics/gene/uchl1" 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=191342[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=191342[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/UCHL1/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000154277" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.gwascentral.org/search?q=UCHL1" 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=UCHL1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=UCHL1&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/PA37160" 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:12513" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0010288.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:103149" 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/UCHL1#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:103149" 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/7345/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/OMIA002298/" 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=7345" 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="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00006721;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00006721 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00006722;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00006722 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00006723;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00006723 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-3844" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:7345" 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=UCHL1&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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191342
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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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UBIQUITIN CARBOXYL-TERMINAL ESTERASE L1; UCHL1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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UBIQUITIN C-TERMINAL HYDROLASE, NEURON-SPECIFIC<br />
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PGP9.5
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=UCHL1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">UCHL1</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: <a href="/geneMap/4/174?start=-3&limit=10&highlight=174">4p13</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr4:41256928-41268455&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'})">4:41,256,928-41,268,455</a> </span>
|
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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Phenotype
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4p13
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{?Parkinson disease 5, susceptibility to}
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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Spastic paraplegia 79A, autosomal dominant
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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Spastic paraplegia 79B, autosomal recessive
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<a href="/entry/615491"> 615491 </a>
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/191342" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/191342" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>UCHL1 is a member of a gene family whose products hydrolyze small C-terminal adducts of ubiquitin to generate the ubiquitin monomer. Expression of UCHL1 is highly specific to neurons and to cells of the diffuse neuroendocrine system and their tumors. It is present in all neurons (<a href="#4" class="mim-tip-reference" title="Doran, J. F., Jackson, P., Kynoch, P., Thompson, R. J. <strong>Isolation of PGP 9.5, a new human neurone-specific protein detected by high resolution two-dimensional electrophoresis.</strong> J. Neurochem. 40: 1542-1547, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6343558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6343558</a>] [<a href="https://doi.org/10.1111/j.1471-4159.1983.tb08124.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6343558">Doran et al., 1983</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6343558" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Cloning and Expression</strong>
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<p><a href="#3" class="mim-tip-reference" title="Day, I. N. M., Thompson, R. J. <strong>Molecular cloning of cDNA coding for human PGP 9.5 protein: a novel cytoplasmic marker for neurones and neuroendocrine cells.</strong> FEBS Lett. 210: 157-160, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2947814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2947814</a>] [<a href="https://doi.org/10.1016/0014-5793(87)81327-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2947814">Day and Thompson (1987)</a> cloned UCHL1 cDNA. The deduced protein, which they called PGP9.5, contains 212 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2947814" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Doran, J. F., Jackson, P., Kynoch, P., Thompson, R. J. <strong>Isolation of PGP 9.5, a new human neurone-specific protein detected by high resolution two-dimensional electrophoresis.</strong> J. Neurochem. 40: 1542-1547, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6343558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6343558</a>] [<a href="https://doi.org/10.1111/j.1471-4159.1983.tb08124.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6343558">Doran et al. (1983)</a> purified the PGP9.5 protein reported by <a href="#8" class="mim-tip-reference" title="Jackson, P., Thompson, R.F. <strong>The demonstration of new human brain-specific proteins by high-resolution two-dimensional polyacrylamide gel electrophoresis.</strong> J Neurol. Sci. 49: 429-438, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7217993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7217993</a>] [<a href="https://doi.org/10.1016/0022-510x(81)90032-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7217993">Jackson and Thompson (1981)</a> and found that it has a molecular mass of 27 kD. They showed that the protein is present in brain at concentrations at least 50 times greater than in other organs and is a major protein component of neuronal cytoplasm. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7217993+6343558" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 Northern blot analysis, <a href="#14" class="mim-tip-reference" title="Leroy, E., Boyer, R., Polymeropoulos, M. H. <strong>Intron-exon structure of ubiquitin C-terminal hydrolase-L1.</strong> DNA Res. 5: 397-400, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10048490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10048490</a>] [<a href="https://doi.org/10.1093/dnares/5.6.397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10048490">Leroy et al. (1998)</a> detected a 1.3-kb transcript expressed only in brain. Examination of specific brain regions revealed expression in all areas tested, particularly in the substantia nigra. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10048490" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#2" class="mim-tip-reference" title="Day, I. N. M., Hinks, L. J., Thompson, R. J. <strong>The structure of the human gene encoding protein gene product 9.5 (PGP9.5), a neuron-specific ubiquitin C-terminal hydrolase.</strong> Biochem. J. 268: 521-524, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2163617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2163617</a>] [<a href="https://doi.org/10.1042/bj2680521" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2163617">Day et al. (1990)</a> determined that the UCHL1 gene contains 9 exons and spans 10 kb. The 5-prime region contains elements common to many genes and other elements that are shared with the 5-prime regions of the genes encoding neurofilament neuron-specific enolase (ENO2; <a href="/entry/131360">131360</a>) and THY1 antigen (<a href="/entry/188230">188230</a>). <a href="#14" class="mim-tip-reference" title="Leroy, E., Boyer, R., Polymeropoulos, M. H. <strong>Intron-exon structure of ubiquitin C-terminal hydrolase-L1.</strong> DNA Res. 5: 397-400, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10048490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10048490</a>] [<a href="https://doi.org/10.1093/dnares/5.6.397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10048490">Leroy et al. (1998)</a> confirmed that UCHL1 has 9 coding exons, and they identified a high GC content between exons 1 and 3. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2163617+10048490" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 PCR analysis of DNA from a panel of human/rodent somatic cell hybrids, <a href="#5" class="mim-tip-reference" title="Edwards, Y. H., Fox, M. F., Povey, S., Hinks, L. J., Day, I. N. M., Thompson, R. J. <strong>The gene for human neuron specific ubiquitin C-terminal hydrolase maps to chromosome 4p14. (Abstract)</strong> Cytogenet. Cell Genet. 58: 1886-1887, 1991."None>Edwards et al. (1991)</a> mapped UCHL1 to chromosome 4. By in situ hybridization, they regionalized the assignment to 4p14.</p><p><a href="#27" class="mim-tip-reference" title="Stumpf, A. M. <strong>Personal Communication.</strong> Baltimore, Md. 01/27/2023."None>Stumpf (2023)</a> mapped the UCHL1 gene to chromosome 4p13 based on an alignment of the UCHL1 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AK315368" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AK315368</a>) with the genomic sequence (GRCh38).</p>
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<p><a href="#16" class="mim-tip-reference" title="Liu, Y., Fallon, L., Lashuel, H. A., Liu, Z., Lansbury, P. T., Jr. <strong>The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility.</strong> Cell 111: 209-218, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12408865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12408865</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)01012-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12408865">Liu et al. (2002)</a> found that UCHL1, especially variants linked to higher susceptibility to Parkinson disease-5 (PARK5; <a href="/entry/613643">613643</a>), caused the accumulation of alpha-synuclein (<a href="/entry/163890">163890</a>) in cultured cells, an effect that could not be explained by its recognized hydrolase activity. UCHL1 exhibited a second, dimerization-dependent ubiquityl ligase activity. A polymorphic variant of UCHL1, ser18 to tyr (S18Y; <a href="#0002">191342.0002</a>), associated in some studies with decreased risk for Parkinson disease, had reduced ligase activity compared with the wildtype enzyme, but it had comparable hydrolase activity. The authors concluded that the ligase and hydrolase activities of UCHL1 may play roles in proteasomal protein degradation, a process critical for neuronal health. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12408865" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 contrast to the UCHL3 (<a href="/entry/603090">603090</a>) isozyme, which is expressed in all tissues, UCHL1 is expressed exclusively in neurons and testis/ovary. <a href="#20" class="mim-tip-reference" title="Osaka, H., Wang, Y.-L., Takada, K., Takizawa, S., Setsuie, R., Li, H., Sato, Y., Nishikawa, K., Sun, Y.-J., Sakurai, M., Harada, T., Hara, Y., Kimura, I., Chiba, S., Namikawa, K., Kiyama, H., Noda, M., Aoki, S., Wada, K. <strong>Ubiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neuron.</strong> Hum. Molec. Genet. 12: 1945-1958, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12913066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12913066</a>] [<a href="https://doi.org/10.1093/hmg/ddg211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12913066">Osaka et al. (2003)</a> observed that UCHL1 associated and colocalized with monoubiquitin and elongated ubiquitin half-life. In the gracile axonal dystrophy (gad) mouse, in which the function of UCHL1 is lost, the authors demonstrated a reduced level of monoubiquitin in neurons. In contrast, overexpression of UCHL1 caused an increase in the level of ubiquitin in both cultured cells and mice. The authors suggested that UCHL1, with avidity and affinity for ubiquitin, may insure ubiquitin stability within neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12913066" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 coimmunoprecipitation analysis in transfected mammalian cells, <a href="#9" class="mim-tip-reference" title="Kabuta, T., Furuta, A., Aoki, S., Furuta, K., Wada, K. <strong>Aberrant interaction between Parkinson disease-associated mutant UCH-L1 and the lysosomal receptor for chaperone-mediated autophagy.</strong> J. Biol. Chem. 283: 23731-23738, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18550537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18550537</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18550537[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M801918200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18550537">Kabuta et al. (2008)</a> showed that human UCHL1 interacted with LAMP2A (<a href="/entry/309060">309060</a>), a lysosomal receptor for chaperone-mediated autophagy (CMA), and the CMA pathway components HSC70 (HSPA8; <a href="/entry/600816">600816</a>) and HSP90 (HSP90AA1; <a href="/entry/140571">140571</a>). Analysis with recombinant proteins revealed that UCHL1 interacted directly with the cytoplasmic region of LAMP2A. UCHL1 was not degraded by CMA pathway, but instead was degraded by macroautophagy. Analysis with UCHL1 mutants showed that interaction of UBCHL1 with the CMA machinery was independent of UCHL1 enzymatic activity and interaction of UCHL1 with monoubiquitin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18550537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 Western blot analysis, <a href="#23" class="mim-tip-reference" title="Reinicke, A. T., Raczkowski, F., Muhlig, M., Schmucker, P., Lischke, T., Reichelt, J., Schneider, E., Zielinski, S., Sachs, M., Jurack, E., Tolosa, E., Kurts, C., Mittrucker, H.-W., Meyer-Schwesinger, C. <strong>Deubiquitinating enzyme UCH-L1 promotes dendritic cell antigen cross-presentation by favoring recycling of MHC class I molecules.</strong> J. Immun. 203: 1730-1742, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31492742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31492742</a>] [<a href="https://doi.org/10.4049/jimmunol.1801133" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31492742"> Reinicke et al. (2019)</a> demonstrated that mouse Uchl1 was expressed in dendritic cells (DCs) and that its expression and enzymatic activity were regulated by immune stimuli. Cross-priming of the Cd8 (see <a href="/entry/186910">186910</a>) T-cell response required Uchl1, and as a result, deletion of Uchl1 in mice impaired the Cd8 T-cell response and affected early innate neutrophil influx upon Listeria infection. Loss of Uchl1 did not interfere with phagocytosis and phagosome maturation in DCs. However, Uchl1 deletion reduced trafficking of recycling major histocompatibility complex class I molecules through cross-presentation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31492742" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Spastic Paraplegia 79B, Autosomal Recessive</em></strong></p><p>
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In 3 sibs, born of consanguineous Turkish parents, with autosomal recessive spastic paraplegia-79B (SPG79B; <a href="/entry/615491">615491</a>), <a href="#1" class="mim-tip-reference" title="Bilguvar, K., Tyagi, N. K., Ozkara, C., Tuysuz, B., Bakircioglu, M., Choi, M., Delil, S., Caglayan, A. O., Baranoski, J. F., Erturk, O., Yalcinkaya, C., Karacorlu, M., and 9 others. <strong>Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration.</strong> Proc. Nat. Acad. Sci. 110: 3489-3494, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23359680/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23359680</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23359680[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.1222732110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23359680">Bilguvar et al. (2013)</a> identified a homozygous missense mutation in the UCHL1 gene (E7A; <a href="#0003">191342.0003</a>). The mutation, which was found by homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies in E. coli showed that the E7A mutant protein had decreased binding to ubiquitin and significantly decreased (less than 10%) hydrolase activity compared to wildtype. The patients had onset of progressive visual loss due to optic atrophy at around age 5 years, followed by spasticity, cerebellar ataxia, peripheral neuropathy, and myokymia, consistent with systemic neurodegeneration and deficits at the neuromuscular junction. The clinical features resembled those of the Uchl1-null mouse (<a href="#30" class="mim-tip-reference" title="Yamazaki, K., Wakasugi, N., Tomita, T., Kikuchi, T., Mukoyama, M., Ando, K. <strong>Gracile axonal dystrophy (GAD), a new neurological mutant in the mouse.</strong> Proc. Soc. Exp. Biol. Med. 187: 209-215, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3340629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3340629</a>] [<a href="https://doi.org/10.3181/00379727-187-42656" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3340629">Yamazaki et al., 1988</a>). <a href="#1" class="mim-tip-reference" title="Bilguvar, K., Tyagi, N. K., Ozkara, C., Tuysuz, B., Bakircioglu, M., Choi, M., Delil, S., Caglayan, A. O., Baranoski, J. F., Erturk, O., Yalcinkaya, C., Karacorlu, M., and 9 others. <strong>Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration.</strong> Proc. Nat. Acad. Sci. 110: 3489-3494, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23359680/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23359680</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23359680[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.1222732110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23359680">Bilguvar et al. (2013)</a> noted that neither parent, each of whom was heterozygous for the mutation, had evidence of Parkinson disease. The findings indicated the importance of UCHL1 in the maintenance of nervous system integrity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23359680+3340629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 sibs with SPG79B, including a pair of monozygotic twin brothers, born of unrelated Norwegian parents, <a href="#25" class="mim-tip-reference" title="Rydning, S. L., Backe, P. H., Sousa, M. M. L., Iqbal, Z., Oye, A.-M., Sheng, Y., Yang, M., Lin, X., Slupphaug, G., Nordenmark, T. H., Vigeland, M. D., Bjoras, M., Tallaksen, C. M., Selmer, K. K. <strong>Novel UCHL1 mutations reveal new insights into ubiquitin processing.</strong> Hum. Molec. Genet. 26: 1031-1040, 2017. Note: Erratum: Hum. Molec. Genet. 26: 1217 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28007905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28007905</a>] [<a href="https://doi.org/10.1093/hmg/ddw391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28007905">Rydning et al. (2017)</a> identified compound heterozygous missense mutations in the UCHL1 gene: R178Q (<a href="#0004">191342.0004</a>) and A216D (<a href="#0005">191342.0005</a>). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies in E. coli showed that the R178Q mutation resulted in a 4-fold increase in enzyme activity compared to controls. Because expression of the A216D mutation resulted in inclusion bodies, containing presumably misfolded, aggregated proteins, activity assays of this mutant were not possible. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28007905" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Spastic Paraplegia 79A with Ataxia, Autosomal Dominant</em></strong></p><p>
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In 34 patients from 18 unrelated families with autosomal dominant spastic paraplegia-79A with ataxia (SPG79A; <a href="/entry/620221">620221</a>), <a href="#21" class="mim-tip-reference" title="Park, J., Tucci, A., Cipriani, V., Demidov, G., Rocca, C., Senderek, J., Butryn, M., Velic, A., Lam, T., Galanaki, E., Cali, E., Vestito, L., and 40 others. <strong>Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy.</strong> Genet. Med. 24: 2079-2090, 2022. Note: Erratum: Genet. Med. 25: 100961 only, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35986737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35986737</a>] [<a href="https://doi.org/10.1016/j.gim.2022.07.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35986737">Park et al. (2022)</a> identified heterozygous putative loss-of-function mutations in the UCHL1 gene (see, e.g., <a href="#0006">191342.0006</a>-<a href="#0010">191342.0010</a>). The mutations, which were found by diagnostic exome and genome sequencing, segregated with the disorder in the families from whom information was available. None were present in the gnomAD database. Functional studies of the variants were not performed, but mass spectrometry analysis of fibroblasts derived from affected members of 3 different families showed a significant decrease in UCHL1 protein levels, suggesting that haploinsufficiency for this gene is the pathogenetic mechanism for this phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35986737" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Possible Role in Parkinson Disease</em></strong></p><p>
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Ubiquitin C-terminal hydrolase L1 represents 1 to 2% of total soluble brain protein (<a href="#29" class="mim-tip-reference" title="Wilkinson, K. D., Lee, K. M., Deshpande, S., Duerksen-Hughes, P., Boss, J. M., Pohl, J. <strong>The neuron-specific protein PGP 9.5 is a ubiquitin carboxyl-terminal hydrolase.</strong> Science 246: 670-672, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2530630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2530630</a>] [<a href="https://doi.org/10.1126/science.2530630" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2530630">Wilkinson et al., 1989</a>). Its occurrence in Lewy bodies and its function in the proteasome pathway make it a compelling candidate gene in Parkinson disease. In a German family with typical Parkinson disease (PARK5; <a href="/entry/613643">613643</a>), <a href="#13" class="mim-tip-reference" title="Leroy, E., Boyer, R., Auburger, G., Leube, B., Ulm, G., Mezey, E., Harta, G., Brownstein, M. J., Jonnalagada, S., Chernova, T., Dehejia, A., Lavedan, C., Gasser, T., Steinbach, P. J., Wilkinson, K. D., Polymeropoulos, M. H. <strong>The ubiquitin pathway in Parkinson's disease. (Letter)</strong> Nature 395: 451-452, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9774100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9774100</a>] [<a href="https://doi.org/10.1038/26652" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9774100">Leroy et al. (1998)</a> identified a missense mutation in the UCHL1 gene, ile93 to met (I93M; <a href="#0001">191342.0001</a>), which caused a partial loss of the catalytic activity of this thiol protease. They suggested that this could lead to aberrations in the proteolytic pathway and aggregation of proteins. <a href="#7" class="mim-tip-reference" title="Healy, D. G., Abou-Sleiman, P. M., Casas, J. P., Ahmadi, K. R., Lynch, T., Gandhi, S., Muqit, M. M. K., Foltynie, T., Barker, R., Bhatia, K. P., Quinn, N. P., Lees, A. J., Gibson, J. M., Holton, J. L., Revesz, T., Goldstein, D. B., Wood, N. W. <strong>UCHL-1 is not a Parkinson's disease susceptibility gene.</strong> Ann. Neurol. 59: 627-633, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16450370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16450370</a>] [<a href="https://doi.org/10.1002/ana.20757" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16450370">Healy et al. (2006)</a> noted that the findings of <a href="#13" class="mim-tip-reference" title="Leroy, E., Boyer, R., Auburger, G., Leube, B., Ulm, G., Mezey, E., Harta, G., Brownstein, M. J., Jonnalagada, S., Chernova, T., Dehejia, A., Lavedan, C., Gasser, T., Steinbach, P. J., Wilkinson, K. D., Polymeropoulos, M. H. <strong>The ubiquitin pathway in Parkinson's disease. (Letter)</strong> Nature 395: 451-452, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9774100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9774100</a>] [<a href="https://doi.org/10.1038/26652" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9774100">Leroy et al. (1998)</a> had never been replicated and thus the association was uncertain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16450370+2530630+9774100" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Lincoln, S., Vaughan, J., Wood, N., Baker, M., Adamson, J., Gwinn-Hardy, K., Lynch, T., Hardy, J., Farrer, M. <strong>Low frequency of pathogenic mutations in the ubiquitin carboxy-terminal hydrolase gene in familial Parkinson's disease.</strong> Neuroreport 10: 427-429, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10203348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10203348</a>] [<a href="https://doi.org/10.1097/00001756-199902050-00040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10203348">Lincoln et al. (1999)</a> sequenced the entire coding region of the UCHL1 gene in 11 families with a pattern of Parkinson disease consistent with autosomal dominant inheritance. Although they found polymorphisms in noncoding regions, the only amino acid change was S18Y (<a href="#0002">191342.0002</a>). The S18Y allele was found in approximately 20% of chromosomes in a Caucasian population, suggesting that it is unlikely to be pathogenic. <a href="#15" class="mim-tip-reference" title="Lincoln, S., Vaughan, J., Wood, N., Baker, M., Adamson, J., Gwinn-Hardy, K., Lynch, T., Hardy, J., Farrer, M. <strong>Low frequency of pathogenic mutations in the ubiquitin carboxy-terminal hydrolase gene in familial Parkinson's disease.</strong> Neuroreport 10: 427-429, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10203348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10203348</a>] [<a href="https://doi.org/10.1097/00001756-199902050-00040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10203348">Lincoln et al. (1999)</a> concluded that the I93M variant must be a rare cause of Parkinson disease or a harmless substitution whose occurrence in the family reflected chance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10203348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 3,023 white individuals, <a href="#7" class="mim-tip-reference" title="Healy, D. G., Abou-Sleiman, P. M., Casas, J. P., Ahmadi, K. R., Lynch, T., Gandhi, S., Muqit, M. M. K., Foltynie, T., Barker, R., Bhatia, K. P., Quinn, N. P., Lees, A. J., Gibson, J. M., Holton, J. L., Revesz, T., Goldstein, D. B., Wood, N. W. <strong>UCHL-1 is not a Parkinson's disease susceptibility gene.</strong> Ann. Neurol. 59: 627-633, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16450370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16450370</a>] [<a href="https://doi.org/10.1002/ana.20757" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16450370">Healy et al. (2006)</a> found that the S18Y variant was not protective against PD under any genetic mode of inheritance. A haplotype-tagging approach also did not detect other associated variants in the UCHL1 gene. Furthermore, no association was observed in an updated metaanalysis including 6,594 individuals. A cumulative metaanalysis showed a trend toward a null effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16450370" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>The gracile axonal dystrophy (gad) mouse is an autosomal recessive mutant that shows sensory ataxia at an early age, followed by motor ataxia later (<a href="#30" class="mim-tip-reference" title="Yamazaki, K., Wakasugi, N., Tomita, T., Kikuchi, T., Mukoyama, M., Ando, K. <strong>Gracile axonal dystrophy (GAD), a new neurological mutant in the mouse.</strong> Proc. Soc. Exp. Biol. Med. 187: 209-215, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3340629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3340629</a>] [<a href="https://doi.org/10.3181/00379727-187-42656" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3340629">Yamazaki et al., 1988</a>). Pathologically, the mutant is characterized by 'dying-back' type axonal degeneration and formation of spheroid bodies in nerve terminals. Pathologic observations in the human have associated brain aging and neurodegenerative diseases with progressive accumulation of ubiquitinated protein conjugates. In gad mice, accumulation of amyloid beta-protein and ubiquitin-positive deposits occur retrogradely along the sensory and motor nervous systems. <a href="#28" class="mim-tip-reference" title="Suh, J. G., Yamanishi, T., Matsui, K., Tanaka, K., Wada, K. <strong>Mapping of the gracile axonal dystrophy (gad) gene to a region between D5Mit197 and D5Mit113 on proximal mouse chromosome 5.</strong> Genomics 27: 549-551, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7558041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7558041</a>] [<a href="https://doi.org/10.1006/geno.1995.1091" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7558041">Suh et al. (1995)</a> showed that the gad mutation is located on mouse chromosome 5. <a href="#26" class="mim-tip-reference" title="Saigoh, K., Wang, Y.-L., Suh, J.-G., Yamanishi, T., Sakai, Y., Kiyosawa, H., Harada, T., Ichihara, N., Wakana, S., Kikuchi, T., Wada, K. <strong>Intragenic deletion in the gene encoding ubiquitin carboxy-terminal hydrolase in gad mice.</strong> Nature Genet. 23: 47-51, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10471497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10471497</a>] [<a href="https://doi.org/10.1038/12647" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10471497">Saigoh et al. (1999)</a> found that the gad mutation is caused by an in-frame deletion including exons 7 and 8 of the Uchl1 gene, encoding the ubiquitin carboxy-terminal hydrolase selectively expressed in the nervous system and testis. The gad allele encodes a truncated Uchl1 protein lacking a segment of 42 amino acids containing a catalytic residue. Since this protein is thought to stimulate protein degradation by generating free monomeric ubiquitin, the gad mutation appears to affect protein turnover. The findings suggested that altered function of the ubiquitin system directly causes neurodegeneration. The gad mouse provides a useful model for investigating human neurodegenerative disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10471497+7558041+3340629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Kurihara, L. J., Semenova, E., Levorse, J. M., Tilghman, S. M. <strong>Expression and functional analysis of Uch-L3 during mouse development.</strong> Molec. Cell. Biol. 20: 2498-2504, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10713173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10713173</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10713173[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/10.1128/MCB.20.7.2498-2504.2000" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10713173">Kurihara et al. (2000)</a> showed that mice homozygous for a targeted deletion of the related Uchl3 gene (<a href="/entry/603090">603090</a>) are indistinguishable from wildtype. To assess whether the 2 hydrolases have redundant function, <a href="#10" class="mim-tip-reference" title="Kurihara, L. J., Kikuchi, T., Wada, K., Tilghman, S. M. <strong>Loss of Uch-L1 and Uch-L3 leads to neurodegeneration, posterior paralysis and dysphagia.</strong> Hum. Molec. Genet. 10: 1963-1970, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11555633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11555633</a>] [<a href="https://doi.org/10.1093/hmg/10.18.1963" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11555633">Kurihara et al. (2001)</a> generated mice homozygous for both Uchl1(gad) and Uchl3(delta3-7). The double homozygotes weighed 30% less than single homozygotes and displayed an earlier onset of lethality, possibly due to dysphagia. Axonal degeneration of the nucleus tractus solitarius and area postrema of the medulla was noted in these mice. The double homozygotes also displayed a more severe axonal degeneration of the gracile tract of the medulla and spinal cord than had been observed in Uchl1(gad) single homozygotes. In addition, degeneration of dorsal root ganglia cell bodies was detected in both the double homozygotes and Uchl3(delta3-7) single homozygotes. Given that both Uchl1(gad) and Uchl3(delta3-7) single homozygotes displayed distinct degenerative defects that were exacerbated in the double homozygotes, the authors concluded that Uchl1 and Uchl3 may have both separate and overlapping functions in the maintenance of neurons of the gracile tract, nucleus tractus solitarius, and area postrema. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11555633+10713173" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Gong, B., Cao, Z., Zheng, P., Vitolo, O. V., Liu, S., Staniszewski, A., Moolman, D., Zhang, H., Shelanski, M., Arancio, O. <strong>Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory.</strong> Cell 126: 775-788, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16923396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16923396</a>] [<a href="https://doi.org/10.1016/j.cell.2006.06.046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16923396">Gong et al. (2006)</a> found that inhibition of Uchl1 in mouse hippocampal slices reduced normal synaptic function and long-term potentiation. Levels of soluble Uchl1 were reduced in hippocampi of App (<a href="/entry/104760">104760</a>)/Ps1 (PSEN1; <a href="/entry/104311">104311</a>) mice, which start depositing amyloid-beta (A-beta) at age 8 to 10 weeks and reproduce some cognitive deficits seen in Alzheimer disease (see <a href="/entry/104300">104300</a>) patients. Restoration of Uchl1 levels in mouse hippocampal slices treated with oligomeric amyloid-beta and in slices from App/Ps1 mice restored enzymatic activity and synaptic function. Injection of Uchl1 improved contextual fear learning in App/Ps1 mice. Treatment of hippocampal slices with Uchl1 before applying A-beta blocked the reduction of protein kinase A (PKA; see <a href="/entry/188830">188830</a>) activity observed in the absence of pretreatment. Uchl1 also reversed the inhibition of Creb (CREB1; <a href="/entry/123810">123810</a>) phosphorylation induced by A-beta. <a href="#6" class="mim-tip-reference" title="Gong, B., Cao, Z., Zheng, P., Vitolo, O. V., Liu, S., Staniszewski, A., Moolman, D., Zhang, H., Shelanski, M., Arancio, O. <strong>Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory.</strong> Cell 126: 775-788, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16923396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16923396</a>] [<a href="https://doi.org/10.1016/j.cell.2006.06.046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16923396">Gong et al. (2006)</a> concluded that the PKA-CREB pathway mediates the effects of UCHL1 on A-beta-induced synaptic dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16923396" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="MacDonald, M. E. <strong>Gadzooks!</strong> Nature Genet. 23: 10-11, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10471487/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10471487</a>] [<a href="https://doi.org/10.1038/12602" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10471487">MacDonald (1999)</a> discussed the significance of the ubiquitin-proteasome system and degenerative disease in general, and the significance of the findings in the gad mouse specifically. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10471487" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 neurons derived from gad mice, <a href="#12" class="mim-tip-reference" title="Kyratzi, E., Pavlaki, M., Stefanis, L. <strong>The S18Y polymorphic variant of UCH-L1 confers an antioxidant function to neuronal cells.</strong> Hum. Molec. Genet. 17: 2160-2171, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18411255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18411255</a>] [<a href="https://doi.org/10.1093/hmg/ddn115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18411255">Kyratzi et al. (2008)</a> found that lack of Uchl1 led to a decrease of free ubiquitin, but no overall decrease in proteasome function or enhanced sensitivity to oxidative stress. The findings suggested that wildtype UCHL1 acts as a stabilizer of monomeric ubiquitin in neuronal cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18411255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Reinicke, A. T., Laban, K., Sachs, M., Kraus, V., Walden, M., Damme, M., Sachs, W., Reichelt, J., Schweizer, M., Janiesch, P. C., Duncan, K. E., Saftig, P., Rinschen, M. M., Morellini, F., Meyer-Schwesinger, C. <strong>Ubiquitin C-terminal hydrolase L1 (UCH-L1) loss causes neurodegeneration by altering protein turnover in the first postnatal weeks.</strong> Proc. Nat. Acad. Sci. 116: 7963-7972, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30923110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30923110</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30923110[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.1812413116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30923110">Reinicke et al. (2019)</a> found that heterozygous or homozygous Uchl1 deficiency resulted in accelerated postnatal sensorimotor reflexes with decreased levels of polyubiquitinated proteins in juvenile mice, followed by motor degeneration in old adult mice. Absence of Uchl1 promoted mTorc1 (<a href="/entry/601231">601231</a>) activity and increased protein synthesis in mouse neurons. Proteasomal degradation was enhanced in Uchl1-deficient juvenile mice and declined in aged mice. As a result, Uchl1-deficient mice exhibited age- and brain area-dependent reduction in monoubiquitin and accumulation of polyubiquitinated proteins when neurodegeneration was already advanced. Furthermore, abnormal protein synthesis and degradation was associated with endoplasmic reticulum stress and ATP depletion, leading to alteration of protein homeostasis strains in Uchl1-deficient neurons. Rapamycin treatment reduced protein synthesis and ubiquitin accumulation in vitro and ameliorated the neurologic phenotype of Uchl1 deficiency in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30923110" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 brother and sister with typical Parkinson disease (PARK5; <a href="/entry/613643">613643</a>), <a href="#13" class="mim-tip-reference" title="Leroy, E., Boyer, R., Auburger, G., Leube, B., Ulm, G., Mezey, E., Harta, G., Brownstein, M. J., Jonnalagada, S., Chernova, T., Dehejia, A., Lavedan, C., Gasser, T., Steinbach, P. J., Wilkinson, K. D., Polymeropoulos, M. H. <strong>The ubiquitin pathway in Parkinson's disease. (Letter)</strong> Nature 395: 451-452, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9774100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9774100</a>] [<a href="https://doi.org/10.1038/26652" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9774100">Leroy et al. (1998)</a> identified a heterozygous 277C-G transversion in exon 2 of the UCHL1 gene, resulting in an ile93-to-met (I93M) substitution in a highly conserved region. A paternal uncle and the paternal grandfather were also affected, but the father was not affected, indicating incomplete penetrance. The mutation was not found in 500 control chromosomes. In vitro functional expression studies in E. coli showed that the mutant protein had about a 50% reduction in catalytic activity compared to wildtype. <a href="#13" class="mim-tip-reference" title="Leroy, E., Boyer, R., Auburger, G., Leube, B., Ulm, G., Mezey, E., Harta, G., Brownstein, M. J., Jonnalagada, S., Chernova, T., Dehejia, A., Lavedan, C., Gasser, T., Steinbach, P. J., Wilkinson, K. D., Polymeropoulos, M. H. <strong>The ubiquitin pathway in Parkinson's disease. (Letter)</strong> Nature 395: 451-452, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9774100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9774100</a>] [<a href="https://doi.org/10.1038/26652" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9774100">Leroy et al. (1998)</a> noted that UCHL1 had been identified as a component of Lewy bodies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9774100" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Healy, D. G., Abou-Sleiman, P. M., Casas, J. P., Ahmadi, K. R., Lynch, T., Gandhi, S., Muqit, M. M. K., Foltynie, T., Barker, R., Bhatia, K. P., Quinn, N. P., Lees, A. J., Gibson, J. M., Holton, J. L., Revesz, T., Goldstein, D. B., Wood, N. W. <strong>UCHL-1 is not a Parkinson's disease susceptibility gene.</strong> Ann. Neurol. 59: 627-633, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16450370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16450370</a>] [<a href="https://doi.org/10.1002/ana.20757" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16450370">Healy et al. (2006)</a> noted that the findings of <a href="#13" class="mim-tip-reference" title="Leroy, E., Boyer, R., Auburger, G., Leube, B., Ulm, G., Mezey, E., Harta, G., Brownstein, M. J., Jonnalagada, S., Chernova, T., Dehejia, A., Lavedan, C., Gasser, T., Steinbach, P. J., Wilkinson, K. D., Polymeropoulos, M. H. <strong>The ubiquitin pathway in Parkinson's disease. (Letter)</strong> Nature 395: 451-452, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9774100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9774100</a>] [<a href="https://doi.org/10.1038/26652" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9774100">Leroy et al. (1998)</a> had never been replicated and thus the association was uncertain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9774100+16450370" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Kabuta, T., Furuta, A., Aoki, S., Furuta, K., Wada, K. <strong>Aberrant interaction between Parkinson disease-associated mutant UCH-L1 and the lysosomal receptor for chaperone-mediated autophagy.</strong> J. Biol. Chem. 283: 23731-23738, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18550537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18550537</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18550537[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M801918200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18550537">Kabuta et al. (2008)</a> showed that human UCHL1 with the I93M mutation exhibited enhanced interaction with the CMA pathway components LAMP2A (<a href="/entry/309060">309060</a>), HSC70 (HSPA8; <a href="/entry/600816">600816</a>), and HSP90 (HSP90AA1; <a href="/entry/140571">140571</a>) compared with wildtype UCHL1 and caused accumulation of alpha-synuclein (SNCA; <a href="/entry/163890">163890</a>) due to inhibition of CMA-dependent degradation of alpha-synuclein. The aberrant interaction of UCHL1 I93M with the CMA machinery was independent of UCHL1 interaction with monoubiquitin and did not affect degradation of proteins by macroautophagy. 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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> rs5030732 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs5030732;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/rs5030732?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=rs5030732" 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=rs5030732" 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=RCV000013092 OR RCV001711069 OR RCV002243640" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013092, RCV001711069, RCV002243640" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013092...</a>
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<p>This variant, formerly titled PARKINSON DISEASE 5, RESISTANCE TO, has been reclassified based on the following conflicting evidence.</p><p><a href="#15" class="mim-tip-reference" title="Lincoln, S., Vaughan, J., Wood, N., Baker, M., Adamson, J., Gwinn-Hardy, K., Lynch, T., Hardy, J., Farrer, M. <strong>Low frequency of pathogenic mutations in the ubiquitin carboxy-terminal hydrolase gene in familial Parkinson's disease.</strong> Neuroreport 10: 427-429, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10203348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10203348</a>] [<a href="https://doi.org/10.1097/00001756-199902050-00040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10203348">Lincoln et al. (1999)</a> identified a ser18-to-tyr (S18Y) polymorphism in exon 3 of the UCHL1 gene. The S18Y allele was found in approximately 20% of chromosomes in a Caucasian population, and the authors suggested that it is unlikely to be pathogenic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10203348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Liu, Y., Fallon, L., Lashuel, H. A., Liu, Z., Lansbury, P. T., Jr. <strong>The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility.</strong> Cell 111: 209-218, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12408865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12408865</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)01012-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12408865">Liu et al. (2002)</a> found that the S18Y variant had reduced ubiquityl ligase activity compared with the wildtype enzyme, but it had comparable hydrolase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12408865" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Maraganore, D. M., Lesnick, T. G., Elbaz, A., Chartier-Harlin, M.-C., Gasser, T., Kruger, R., Hattori, N., Mellick, G. D., Quattrone, A., Satoh, J., Toda, T., Wang, J., Ioannidis, J. P. A., de Andrade, M., Rocca, W. A., UCHL1 Global Genetics Consortium. <strong>UCHL1 is a Parkinson's disease susceptibility gene.</strong> Ann. Neurol. 55: 512-521, 2004. Note: Erratum: Ann. Neurol. 55: 899 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15048890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15048890</a>] [<a href="https://doi.org/10.1002/ana.20017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15048890">Maraganore et al. (2004)</a> performed a collaborative pooled analysis of data from 11 published studies of the UCHL1 S18Y variant and Parkinson disease (<a href="/entry/613643">613643</a>): 3 studies had reported no association for the variant and PD, 4 reported associations in PD subgroups only, and 4 reported an inverse association of S18Y and PD. From a total of 1,970 cases and 2,224 controls, <a href="#18" class="mim-tip-reference" title="Maraganore, D. M., Lesnick, T. G., Elbaz, A., Chartier-Harlin, M.-C., Gasser, T., Kruger, R., Hattori, N., Mellick, G. D., Quattrone, A., Satoh, J., Toda, T., Wang, J., Ioannidis, J. P. A., de Andrade, M., Rocca, W. A., UCHL1 Global Genetics Consortium. <strong>UCHL1 is a Parkinson's disease susceptibility gene.</strong> Ann. Neurol. 55: 512-521, 2004. Note: Erratum: Ann. Neurol. 55: 899 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15048890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15048890</a>] [<a href="https://doi.org/10.1002/ana.20017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15048890">Maraganore et al. (2004)</a> found an overall inverse association of S18Y with PD. Carriers of the variant allele (Y/Y plus Y/S compared to S/S) had an odds ratio (OR) of 0.84, and homozygotes for the variant allele (Y/Y compared to S/S plus Y/S) had an OR of 0.71. There was a linear trend in the log OR consistent with a gene dosage effect. The inverse association was most apparent for young cases compared with young controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15048890" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 3,023 white individuals, <a href="#7" class="mim-tip-reference" title="Healy, D. G., Abou-Sleiman, P. M., Casas, J. P., Ahmadi, K. R., Lynch, T., Gandhi, S., Muqit, M. M. K., Foltynie, T., Barker, R., Bhatia, K. P., Quinn, N. P., Lees, A. J., Gibson, J. M., Holton, J. L., Revesz, T., Goldstein, D. B., Wood, N. W. <strong>UCHL-1 is not a Parkinson's disease susceptibility gene.</strong> Ann. Neurol. 59: 627-633, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16450370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16450370</a>] [<a href="https://doi.org/10.1002/ana.20757" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16450370">Healy et al. (2006)</a> found that the S18Y variant was not protective against PD under any genetic mode of inheritance. Furthermore, no association was observed in an updated metaanalysis including 6,594 individuals. A cumulative metaanalysis showed a trend toward a null effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16450370" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Kyratzi, E., Pavlaki, M., Stefanis, L. <strong>The S18Y polymorphic variant of UCH-L1 confers an antioxidant function to neuronal cells.</strong> Hum. Molec. Genet. 17: 2160-2171, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18411255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18411255</a>] [<a href="https://doi.org/10.1093/hmg/ddn115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18411255">Kyratzi et al. (2008)</a> found that the S18Y variant of the UCHL1 gene, but not wildtype, conferred a specific antioxidant protective function when expressed at physiologic levels in human neuroblastoma cells and primary cortical neurons. The effect appeared to result from a decrease in reactive oxygen species in response to insult. The results provided indirect evidence for the importance of oxidative stress as a pathogenetic factor in certain forms of sporadic PD. Overexpression of wildtype or the S18Y variant did not appear to directly impact the proteasome, although they both led to stabilization of free ubiquitin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18411255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#24" class="mim-tip-reference" title="Rudolph, T., Sjolander, A., Palmer, M. S., Minthon, L., Wallin, A., Andreasen, N., Tasa, G., Juronen, E., Blennow, K., Zetterberg, H., Zetterberg, M. <strong>Ubiquitin carboxyl-terminal esterase L1 (UCHL1) S18Y polymorphism in patients with cataracts.</strong> Ophthalmic Genet. 32: 75-79, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21268678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21268678</a>] [<a href="https://doi.org/10.3109/13816810.2010.544360" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21268678">Rudolph et al. (2011)</a> examined the possible effects of the S18Y polymorphism on cataract formation. Using dynamic allele-specific hybridization, they analyzed 493 patients with cataract and 142 controls for the S18Y polymorphism. Significant differences were observed in allele and genotype frequencies between controls and cataract patients with a positive UCHL1 allele A carrier status associated with the cataract diagnosis. <a href="#24" class="mim-tip-reference" title="Rudolph, T., Sjolander, A., Palmer, M. S., Minthon, L., Wallin, A., Andreasen, N., Tasa, G., Juronen, E., Blennow, K., Zetterberg, H., Zetterberg, M. <strong>Ubiquitin carboxyl-terminal esterase L1 (UCHL1) S18Y polymorphism in patients with cataracts.</strong> Ophthalmic Genet. 32: 75-79, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21268678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21268678</a>] [<a href="https://doi.org/10.3109/13816810.2010.544360" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21268678">Rudolph et al. (2011)</a> concluded that their study did not support a protective role for the S18Y polymorphism in cataract development. Instead, their findings suggested that this polymorphism might have a disease-promoting effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21268678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs397515634 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515634;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/rs397515634?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=rs397515634" 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=rs397515634" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 3 sibs, born of consanguineous Turkish parents, with autosomal recessive spastic paraplegia-79B (SPG79B; <a href="/entry/615491">615491</a>), <a href="#1" class="mim-tip-reference" title="Bilguvar, K., Tyagi, N. K., Ozkara, C., Tuysuz, B., Bakircioglu, M., Choi, M., Delil, S., Caglayan, A. O., Baranoski, J. F., Erturk, O., Yalcinkaya, C., Karacorlu, M., and 9 others. <strong>Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration.</strong> Proc. Nat. Acad. Sci. 110: 3489-3494, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23359680/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23359680</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23359680[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.1222732110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23359680">Bilguvar et al. (2013)</a> identified a homozygous A-to-C transversion in the UCHL1 gene, resulting in a glu7-to-ala (E7A) substitution at a highly conserved residue in the ubiquitin-binding domain. The mutation, which was found by homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the dbSNP or 1000 Genomes Project databases, in 2,400 control exomes of European individuals, or in 948 Turkish control chromosomes. Molecular modeling predicted that the E7A substitution may interfere with substrate binding by restricting the proper positioning of the substrate for tunneling underneath the crossover L8 loop spanning the catalytic cleft. In vitro functional expression studies in E. coli showed that the E7A mutant protein had decreased binding to ubiquitin and significantly decreased (less than 10%) hydrolase activity compared to wildtype. The patients had onset of progressive visual loss due to optic atrophy at around age 5 years, followed by spasticity, cerebellar ataxia, peripheral neuropathy, and myokymia, consistent with systemic neurodegeneration and deficits at the neuromuscular junction. The clinical features resembled those of the Uchl1-null mouse (<a href="#30" class="mim-tip-reference" title="Yamazaki, K., Wakasugi, N., Tomita, T., Kikuchi, T., Mukoyama, M., Ando, K. <strong>Gracile axonal dystrophy (GAD), a new neurological mutant in the mouse.</strong> Proc. Soc. Exp. Biol. Med. 187: 209-215, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3340629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3340629</a>] [<a href="https://doi.org/10.3181/00379727-187-42656" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3340629">Yamazaki et al., 1988</a>). <a href="#1" class="mim-tip-reference" title="Bilguvar, K., Tyagi, N. K., Ozkara, C., Tuysuz, B., Bakircioglu, M., Choi, M., Delil, S., Caglayan, A. O., Baranoski, J. F., Erturk, O., Yalcinkaya, C., Karacorlu, M., and 9 others. <strong>Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration.</strong> Proc. Nat. Acad. Sci. 110: 3489-3494, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23359680/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23359680</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23359680[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.1222732110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23359680">Bilguvar et al. (2013)</a> noted that neither parent, each of whom was heterozygous for the mutation, had evidence of Parkinson disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23359680+3340629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 SPASTIC PARAPLEGIA 79B, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs768996179 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs768996179;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/rs768996179?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=rs768996179" 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=rs768996179" 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=RCV000417182 OR RCV001146776" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000417182, RCV001146776" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000417182...</a>
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<p>In 3 sibs, including a pair of monozygotic twin brothers, born of unrelated Norwegian parents, with autosomal recessive spastic paraplegia-79B (SPG79B; <a href="/entry/615491">615491</a>), <a href="#25" class="mim-tip-reference" title="Rydning, S. L., Backe, P. H., Sousa, M. M. L., Iqbal, Z., Oye, A.-M., Sheng, Y., Yang, M., Lin, X., Slupphaug, G., Nordenmark, T. H., Vigeland, M. D., Bjoras, M., Tallaksen, C. M., Selmer, K. K. <strong>Novel UCHL1 mutations reveal new insights into ubiquitin processing.</strong> Hum. Molec. Genet. 26: 1031-1040, 2017. Note: Erratum: Hum. Molec. Genet. 26: 1217 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28007905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28007905</a>] [<a href="https://doi.org/10.1093/hmg/ddw391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28007905">Rydning et al. (2017)</a> identified compound heterozygous missense mutations in the UCHL1 gene: a c.533G-A transition (c.533G-A, NM_004181.4), resulting in an arg178-to-gln (R178Q) substitution at a highly conserved residue in the active site, and a c.647C-A transversion, resulting in an ala216-to-asp (A216D; <a href="#0005">191342.0005</a>) substitution in a beta-sheet that constitutes a hydrophobic core. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was found in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases, or in 961 controls. In the ExAC database, the c.647C-A variant was absent, whereas the c.533G-A variant was reported in heterozygous state in 10 individuals. In vitro functional expression studies in E. coli showed that the R178Q mutation resulted in a 4-fold increase in enzyme activity compared to controls. Because expression of the A216D mutation resulted in inclusion bodies, containing presumably misfolded, aggregated proteins, no activity assays of this mutant were possible. Patient fibroblasts showed decreased levels of the UCHL1 protein, at about 25 to 35% of controls, and consisted only of the R178Q mutant; the A216D mutant protein was not detected in patient cells, suggesting that it is degraded. <a href="#25" class="mim-tip-reference" title="Rydning, S. L., Backe, P. H., Sousa, M. M. L., Iqbal, Z., Oye, A.-M., Sheng, Y., Yang, M., Lin, X., Slupphaug, G., Nordenmark, T. H., Vigeland, M. D., Bjoras, M., Tallaksen, C. M., Selmer, K. K. <strong>Novel UCHL1 mutations reveal new insights into ubiquitin processing.</strong> Hum. Molec. Genet. 26: 1031-1040, 2017. Note: Erratum: Hum. Molec. Genet. 26: 1217 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28007905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28007905</a>] [<a href="https://doi.org/10.1093/hmg/ddw391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28007905">Rydning et al. (2017)</a> noted that the patients did not have cognitive dysfunction, and speculated that the nonsoluble A216D protein results in reduction of UCHL1 function and contributes to neurodegeneration, whereas the increased enzymatic activity of R178Q many compensate and even protect cognitive function. This family had previously been reported by <a href="#19" class="mim-tip-reference" title="Nyberg-Hansen, R., Refsum, S. <strong>Spastic paraparesis associated with optic atrophy in monozygotic twins.</strong> Acta Neurol. Scand. Suppl. 51: 261-263, 1972.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4514348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4514348</a>]" pmid="4514348">Nyberg-Hansen and Refsum (1972)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28007905+4514348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 SPASTIC PARAPLEGIA 79B, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1057519600 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519600;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=rs1057519600" 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=rs1057519600" 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=RCV000417145" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000417145" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000417145</a>
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<p>For discussion of the c.647C-A transversion (c.647C-A, NM_004181.4) in the UCHL1 gene, resulting in an ala216-to-asp (A216D) substitution, that was found in compound heterozygous state in 3 sibs with autosomal recessive spastic paraplegia-79B (SPG79B; <a href="/entry/615491">615491</a>) by <a href="#25" class="mim-tip-reference" title="Rydning, S. L., Backe, P. H., Sousa, M. M. L., Iqbal, Z., Oye, A.-M., Sheng, Y., Yang, M., Lin, X., Slupphaug, G., Nordenmark, T. H., Vigeland, M. D., Bjoras, M., Tallaksen, C. M., Selmer, K. K. <strong>Novel UCHL1 mutations reveal new insights into ubiquitin processing.</strong> Hum. Molec. Genet. 26: 1031-1040, 2017. Note: Erratum: Hum. Molec. Genet. 26: 1217 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28007905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28007905</a>] [<a href="https://doi.org/10.1093/hmg/ddw391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28007905">Rydning et al. (2017)</a>, see <a href="#0004">191342.0004</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28007905" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 SPASTIC PARAPLEGIA 79A, AUTOSOMAL DOMINANT, WITH ATAXIA</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">rs1781001592 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1781001592;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=rs1781001592" 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=rs1781001592" 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=RCV001267902 OR RCV003225965" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001267902, RCV003225965" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001267902...</a>
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<p>In 6 affected members of a multigenerational family (family 1) with autosomal dominant spastic paraplegia-79A with ataxia (SPG79A; <a href="/entry/620221">620221</a>), <a href="#21" class="mim-tip-reference" title="Park, J., Tucci, A., Cipriani, V., Demidov, G., Rocca, C., Senderek, J., Butryn, M., Velic, A., Lam, T., Galanaki, E., Cali, E., Vestito, L., and 40 others. <strong>Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy.</strong> Genet. Med. 24: 2079-2090, 2022. Note: Erratum: Genet. Med. 25: 100961 only, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35986737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35986737</a>] [<a href="https://doi.org/10.1016/j.gim.2022.07.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35986737">Park et al. (2022)</a> identified a heterozygous 1-bp duplication (c.64_dup, NM_004181.4) in the UCHL1 gene, resulting in a frameshift and premature termination (Val22GlyfsTer39). The mutation, which was found by diagnostic exome and genome sequencing, segregated with the disorder in the family and was not present in the gnomAD database. Functional studies of the variant were not performed, but mass spectrometry analysis of patient fibroblasts showed a significant decrease in UCHL1 protein levels, suggesting that haploinsufficiency for this gene is the pathogenetic mechanism for this phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35986737" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 SPASTIC PARAPLEGIA 79A, AUTOSOMAL DOMINANT, WITH ATAXIA</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">rs1781070341 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1781070341;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=rs1781070341" 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=rs1781070341" 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=RCV001268796 OR RCV003152622" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001268796, RCV003152622" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001268796...</a>
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<p>In 4 affected members of a multigenerational family (family 2) with autosomal dominant spastic paraplegia-79A with ataxia (SPG79A; <a href="/entry/620221">620221</a>), <a href="#21" class="mim-tip-reference" title="Park, J., Tucci, A., Cipriani, V., Demidov, G., Rocca, C., Senderek, J., Butryn, M., Velic, A., Lam, T., Galanaki, E., Cali, E., Vestito, L., and 40 others. <strong>Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy.</strong> Genet. Med. 24: 2079-2090, 2022. Note: Erratum: Genet. Med. 25: 100961 only, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35986737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35986737</a>] [<a href="https://doi.org/10.1016/j.gim.2022.07.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35986737">Park et al. (2022)</a> identified a heterozygous 16-bp deletion (c.349_364del, NM_004181.4) in the UCHL1 gene, resulting in a frameshift and premature termination (Phe117ArgfsTer33). The mutation, which was found by diagnostic exome and genome sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed, but mass spectrometry analysis of patient fibroblasts showed a significant decrease in UCHL1 protein levels, suggesting that haploinsufficiency for this gene is the pathogenetic mechanism for this phenotype. One of the patients in this family had an additional diagnosis of ALS (<a href="/entry/105400">105400</a>) and carried a heterozygous pathogenic missense mutation (D91A) in the SOD1 gene (<a href="/entry/147450">147450</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35986737" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 SPASTIC PARAPLEGIA 79A, AUTOSOMAL DOMINANT, WITH ATAXIA</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003152407" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003152407" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003152407</a>
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<p>In 4 affected members of 2 unrelated families (families 6 and 7) with autosomal dominant spastic paraplegia-79A with ataxia (SPG79A; <a href="/entry/620221">620221</a>), <a href="#21" class="mim-tip-reference" title="Park, J., Tucci, A., Cipriani, V., Demidov, G., Rocca, C., Senderek, J., Butryn, M., Velic, A., Lam, T., Galanaki, E., Cali, E., Vestito, L., and 40 others. <strong>Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy.</strong> Genet. Med. 24: 2079-2090, 2022. Note: Erratum: Genet. Med. 25: 100961 only, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35986737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35986737</a>] [<a href="https://doi.org/10.1016/j.gim.2022.07.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35986737">Park et al. (2022)</a> identified a heterozygous c.73C-T transition (c.73C-T, NM_004181.4) in the UCHL1 gene, resulting in a gln25-to-ter (Q25X) substitution. The mutation, which was found by diagnostic exome and genome sequencing, segregated with the disorder in family 6 (information from members of family 7 was not available), and was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function and cause haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35986737" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0009 SPASTIC PARAPLEGIA 79A, AUTOSOMAL DOMINANT, WITH ATAXIA</strong>
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UCHL1, 4-BP DUP, NT95
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003152408" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003152408" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003152408</a>
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<p>In a mother and daughter (family 12) with autosomal dominant spastic paraplegia-79A with ataxia (SPG79A; <a href="/entry/620221">620221</a>), <a href="#21" class="mim-tip-reference" title="Park, J., Tucci, A., Cipriani, V., Demidov, G., Rocca, C., Senderek, J., Butryn, M., Velic, A., Lam, T., Galanaki, E., Cali, E., Vestito, L., and 40 others. <strong>Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy.</strong> Genet. Med. 24: 2079-2090, 2022. Note: Erratum: Genet. Med. 25: 100961 only, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35986737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35986737</a>] [<a href="https://doi.org/10.1016/j.gim.2022.07.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35986737">Park et al. (2022)</a> identified a heterozygous 4-bp duplication (c.95_98dup, NM_004181.4) in the UCHL1 gene, resulting in a frameshift and premature termination (Leu34GlyfsTer28). The mutation, which was found by diagnostic exome and genome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function and cause haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35986737" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV002976538 OR RCV003152652" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002976538, RCV003152652" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002976538...</a>
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<p>In 5 members of 3 unrelated families (families 15-17) with autosomal dominant spastic paraplegia-79A with ataxia (SPG79A; <a href="/entry/620221">620221</a>), <a href="#21" class="mim-tip-reference" title="Park, J., Tucci, A., Cipriani, V., Demidov, G., Rocca, C., Senderek, J., Butryn, M., Velic, A., Lam, T., Galanaki, E., Cali, E., Vestito, L., and 40 others. <strong>Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy.</strong> Genet. Med. 24: 2079-2090, 2022. Note: Erratum: Genet. Med. 25: 100961 only, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35986737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35986737</a>] [<a href="https://doi.org/10.1016/j.gim.2022.07.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35986737">Park et al. (2022)</a> identified a heterozygous 3-bp in-frame duplication (c.154_156dup, NM_004181.4) in the UCHL1 gene, resulting in the duplication of residue leu52 (Leu52dup). The mutation, which was found by extended screening for UCHL1 variants, segregated with the disorder in family 17 and was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to be pathogenic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35986737" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<strong>Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration.</strong>
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Day, I. N. M., Hinks, L. J., Thompson, R. J.
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<strong>The structure of the human gene encoding protein gene product 9.5 (PGP9.5), a neuron-specific ubiquitin C-terminal hydrolase.</strong>
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[<a href="https://doi.org/10.1042/bj2680521" target="_blank">Full Text</a>]
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Day, I. N. M., Thompson, R. J.
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<strong>Molecular cloning of cDNA coding for human PGP 9.5 protein: a novel cytoplasmic marker for neurones and neuroendocrine cells.</strong>
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FEBS Lett. 210: 157-160, 1987.
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Doran, J. F., Jackson, P., Kynoch, P., Thompson, R. J.
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<strong>Isolation of PGP 9.5, a new human neurone-specific protein detected by high resolution two-dimensional electrophoresis.</strong>
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J. Neurochem. 40: 1542-1547, 1983.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6343558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6343558</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6343558" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1471-4159.1983.tb08124.x" target="_blank">Full Text</a>]
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Edwards, Y. H., Fox, M. F., Povey, S., Hinks, L. J., Day, I. N. M., Thompson, R. J.
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<strong>The gene for human neuron specific ubiquitin C-terminal hydrolase maps to chromosome 4p14. (Abstract)</strong>
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Cytogenet. Cell Genet. 58: 1886-1887, 1991.
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Gong, B., Cao, Z., Zheng, P., Vitolo, O. V., Liu, S., Staniszewski, A., Moolman, D., Zhang, H., Shelanski, M., Arancio, O.
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<strong>Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16923396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16923396</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16923396" 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.cell.2006.06.046" target="_blank">Full Text</a>]
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Healy, D. G., Abou-Sleiman, P. M., Casas, J. P., Ahmadi, K. R., Lynch, T., Gandhi, S., Muqit, M. M. K., Foltynie, T., Barker, R., Bhatia, K. P., Quinn, N. P., Lees, A. J., Gibson, J. M., Holton, J. L., Revesz, T., Goldstein, D. B., Wood, N. W.
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Ann. Neurol. 59: 627-633, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16450370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16450370</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16450370" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.20757" target="_blank">Full Text</a>]
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Jackson, P., Thompson, R.F.
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<strong>The demonstration of new human brain-specific proteins by high-resolution two-dimensional polyacrylamide gel electrophoresis.</strong>
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J Neurol. Sci. 49: 429-438, 1981.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7217993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7217993</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7217993" 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/10.1016/0022-510x(81)90032-0" target="_blank">Full Text</a>]
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Kabuta, T., Furuta, A., Aoki, S., Furuta, K., Wada, K.
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<strong>Aberrant interaction between Parkinson disease-associated mutant UCH-L1 and the lysosomal receptor for chaperone-mediated autophagy.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18550537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18550537</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18550537[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=18550537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M801918200" target="_blank">Full Text</a>]
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Kurihara, L. J., Kikuchi, T., Wada, K., Tilghman, S. M.
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<strong>Loss of Uch-L1 and Uch-L3 leads to neurodegeneration, posterior paralysis and dysphagia.</strong>
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Hum. Molec. Genet. 10: 1963-1970, 2001.
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[<a href="https://doi.org/10.1073/pnas.1812413116" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10471497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10471497</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10471497" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/12647" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="27" class="mim-anchor"></a>
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<a id="Stumpf2023" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
|
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Stumpf, A. M.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 01/27/2023.
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</p>
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</div>
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</li>
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<li>
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<a id="28" class="mim-anchor"></a>
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<a id="Suh1995" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
|
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Suh, J. G., Yamanishi, T., Matsui, K., Tanaka, K., Wada, K.
|
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<strong>Mapping of the gracile axonal dystrophy (gad) gene to a region between D5Mit197 and D5Mit113 on proximal mouse chromosome 5.</strong>
|
|
Genomics 27: 549-551, 1995.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7558041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7558041</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7558041" 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/10.1006/geno.1995.1091" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="29" class="mim-anchor"></a>
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<a id="Wilkinson1989" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
|
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Wilkinson, K. D., Lee, K. M., Deshpande, S., Duerksen-Hughes, P., Boss, J. M., Pohl, J.
|
|
<strong>The neuron-specific protein PGP 9.5 is a ubiquitin carboxyl-terminal hydrolase.</strong>
|
|
Science 246: 670-672, 1989.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2530630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2530630</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2530630" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.2530630" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="30" class="mim-anchor"></a>
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<a id="Yamazaki1988" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yamazaki, K., Wakasugi, N., Tomita, T., Kikuchi, T., Mukoyama, M., Ando, K.
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<strong>Gracile axonal dystrophy (GAD), a new neurological mutant in the mouse.</strong>
|
|
Proc. Soc. Exp. Biol. Med. 187: 209-215, 1988.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3340629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3340629</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3340629" 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/10.3181/00379727-187-42656" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Anne M. Stumpf - updated : 01/27/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 01/23/2023<br>Bao Lige - updated : 03/19/2020<br>Cassandra L. Kniffin - updated : 02/15/2017<br>Cassandra L. Kniffin - updated : 10/28/2013<br>Jane Kelly - updated : 8/26/2011<br>Cassandra L. Kniffin - updated : 11/16/2010<br>Joanna S. Amberger - updated : 9/25/2009<br>Cassandra L. Kniffin - updated : 8/27/2009<br>Cassandra L. Kniffin - updated : 9/12/2007<br>Paul J. Converse - updated : 2/13/2007<br>George E. Tiller - updated : 5/25/2005<br>Cassandra L. Kniffin - updated : 6/8/2004<br>Stylianos E. Antonarakis - updated : 12/2/2002<br>Patricia A. Hartz - updated : 11/20/2002<br>George E. Tiller - updated : 1/31/2002<br>Victor A. McKusick - updated : 5/4/2001<br>Victor A. McKusick - updated : 8/30/1999<br>Victor A. McKusick - updated : 6/17/1999
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 8/6/1991
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 01/30/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 01/29/2024<br>alopez : 01/27/2023<br>ckniffin : 01/23/2023<br>carol : 03/26/2020<br>mgross : 03/19/2020<br>carol : 01/24/2018<br>carol : 04/13/2017<br>carol : 02/16/2017<br>carol : 02/15/2017<br>ckniffin : 02/15/2017<br>alopez : 08/12/2016<br>alopez : 04/21/2015<br>carol : 10/28/2013<br>carol : 10/28/2013<br>ckniffin : 10/28/2013<br>carol : 8/29/2011<br>carol : 8/29/2011<br>terry : 8/26/2011<br>carol : 11/17/2010<br>ckniffin : 11/16/2010<br>carol : 7/12/2010<br>wwang : 10/1/2009<br>joanna : 9/25/2009<br>ckniffin : 8/27/2009<br>wwang : 9/21/2007<br>ckniffin : 9/12/2007<br>mgross : 2/13/2007<br>mgross : 2/13/2007<br>alopez : 5/25/2005<br>tkritzer : 7/19/2004<br>tkritzer : 6/11/2004<br>ckniffin : 6/8/2004<br>alopez : 3/17/2004<br>tkritzer : 12/31/2002<br>mgross : 12/2/2002<br>mgross : 11/20/2002<br>cwells : 2/6/2002<br>cwells : 1/31/2002<br>mgross : 5/4/2001<br>terry : 5/4/2001<br>mcapotos : 12/7/1999<br>alopez : 8/30/1999<br>terry : 8/30/1999<br>jlewis : 6/23/1999<br>jlewis : 6/23/1999<br>jlewis : 6/23/1999<br>terry : 6/17/1999<br>alopez : 10/5/1998<br>mark : 1/27/1997<br>supermim : 3/16/1992<br>carol : 2/26/1992<br>carol : 2/23/1992<br>carol : 8/6/1991
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
|
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<span class="mim-font">
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<strong>*</strong> 191342
|
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</span>
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</h3>
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</div>
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<div>
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<h3>
|
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<span class="mim-font">
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|
|
UBIQUITIN CARBOXYL-TERMINAL ESTERASE L1; UCHL1
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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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<div >
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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UBIQUITIN C-TERMINAL HYDROLASE, NEURON-SPECIFIC<br />
|
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PGP9.5
|
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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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<p>
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: UCHL1</em></strong>
|
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: 4p13
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 4:41,256,928-41,268,455 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
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</p>
|
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
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<tr>
|
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<td rowspan="3">
|
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<span class="mim-font">
|
|
4p13
|
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</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
{?Parkinson disease 5, susceptibility to}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
613643
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Spastic paraplegia 79A, autosomal dominant
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
620221
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
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</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Spastic paraplegia 79B, autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
615491
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
|
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</div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<span class="mim-text-font">
|
|
<p>UCHL1 is a member of a gene family whose products hydrolyze small C-terminal adducts of ubiquitin to generate the ubiquitin monomer. Expression of UCHL1 is highly specific to neurons and to cells of the diffuse neuroendocrine system and their tumors. It is present in all neurons (Doran et al., 1983). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
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</h4>
|
|
</div>
|
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<span class="mim-text-font">
|
|
<p>Day and Thompson (1987) cloned UCHL1 cDNA. The deduced protein, which they called PGP9.5, contains 212 amino acids. </p><p>Doran et al. (1983) purified the PGP9.5 protein reported by Jackson and Thompson (1981) and found that it has a molecular mass of 27 kD. They showed that the protein is present in brain at concentrations at least 50 times greater than in other organs and is a major protein component of neuronal cytoplasm. </p><p>By Northern blot analysis, Leroy et al. (1998) detected a 1.3-kb transcript expressed only in brain. Examination of specific brain regions revealed expression in all areas tested, particularly in the substantia nigra. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
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|
|
<span class="mim-text-font">
|
|
<p>Day et al. (1990) determined that the UCHL1 gene contains 9 exons and spans 10 kb. The 5-prime region contains elements common to many genes and other elements that are shared with the 5-prime regions of the genes encoding neurofilament neuron-specific enolase (ENO2; 131360) and THY1 antigen (188230). Leroy et al. (1998) confirmed that UCHL1 has 9 coding exons, and they identified a high GC content between exons 1 and 3. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
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|
|
|
<span class="mim-text-font">
|
|
<p>By PCR analysis of DNA from a panel of human/rodent somatic cell hybrids, Edwards et al. (1991) mapped UCHL1 to chromosome 4. By in situ hybridization, they regionalized the assignment to 4p14.</p><p>Stumpf (2023) mapped the UCHL1 gene to chromosome 4p13 based on an alignment of the UCHL1 sequence (GenBank AK315368) with the genomic sequence (GRCh38).</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<span class="mim-text-font">
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<p>Liu et al. (2002) found that UCHL1, especially variants linked to higher susceptibility to Parkinson disease-5 (PARK5; 613643), caused the accumulation of alpha-synuclein (163890) in cultured cells, an effect that could not be explained by its recognized hydrolase activity. UCHL1 exhibited a second, dimerization-dependent ubiquityl ligase activity. A polymorphic variant of UCHL1, ser18 to tyr (S18Y; 191342.0002), associated in some studies with decreased risk for Parkinson disease, had reduced ligase activity compared with the wildtype enzyme, but it had comparable hydrolase activity. The authors concluded that the ligase and hydrolase activities of UCHL1 may play roles in proteasomal protein degradation, a process critical for neuronal health. </p><p>In contrast to the UCHL3 (603090) isozyme, which is expressed in all tissues, UCHL1 is expressed exclusively in neurons and testis/ovary. Osaka et al. (2003) observed that UCHL1 associated and colocalized with monoubiquitin and elongated ubiquitin half-life. In the gracile axonal dystrophy (gad) mouse, in which the function of UCHL1 is lost, the authors demonstrated a reduced level of monoubiquitin in neurons. In contrast, overexpression of UCHL1 caused an increase in the level of ubiquitin in both cultured cells and mice. The authors suggested that UCHL1, with avidity and affinity for ubiquitin, may insure ubiquitin stability within neurons. </p><p>Using coimmunoprecipitation analysis in transfected mammalian cells, Kabuta et al. (2008) showed that human UCHL1 interacted with LAMP2A (309060), a lysosomal receptor for chaperone-mediated autophagy (CMA), and the CMA pathway components HSC70 (HSPA8; 600816) and HSP90 (HSP90AA1; 140571). Analysis with recombinant proteins revealed that UCHL1 interacted directly with the cytoplasmic region of LAMP2A. UCHL1 was not degraded by CMA pathway, but instead was degraded by macroautophagy. Analysis with UCHL1 mutants showed that interaction of UBCHL1 with the CMA machinery was independent of UCHL1 enzymatic activity and interaction of UCHL1 with monoubiquitin. </p><p>Using Western blot analysis, Reinicke et al. (2019) demonstrated that mouse Uchl1 was expressed in dendritic cells (DCs) and that its expression and enzymatic activity were regulated by immune stimuli. Cross-priming of the Cd8 (see 186910) T-cell response required Uchl1, and as a result, deletion of Uchl1 in mice impaired the Cd8 T-cell response and affected early innate neutrophil influx upon Listeria infection. Loss of Uchl1 did not interfere with phagocytosis and phagosome maturation in DCs. However, Uchl1 deletion reduced trafficking of recycling major histocompatibility complex class I molecules through cross-presentation. </p>
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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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<span class="mim-text-font">
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<p><strong><em>Spastic Paraplegia 79B, Autosomal Recessive</em></strong></p><p>
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In 3 sibs, born of consanguineous Turkish parents, with autosomal recessive spastic paraplegia-79B (SPG79B; 615491), Bilguvar et al. (2013) identified a homozygous missense mutation in the UCHL1 gene (E7A; 191342.0003). The mutation, which was found by homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies in E. coli showed that the E7A mutant protein had decreased binding to ubiquitin and significantly decreased (less than 10%) hydrolase activity compared to wildtype. The patients had onset of progressive visual loss due to optic atrophy at around age 5 years, followed by spasticity, cerebellar ataxia, peripheral neuropathy, and myokymia, consistent with systemic neurodegeneration and deficits at the neuromuscular junction. The clinical features resembled those of the Uchl1-null mouse (Yamazaki et al., 1988). Bilguvar et al. (2013) noted that neither parent, each of whom was heterozygous for the mutation, had evidence of Parkinson disease. The findings indicated the importance of UCHL1 in the maintenance of nervous system integrity. </p><p>In 3 sibs with SPG79B, including a pair of monozygotic twin brothers, born of unrelated Norwegian parents, Rydning et al. (2017) identified compound heterozygous missense mutations in the UCHL1 gene: R178Q (191342.0004) and A216D (191342.0005). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies in E. coli showed that the R178Q mutation resulted in a 4-fold increase in enzyme activity compared to controls. Because expression of the A216D mutation resulted in inclusion bodies, containing presumably misfolded, aggregated proteins, activity assays of this mutant were not possible. </p><p><strong><em>Spastic Paraplegia 79A with Ataxia, Autosomal Dominant</em></strong></p><p>
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In 34 patients from 18 unrelated families with autosomal dominant spastic paraplegia-79A with ataxia (SPG79A; 620221), Park et al. (2022) identified heterozygous putative loss-of-function mutations in the UCHL1 gene (see, e.g., 191342.0006-191342.0010). The mutations, which were found by diagnostic exome and genome sequencing, segregated with the disorder in the families from whom information was available. None were present in the gnomAD database. Functional studies of the variants were not performed, but mass spectrometry analysis of fibroblasts derived from affected members of 3 different families showed a significant decrease in UCHL1 protein levels, suggesting that haploinsufficiency for this gene is the pathogenetic mechanism for this phenotype. </p><p><strong><em>Possible Role in Parkinson Disease</em></strong></p><p>
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Ubiquitin C-terminal hydrolase L1 represents 1 to 2% of total soluble brain protein (Wilkinson et al., 1989). Its occurrence in Lewy bodies and its function in the proteasome pathway make it a compelling candidate gene in Parkinson disease. In a German family with typical Parkinson disease (PARK5; 613643), Leroy et al. (1998) identified a missense mutation in the UCHL1 gene, ile93 to met (I93M; 191342.0001), which caused a partial loss of the catalytic activity of this thiol protease. They suggested that this could lead to aberrations in the proteolytic pathway and aggregation of proteins. Healy et al. (2006) noted that the findings of Leroy et al. (1998) had never been replicated and thus the association was uncertain. </p><p>Lincoln et al. (1999) sequenced the entire coding region of the UCHL1 gene in 11 families with a pattern of Parkinson disease consistent with autosomal dominant inheritance. Although they found polymorphisms in noncoding regions, the only amino acid change was S18Y (191342.0002). The S18Y allele was found in approximately 20% of chromosomes in a Caucasian population, suggesting that it is unlikely to be pathogenic. Lincoln et al. (1999) concluded that the I93M variant must be a rare cause of Parkinson disease or a harmless substitution whose occurrence in the family reflected chance. </p><p>Among 3,023 white individuals, Healy et al. (2006) found that the S18Y variant was not protective against PD under any genetic mode of inheritance. A haplotype-tagging approach also did not detect other associated variants in the UCHL1 gene. Furthermore, no association was observed in an updated metaanalysis including 6,594 individuals. A cumulative metaanalysis showed a trend toward a null effect. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The gracile axonal dystrophy (gad) mouse is an autosomal recessive mutant that shows sensory ataxia at an early age, followed by motor ataxia later (Yamazaki et al., 1988). Pathologically, the mutant is characterized by 'dying-back' type axonal degeneration and formation of spheroid bodies in nerve terminals. Pathologic observations in the human have associated brain aging and neurodegenerative diseases with progressive accumulation of ubiquitinated protein conjugates. In gad mice, accumulation of amyloid beta-protein and ubiquitin-positive deposits occur retrogradely along the sensory and motor nervous systems. Suh et al. (1995) showed that the gad mutation is located on mouse chromosome 5. Saigoh et al. (1999) found that the gad mutation is caused by an in-frame deletion including exons 7 and 8 of the Uchl1 gene, encoding the ubiquitin carboxy-terminal hydrolase selectively expressed in the nervous system and testis. The gad allele encodes a truncated Uchl1 protein lacking a segment of 42 amino acids containing a catalytic residue. Since this protein is thought to stimulate protein degradation by generating free monomeric ubiquitin, the gad mutation appears to affect protein turnover. The findings suggested that altered function of the ubiquitin system directly causes neurodegeneration. The gad mouse provides a useful model for investigating human neurodegenerative disorders. </p><p>Kurihara et al. (2000) showed that mice homozygous for a targeted deletion of the related Uchl3 gene (603090) are indistinguishable from wildtype. To assess whether the 2 hydrolases have redundant function, Kurihara et al. (2001) generated mice homozygous for both Uchl1(gad) and Uchl3(delta3-7). The double homozygotes weighed 30% less than single homozygotes and displayed an earlier onset of lethality, possibly due to dysphagia. Axonal degeneration of the nucleus tractus solitarius and area postrema of the medulla was noted in these mice. The double homozygotes also displayed a more severe axonal degeneration of the gracile tract of the medulla and spinal cord than had been observed in Uchl1(gad) single homozygotes. In addition, degeneration of dorsal root ganglia cell bodies was detected in both the double homozygotes and Uchl3(delta3-7) single homozygotes. Given that both Uchl1(gad) and Uchl3(delta3-7) single homozygotes displayed distinct degenerative defects that were exacerbated in the double homozygotes, the authors concluded that Uchl1 and Uchl3 may have both separate and overlapping functions in the maintenance of neurons of the gracile tract, nucleus tractus solitarius, and area postrema. </p><p>Gong et al. (2006) found that inhibition of Uchl1 in mouse hippocampal slices reduced normal synaptic function and long-term potentiation. Levels of soluble Uchl1 were reduced in hippocampi of App (104760)/Ps1 (PSEN1; 104311) mice, which start depositing amyloid-beta (A-beta) at age 8 to 10 weeks and reproduce some cognitive deficits seen in Alzheimer disease (see 104300) patients. Restoration of Uchl1 levels in mouse hippocampal slices treated with oligomeric amyloid-beta and in slices from App/Ps1 mice restored enzymatic activity and synaptic function. Injection of Uchl1 improved contextual fear learning in App/Ps1 mice. Treatment of hippocampal slices with Uchl1 before applying A-beta blocked the reduction of protein kinase A (PKA; see 188830) activity observed in the absence of pretreatment. Uchl1 also reversed the inhibition of Creb (CREB1; 123810) phosphorylation induced by A-beta. Gong et al. (2006) concluded that the PKA-CREB pathway mediates the effects of UCHL1 on A-beta-induced synaptic dysfunction. </p><p>MacDonald (1999) discussed the significance of the ubiquitin-proteasome system and degenerative disease in general, and the significance of the findings in the gad mouse specifically. </p><p>In neurons derived from gad mice, Kyratzi et al. (2008) found that lack of Uchl1 led to a decrease of free ubiquitin, but no overall decrease in proteasome function or enhanced sensitivity to oxidative stress. The findings suggested that wildtype UCHL1 acts as a stabilizer of monomeric ubiquitin in neuronal cells. </p><p>Reinicke et al. (2019) found that heterozygous or homozygous Uchl1 deficiency resulted in accelerated postnatal sensorimotor reflexes with decreased levels of polyubiquitinated proteins in juvenile mice, followed by motor degeneration in old adult mice. Absence of Uchl1 promoted mTorc1 (601231) activity and increased protein synthesis in mouse neurons. Proteasomal degradation was enhanced in Uchl1-deficient juvenile mice and declined in aged mice. As a result, Uchl1-deficient mice exhibited age- and brain area-dependent reduction in monoubiquitin and accumulation of polyubiquitinated proteins when neurodegeneration was already advanced. Furthermore, abnormal protein synthesis and degradation was associated with endoplasmic reticulum stress and ATP depletion, leading to alteration of protein homeostasis strains in Uchl1-deficient neurons. Rapamycin treatment reduced protein synthesis and ubiquitin accumulation in vitro and ameliorated the neurologic phenotype of Uchl1 deficiency in vivo. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>10 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 PARKINSON DISEASE 5, AUTOSOMAL DOMINANT, SUSCEPTIBILITY TO (1 family)</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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UCHL1, ILE93MET
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<br />
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SNP: rs121917767,
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gnomAD: rs121917767,
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ClinVar: RCV000013091
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a brother and sister with typical Parkinson disease (PARK5; 613643), Leroy et al. (1998) identified a heterozygous 277C-G transversion in exon 2 of the UCHL1 gene, resulting in an ile93-to-met (I93M) substitution in a highly conserved region. A paternal uncle and the paternal grandfather were also affected, but the father was not affected, indicating incomplete penetrance. The mutation was not found in 500 control chromosomes. In vitro functional expression studies in E. coli showed that the mutant protein had about a 50% reduction in catalytic activity compared to wildtype. Leroy et al. (1998) noted that UCHL1 had been identified as a component of Lewy bodies. </p><p>Healy et al. (2006) noted that the findings of Leroy et al. (1998) had never been replicated and thus the association was uncertain. </p><p>Kabuta et al. (2008) showed that human UCHL1 with the I93M mutation exhibited enhanced interaction with the CMA pathway components LAMP2A (309060), HSC70 (HSPA8; 600816), and HSP90 (HSP90AA1; 140571) compared with wildtype UCHL1 and caused accumulation of alpha-synuclein (SNCA; 163890) due to inhibition of CMA-dependent degradation of alpha-synuclein. The aberrant interaction of UCHL1 I93M with the CMA machinery was independent of UCHL1 interaction with monoubiquitin and did not affect degradation of proteins by macroautophagy. Furthermore, the I93M mutation did not cause loss of UCHL1 function, and the aberrant interaction was independent of UCHL1 enzymatic activity. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</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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UCHL1, SER18TYR
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<br />
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SNP: rs5030732,
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gnomAD: rs5030732,
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ClinVar: RCV000013092, RCV001711069, RCV002243640
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>This variant, formerly titled PARKINSON DISEASE 5, RESISTANCE TO, has been reclassified based on the following conflicting evidence.</p><p>Lincoln et al. (1999) identified a ser18-to-tyr (S18Y) polymorphism in exon 3 of the UCHL1 gene. The S18Y allele was found in approximately 20% of chromosomes in a Caucasian population, and the authors suggested that it is unlikely to be pathogenic. </p><p>Liu et al. (2002) found that the S18Y variant had reduced ubiquityl ligase activity compared with the wildtype enzyme, but it had comparable hydrolase activity. </p><p>Maraganore et al. (2004) performed a collaborative pooled analysis of data from 11 published studies of the UCHL1 S18Y variant and Parkinson disease (613643): 3 studies had reported no association for the variant and PD, 4 reported associations in PD subgroups only, and 4 reported an inverse association of S18Y and PD. From a total of 1,970 cases and 2,224 controls, Maraganore et al. (2004) found an overall inverse association of S18Y with PD. Carriers of the variant allele (Y/Y plus Y/S compared to S/S) had an odds ratio (OR) of 0.84, and homozygotes for the variant allele (Y/Y compared to S/S plus Y/S) had an OR of 0.71. There was a linear trend in the log OR consistent with a gene dosage effect. The inverse association was most apparent for young cases compared with young controls. </p><p>Among 3,023 white individuals, Healy et al. (2006) found that the S18Y variant was not protective against PD under any genetic mode of inheritance. Furthermore, no association was observed in an updated metaanalysis including 6,594 individuals. A cumulative metaanalysis showed a trend toward a null effect. </p><p>Kyratzi et al. (2008) found that the S18Y variant of the UCHL1 gene, but not wildtype, conferred a specific antioxidant protective function when expressed at physiologic levels in human neuroblastoma cells and primary cortical neurons. The effect appeared to result from a decrease in reactive oxygen species in response to insult. The results provided indirect evidence for the importance of oxidative stress as a pathogenetic factor in certain forms of sporadic PD. Overexpression of wildtype or the S18Y variant did not appear to directly impact the proteasome, although they both led to stabilization of free ubiquitin. </p><p>Rudolph et al. (2011) examined the possible effects of the S18Y polymorphism on cataract formation. Using dynamic allele-specific hybridization, they analyzed 493 patients with cataract and 142 controls for the S18Y polymorphism. Significant differences were observed in allele and genotype frequencies between controls and cataract patients with a positive UCHL1 allele A carrier status associated with the cataract diagnosis. Rudolph et al. (2011) concluded that their study did not support a protective role for the S18Y polymorphism in cataract development. Instead, their findings suggested that this polymorphism might have a disease-promoting effect. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 SPASTIC PARAPLEGIA 79B, AUTOSOMAL RECESSIVE</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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UCHL1, GLU7ALA
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<br />
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SNP: rs397515634,
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gnomAD: rs397515634,
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ClinVar: RCV000074332, RCV002514325
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 sibs, born of consanguineous Turkish parents, with autosomal recessive spastic paraplegia-79B (SPG79B; 615491), Bilguvar et al. (2013) identified a homozygous A-to-C transversion in the UCHL1 gene, resulting in a glu7-to-ala (E7A) substitution at a highly conserved residue in the ubiquitin-binding domain. The mutation, which was found by homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the dbSNP or 1000 Genomes Project databases, in 2,400 control exomes of European individuals, or in 948 Turkish control chromosomes. Molecular modeling predicted that the E7A substitution may interfere with substrate binding by restricting the proper positioning of the substrate for tunneling underneath the crossover L8 loop spanning the catalytic cleft. In vitro functional expression studies in E. coli showed that the E7A mutant protein had decreased binding to ubiquitin and significantly decreased (less than 10%) hydrolase activity compared to wildtype. The patients had onset of progressive visual loss due to optic atrophy at around age 5 years, followed by spasticity, cerebellar ataxia, peripheral neuropathy, and myokymia, consistent with systemic neurodegeneration and deficits at the neuromuscular junction. The clinical features resembled those of the Uchl1-null mouse (Yamazaki et al., 1988). Bilguvar et al. (2013) noted that neither parent, each of whom was heterozygous for the mutation, had evidence of Parkinson disease. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 SPASTIC PARAPLEGIA 79B, AUTOSOMAL RECESSIVE</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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UCHL1, ARG178GLN
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<br />
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SNP: rs768996179,
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gnomAD: rs768996179,
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ClinVar: RCV000417182, RCV001146776
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 sibs, including a pair of monozygotic twin brothers, born of unrelated Norwegian parents, with autosomal recessive spastic paraplegia-79B (SPG79B; 615491), Rydning et al. (2017) identified compound heterozygous missense mutations in the UCHL1 gene: a c.533G-A transition (c.533G-A, NM_004181.4), resulting in an arg178-to-gln (R178Q) substitution at a highly conserved residue in the active site, and a c.647C-A transversion, resulting in an ala216-to-asp (A216D; 191342.0005) substitution in a beta-sheet that constitutes a hydrophobic core. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was found in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases, or in 961 controls. In the ExAC database, the c.647C-A variant was absent, whereas the c.533G-A variant was reported in heterozygous state in 10 individuals. In vitro functional expression studies in E. coli showed that the R178Q mutation resulted in a 4-fold increase in enzyme activity compared to controls. Because expression of the A216D mutation resulted in inclusion bodies, containing presumably misfolded, aggregated proteins, no activity assays of this mutant were possible. Patient fibroblasts showed decreased levels of the UCHL1 protein, at about 25 to 35% of controls, and consisted only of the R178Q mutant; the A216D mutant protein was not detected in patient cells, suggesting that it is degraded. Rydning et al. (2017) noted that the patients did not have cognitive dysfunction, and speculated that the nonsoluble A216D protein results in reduction of UCHL1 function and contributes to neurodegeneration, whereas the increased enzymatic activity of R178Q many compensate and even protect cognitive function. This family had previously been reported by Nyberg-Hansen and Refsum (1972). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 SPASTIC PARAPLEGIA 79B, AUTOSOMAL RECESSIVE</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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UCHL1, ALA216ASP
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<br />
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SNP: rs1057519600,
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ClinVar: RCV000417145
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the c.647C-A transversion (c.647C-A, NM_004181.4) in the UCHL1 gene, resulting in an ala216-to-asp (A216D) substitution, that was found in compound heterozygous state in 3 sibs with autosomal recessive spastic paraplegia-79B (SPG79B; 615491) by Rydning et al. (2017), see 191342.0004. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 SPASTIC PARAPLEGIA 79A, AUTOSOMAL DOMINANT, WITH ATAXIA</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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UCHL1, 1-BP DUP, NT64
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<br />
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SNP: rs1781001592,
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ClinVar: RCV001267902, RCV003225965
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In 6 affected members of a multigenerational family (family 1) with autosomal dominant spastic paraplegia-79A with ataxia (SPG79A; 620221), Park et al. (2022) identified a heterozygous 1-bp duplication (c.64_dup, NM_004181.4) in the UCHL1 gene, resulting in a frameshift and premature termination (Val22GlyfsTer39). The mutation, which was found by diagnostic exome and genome sequencing, segregated with the disorder in the family and was not present in the gnomAD database. Functional studies of the variant were not performed, but mass spectrometry analysis of patient fibroblasts showed a significant decrease in UCHL1 protein levels, suggesting that haploinsufficiency for this gene is the pathogenetic mechanism for this phenotype. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0007 SPASTIC PARAPLEGIA 79A, AUTOSOMAL DOMINANT, WITH ATAXIA</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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UCHL1, 16-BP DEL
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<br />
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SNP: rs1781070341,
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ClinVar: RCV001268796, RCV003152622
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 4 affected members of a multigenerational family (family 2) with autosomal dominant spastic paraplegia-79A with ataxia (SPG79A; 620221), Park et al. (2022) identified a heterozygous 16-bp deletion (c.349_364del, NM_004181.4) in the UCHL1 gene, resulting in a frameshift and premature termination (Phe117ArgfsTer33). The mutation, which was found by diagnostic exome and genome sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed, but mass spectrometry analysis of patient fibroblasts showed a significant decrease in UCHL1 protein levels, suggesting that haploinsufficiency for this gene is the pathogenetic mechanism for this phenotype. One of the patients in this family had an additional diagnosis of ALS (105400) and carried a heterozygous pathogenic missense mutation (D91A) in the SOD1 gene (147450). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 SPASTIC PARAPLEGIA 79A, AUTOSOMAL DOMINANT, WITH ATAXIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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UCHL1, GLN25TER
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<br />
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|
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ClinVar: RCV003152407
|
|
|
|
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 affected members of 2 unrelated families (families 6 and 7) with autosomal dominant spastic paraplegia-79A with ataxia (SPG79A; 620221), Park et al. (2022) identified a heterozygous c.73C-T transition (c.73C-T, NM_004181.4) in the UCHL1 gene, resulting in a gln25-to-ter (Q25X) substitution. The mutation, which was found by diagnostic exome and genome sequencing, segregated with the disorder in family 6 (information from members of family 7 was not available), and was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function and cause haploinsufficiency. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 SPASTIC PARAPLEGIA 79A, AUTOSOMAL DOMINANT, WITH ATAXIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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UCHL1, 4-BP DUP, NT95
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|
|
<br />
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|
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|
|
|
|
ClinVar: RCV003152408
|
|
|
|
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a mother and daughter (family 12) with autosomal dominant spastic paraplegia-79A with ataxia (SPG79A; 620221), Park et al. (2022) identified a heterozygous 4-bp duplication (c.95_98dup, NM_004181.4) in the UCHL1 gene, resulting in a frameshift and premature termination (Leu34GlyfsTer28). The mutation, which was found by diagnostic exome and genome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function and cause haploinsufficiency. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 SPASTIC PARAPLEGIA 79A, AUTOSOMAL DOMINANT, WITH ATAXIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
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|
|
|
UCHL1, 3-BP DUP, NT154
|
|
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|
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<br />
|
|
|
|
|
|
|
|
ClinVar: RCV002976538, RCV003152652
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 members of 3 unrelated families (families 15-17) with autosomal dominant spastic paraplegia-79A with ataxia (SPG79A; 620221), Park et al. (2022) identified a heterozygous 3-bp in-frame duplication (c.154_156dup, NM_004181.4) in the UCHL1 gene, resulting in the duplication of residue leu52 (Leu52dup). The mutation, which was found by extended screening for UCHL1 variants, segregated with the disorder in family 17 and was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to be pathogenic. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
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<div>
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<p />
|
|
</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Bilguvar, K., Tyagi, N. K., Ozkara, C., Tuysuz, B., Bakircioglu, M., Choi, M., Delil, S., Caglayan, A. O., Baranoski, J. F., Erturk, O., Yalcinkaya, C., Karacorlu, M., and 9 others.
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<strong>Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration.</strong>
|
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Proc. Nat. Acad. Sci. 110: 3489-3494, 2013.
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[Full Text: https://doi.org/10.1073/pnas.1222732110]
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Day, I. N. M., Hinks, L. J., Thompson, R. J.
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<strong>The structure of the human gene encoding protein gene product 9.5 (PGP9.5), a neuron-specific ubiquitin C-terminal hydrolase.</strong>
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Day, I. N. M., Thompson, R. J.
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<strong>Molecular cloning of cDNA coding for human PGP 9.5 protein: a novel cytoplasmic marker for neurones and neuroendocrine cells.</strong>
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FEBS Lett. 210: 157-160, 1987.
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Doran, J. F., Jackson, P., Kynoch, P., Thompson, R. J.
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<strong>Isolation of PGP 9.5, a new human neurone-specific protein detected by high resolution two-dimensional electrophoresis.</strong>
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J. Neurochem. 40: 1542-1547, 1983.
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[Full Text: https://doi.org/10.1111/j.1471-4159.1983.tb08124.x]
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Edwards, Y. H., Fox, M. F., Povey, S., Hinks, L. J., Day, I. N. M., Thompson, R. J.
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<strong>The gene for human neuron specific ubiquitin C-terminal hydrolase maps to chromosome 4p14. (Abstract)</strong>
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Cytogenet. Cell Genet. 58: 1886-1887, 1991.
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Gong, B., Cao, Z., Zheng, P., Vitolo, O. V., Liu, S., Staniszewski, A., Moolman, D., Zhang, H., Shelanski, M., Arancio, O.
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<strong>Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory.</strong>
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Cell 126: 775-788, 2006.
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[PubMed: 16923396]
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[Full Text: https://doi.org/10.1016/j.cell.2006.06.046]
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Healy, D. G., Abou-Sleiman, P. M., Casas, J. P., Ahmadi, K. R., Lynch, T., Gandhi, S., Muqit, M. M. K., Foltynie, T., Barker, R., Bhatia, K. P., Quinn, N. P., Lees, A. J., Gibson, J. M., Holton, J. L., Revesz, T., Goldstein, D. B., Wood, N. W.
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<strong>UCHL-1 is not a Parkinson's disease susceptibility gene.</strong>
|
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Ann. Neurol. 59: 627-633, 2006.
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[PubMed: 16450370]
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[Full Text: https://doi.org/10.1002/ana.20757]
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<p class="mim-text-font">
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Jackson, P., Thompson, R.F.
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<strong>The demonstration of new human brain-specific proteins by high-resolution two-dimensional polyacrylamide gel electrophoresis.</strong>
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J Neurol. Sci. 49: 429-438, 1981.
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[PubMed: 7217993]
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[Full Text: https://doi.org/10.1016/0022-510x(81)90032-0]
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</p>
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<p class="mim-text-font">
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Kabuta, T., Furuta, A., Aoki, S., Furuta, K., Wada, K.
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<strong>Aberrant interaction between Parkinson disease-associated mutant UCH-L1 and the lysosomal receptor for chaperone-mediated autophagy.</strong>
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J. Biol. Chem. 283: 23731-23738, 2008.
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[PubMed: 18550537]
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[Full Text: https://doi.org/10.1074/jbc.M801918200]
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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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Kurihara, L. J., Kikuchi, T., Wada, K., Tilghman, S. M.
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<strong>Loss of Uch-L1 and Uch-L3 leads to neurodegeneration, posterior paralysis and dysphagia.</strong>
|
|
Hum. Molec. Genet. 10: 1963-1970, 2001.
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[PubMed: 11555633]
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[Full Text: https://doi.org/10.1093/hmg/10.18.1963]
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</p>
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</li>
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<p class="mim-text-font">
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Kurihara, L. J., Semenova, E., Levorse, J. M., Tilghman, S. M.
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<strong>Expression and functional analysis of Uch-L3 during mouse development.</strong>
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Molec. Cell. Biol. 20: 2498-2504, 2000.
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[Full Text: https://doi.org/10.1128/MCB.20.7.2498-2504.2000]
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</p>
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<p class="mim-text-font">
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Kyratzi, E., Pavlaki, M., Stefanis, L.
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<strong>The S18Y polymorphic variant of UCH-L1 confers an antioxidant function to neuronal cells.</strong>
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Hum. Molec. Genet. 17: 2160-2171, 2008.
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[PubMed: 18411255]
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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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Leroy, E., Boyer, R., Auburger, G., Leube, B., Ulm, G., Mezey, E., Harta, G., Brownstein, M. J., Jonnalagada, S., Chernova, T., Dehejia, A., Lavedan, C., Gasser, T., Steinbach, P. J., Wilkinson, K. D., Polymeropoulos, M. H.
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<strong>The ubiquitin pathway in Parkinson's disease. (Letter)</strong>
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Nature 395: 451-452, 1998.
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[PubMed: 9774100]
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[Full Text: https://doi.org/10.1038/26652]
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</p>
|
|
</li>
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<li>
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<p class="mim-text-font">
|
|
Leroy, E., Boyer, R., Polymeropoulos, M. H.
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<strong>Intron-exon structure of ubiquitin C-terminal hydrolase-L1.</strong>
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DNA Res. 5: 397-400, 1998.
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[PubMed: 10048490]
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[Full Text: https://doi.org/10.1093/dnares/5.6.397]
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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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|
Lincoln, S., Vaughan, J., Wood, N., Baker, M., Adamson, J., Gwinn-Hardy, K., Lynch, T., Hardy, J., Farrer, M.
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<strong>Low frequency of pathogenic mutations in the ubiquitin carboxy-terminal hydrolase gene in familial Parkinson's disease.</strong>
|
|
Neuroreport 10: 427-429, 1999.
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|
|
|
|
|
[PubMed: 10203348]
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|
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|
|
[Full Text: https://doi.org/10.1097/00001756-199902050-00040]
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|
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</p>
|
|
</li>
|
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<li>
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|
<p class="mim-text-font">
|
|
Liu, Y., Fallon, L., Lashuel, H. A., Liu, Z., Lansbury, P. T., Jr.
|
|
<strong>The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility.</strong>
|
|
Cell 111: 209-218, 2002.
|
|
|
|
|
|
[PubMed: 12408865]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0092-8674(02)01012-7]
|
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|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
MacDonald, M. E.
|
|
<strong>Gadzooks!</strong>
|
|
Nature Genet. 23: 10-11, 1999.
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|
|
|
|
|
[PubMed: 10471487]
|
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|
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|
|
[Full Text: https://doi.org/10.1038/12602]
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|
|
</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Maraganore, D. M., Lesnick, T. G., Elbaz, A., Chartier-Harlin, M.-C., Gasser, T., Kruger, R., Hattori, N., Mellick, G. D., Quattrone, A., Satoh, J., Toda, T., Wang, J., Ioannidis, J. P. A., de Andrade, M., Rocca, W. A., UCHL1 Global Genetics Consortium.
|
|
<strong>UCHL1 is a Parkinson's disease susceptibility gene.</strong>
|
|
Ann. Neurol. 55: 512-521, 2004. Note: Erratum: Ann. Neurol. 55: 899 only, 2004.
|
|
|
|
|
|
[PubMed: 15048890]
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|
|
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|
|
[Full Text: https://doi.org/10.1002/ana.20017]
|
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|
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</p>
|
|
</li>
|
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Nyberg-Hansen, R., Refsum, S.
|
|
<strong>Spastic paraparesis associated with optic atrophy in monozygotic twins.</strong>
|
|
Acta Neurol. Scand. Suppl. 51: 261-263, 1972.
|
|
|
|
|
|
[PubMed: 4514348]
|
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|
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|
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</p>
|
|
</li>
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|
<li>
|
|
<p class="mim-text-font">
|
|
Osaka, H., Wang, Y.-L., Takada, K., Takizawa, S., Setsuie, R., Li, H., Sato, Y., Nishikawa, K., Sun, Y.-J., Sakurai, M., Harada, T., Hara, Y., Kimura, I., Chiba, S., Namikawa, K., Kiyama, H., Noda, M., Aoki, S., Wada, K.
|
|
<strong>Ubiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neuron.</strong>
|
|
Hum. Molec. Genet. 12: 1945-1958, 2003.
|
|
|
|
|
|
[PubMed: 12913066]
|
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|
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|
|
[Full Text: https://doi.org/10.1093/hmg/ddg211]
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</p>
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</li>
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<li>
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Anne M. Stumpf - updated : 01/27/2023<br>Cassandra L. Kniffin - updated : 01/23/2023<br>Bao Lige - updated : 03/19/2020<br>Cassandra L. Kniffin - updated : 02/15/2017<br>Cassandra L. Kniffin - updated : 10/28/2013<br>Jane Kelly - updated : 8/26/2011<br>Cassandra L. Kniffin - updated : 11/16/2010<br>Joanna S. Amberger - updated : 9/25/2009<br>Cassandra L. Kniffin - updated : 8/27/2009<br>Cassandra L. Kniffin - updated : 9/12/2007<br>Paul J. Converse - updated : 2/13/2007<br>George E. Tiller - updated : 5/25/2005<br>Cassandra L. Kniffin - updated : 6/8/2004<br>Stylianos E. Antonarakis - updated : 12/2/2002<br>Patricia A. Hartz - updated : 11/20/2002<br>George E. Tiller - updated : 1/31/2002<br>Victor A. McKusick - updated : 5/4/2001<br>Victor A. McKusick - updated : 8/30/1999<br>Victor A. McKusick - updated : 6/17/1999
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Victor A. McKusick : 8/6/1991
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