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<title>
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Entry
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- *607998 - TRIPEPTIDYL PEPTIDASE I; TPP1
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- OMIM
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<div id="mimSearch" class="hidden-print">
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<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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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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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*607998</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>
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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>
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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>
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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="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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</li>
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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>
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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/607998">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=ENSG00000166340;t=ENST00000299427" 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=1200" 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=607998" 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=ENSG00000166340;t=ENST00000299427" 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_000391" 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_000391" 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=607998" 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=06415&isoform_id=06415_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/TPP1" 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/2408232,4063841,5729770,15928808,34452679,37182127,50834228,62896557,62896635,108936017,119589091,119589092,189065466,194374209,194374537,194375009,194381332,194382040,194389174" 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/O14773" 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=1200" 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=ENSG00000166340;t=ENST00000299427" 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=TPP1" 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=TPP1" 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+1200" 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/TPP1" 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:1200" 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/1200" 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=chr11&hgg_gene=ENST00000532191.2&hgg_start=6612768&hgg_end=6619422&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:2073" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=607998[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=607998[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000166340" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=TPP1" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=TPP1" 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=TPP1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.ucl.ac.uk/ncl/" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=TPP1&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/PA26600" 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:2073" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1336194" 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/TPP1#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:1336194" 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/1200/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/OMIA001472/" 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=1200" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-6654" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
|
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</div>
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:607998" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
|
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</div>
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</a>
|
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</span>
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</span>
|
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:1200" 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=TPP1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
|
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 785301002<br />
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
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607998
|
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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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TRIPEPTIDYL PEPTIDASE I; TPP1
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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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TPP I<br />
|
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CLN2 GENE; CLN2
|
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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=TPP1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TPP1</a></em></strong>
|
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/11/136?start=-3&limit=10&highlight=136">11p15.4</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr11:6612768-6619422&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'})">11:6,612,768-6,619,422</a> </span>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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Phenotype <br /> MIM number
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Ceroid lipofuscinosis, neuronal, 2
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<a href="/entry/204500"> 204500 </a>
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Spinocerebellar ataxia, autosomal recessive 7
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<a href="/entry/609270"> 609270 </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/607998" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/607998" 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>TPP1 (<a href="https://enzyme.expasy.org/EC/3.4.14.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 3.4.14.9</a>) is a lysosomal exopeptidase that sequentially removes tripeptides from the N termini of proteins. It also has a minor endoprotease activity (<a href="#6" class="mim-tip-reference" title="Golabek, A. A., Walus, M., Wisniewski, K. E., Kida, E. <strong>Glycosaminoglycans modulate activation, activity, and stability of tripeptidyl-peptidase I in vitro and in vivo.</strong> J. Biol. Chem. 280: 7550-7561, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15582991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15582991</a>] [<a href="https://doi.org/10.1074/jbc.M412047200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15582991">Golabek et al., 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15582991" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#13" class="mim-tip-reference" title="Sleat, D. E., Donnelly, R. J., Lackland, H., Liu, C.-G., Sohar, I., Pullarkat, R. K., Lobel, P. <strong>Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid lipofuscinosis.</strong> Science 277: 1802-1805, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9295267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9295267</a>] [<a href="https://doi.org/10.1126/science.277.5333.1802" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9295267">Sleat et al. (1997)</a> used an approach applicable to other lysosomal storage diseases to identify the molecular basis of 'late infantile neuronal ceroid lipofuscinosis' (LINCL, or CLN2; <a href="/entry/204500">204500</a>). By purifying mannose 6-phosphate-containing glycoproteins, which are present on newly synthesized lysosomal enzymes, from normal brain by affinity chromatography and fractionation by SDS-polyacrylamide gel electrophoresis, they identified a single protein absent in CLN2 specimens. Comparisons with EST databases resulted in the assembly of a nearly complete sequence for the human CLN2 gene. Northern blot analysis showed 2 transcripts, and mRNA was detected in all tissues examined with highest levels in heart and placenta. The CLN2 transcript encodes a 563-residue protein with a molecular mass of 46 kD. Sequence comparisons suggested that this protein is a pepstatin-insensitive lysosomal peptidase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9295267" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Liu, C.-G., Sleat, D. E., Donnelly, R. J., Lobel, P. <strong>Structural organization and sequence of CLN2, the defective gene in classical late infantile neuronal ceroid lipofuscinosis.</strong> Genomics 50: 206-212, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9653647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9653647</a>] [<a href="https://doi.org/10.1006/geno.1998.5328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9653647">Liu et al. (1998)</a> reported the complete sequence of the CLN2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9653647" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#5" class="mim-tip-reference" title="Golabek, A. A., Kida, E., Walus, M., Wujek, P., Mehta, P., Wisniewski, K. E. <strong>Biosynthesis, glycosylation, and enzymatic processing in vivo of human tripeptidyl-peptidase I.</strong> J. Biol. Chem. 278: 7135-7145, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12488460/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12488460</a>] [<a href="https://doi.org/10.1074/jbc.M211872200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12488460">Golabek et al. (2003)</a> stated that TPP1 encodes a 563-amino acid preproenzyme with a 19-amino acid signal peptide and a 176-amino acid prodomain that are removed during maturation, yielding a 368-amino acid mature enzyme. TPP1 also contains 5 N-glycosylation sites. The proenzyme has an apparent molecular mass of 66 kD, and the mature enzyme has an apparent molecular mass of 46 to 48 kD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12488460" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#9" class="mim-tip-reference" title="Liu, C.-G., Sleat, D. E., Donnelly, R. J., Lobel, P. <strong>Structural organization and sequence of CLN2, the defective gene in classical late infantile neuronal ceroid lipofuscinosis.</strong> Genomics 50: 206-212, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9653647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9653647</a>] [<a href="https://doi.org/10.1006/geno.1998.5328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9653647">Liu et al. (1998)</a> determined that the CLN2 gene contains 13 exons and spans 6.65 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9653647" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Mapping</strong>
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<p>By genomewide analysis, <a href="#7" class="mim-tip-reference" title="Haines, J. L., Boustany, R.-M., N., Alroy, J., Auger, K. J., Shook, K. S., Terwedow, H., Lerner, T. J. <strong>Chromosomal localization of two genes underlying late-infantile neuronal ceroid lipofuscinosis.</strong> Neurogenetics 1: 217-222, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10737126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10737126</a>] [<a href="https://doi.org/10.1007/s100480050032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10737126">Haines et al. (1998)</a> mapped the CLN2 gene to chromosome 11p15.5. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10737126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Using immunostaining and confocal microscopy, <a href="#5" class="mim-tip-reference" title="Golabek, A. A., Kida, E., Walus, M., Wujek, P., Mehta, P., Wisniewski, K. E. <strong>Biosynthesis, glycosylation, and enzymatic processing in vivo of human tripeptidyl-peptidase I.</strong> J. Biol. Chem. 278: 7135-7145, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12488460/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12488460</a>] [<a href="https://doi.org/10.1074/jbc.M211872200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12488460">Golabek et al. (2003)</a> found that TPP1 was present in lysosomes of Chinese hamster ovary cells expressing human TPP1, similar to the endogenous enzyme in human cells. Immunoblot analysis of cell lysates revealed a 68-kD precursor that was converted to a mature 48-kD enzyme. Compounds affecting the pH of intracellular acidic compartments and those interfering with intracellular vesicular transport, as well as inhibition of fusion between late endosomes and lysosomes, hampered conversion of TPP1 proenzyme into the mature form, suggesting that this process takes place in lysosomes. Digestion of immunoprecipitated TPP1 with glycosidases or chemical inhibition of N-glycosylation in cells reduced the molecular mass of TPP1 proenzyme by about 10 kD, indicating that all 5 N-glycosylation sites of TPP1 are used. Further analysis showed that a serine protease sensitive to the inhibitor AEBSF participated in processing the TPP1 proenzyme to the mature form in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12488460" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>TPP1 proenzyme autoactivates in vitro via an unimolecular mechanism. <a href="#6" class="mim-tip-reference" title="Golabek, A. A., Walus, M., Wisniewski, K. E., Kida, E. <strong>Glycosaminoglycans modulate activation, activity, and stability of tripeptidyl-peptidase I in vitro and in vivo.</strong> J. Biol. Chem. 280: 7550-7561, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15582991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15582991</a>] [<a href="https://doi.org/10.1074/jbc.M412047200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15582991">Golabek et al. (2005)</a> found that high ionic strength and glycosaminoglycans (GAGs) increased yield (ionic strength) or yield and rate (GAGs) of TPP1 activation, enhanced degradation of liberated TPP1 prosegment fragments, and increased the pH of autoactivation up to 6.0. Although ionic strength and GAGs also inhibited TPP1 activity in vitro and in living cells, the degree of inhibition (from 20 to 60%) appeared to be of limited functional significance. Binding of TPP1 to GAGs improved its thermal stability and protected the enzyme against alkaline pH-induced denaturation in vitro and in vivo. <a href="#6" class="mim-tip-reference" title="Golabek, A. A., Walus, M., Wisniewski, K. E., Kida, E. <strong>Glycosaminoglycans modulate activation, activity, and stability of tripeptidyl-peptidase I in vitro and in vivo.</strong> J. Biol. Chem. 280: 7550-7561, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15582991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15582991</a>] [<a href="https://doi.org/10.1074/jbc.M412047200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15582991">Golabek et al. (2005)</a> concluded that TPP1 can be autoactivated in vivo at lysosomal pH and that GAGs can regulate this process. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15582991" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Oyama, H., Fujisawa, T., Suzuki, T., Dunn, B. M., Wlodawer, A., Oda, K. <strong>Catalytic residues and substrate specificity of recombinant human tripeptidyl peptidase I (CLN2).</strong> J. Biochem. 138: 127-134, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16091586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16091586</a>] [<a href="https://doi.org/10.1093/jb/mvi110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16091586">Oyama et al. (2005)</a> purified recombinant human TPP1 from virus-TPP1-infected silkworm pupae and found that it had been processed to the mature enzyme. Using a synthetic substrate, they showed that mature TPP1 was stable in a pH range of 2.5 to 5.0, with an optimum pH for activity of 4.0; activity was lost above pH 7. <a href="#12" class="mim-tip-reference" title="Oyama, H., Fujisawa, T., Suzuki, T., Dunn, B. M., Wlodawer, A., Oda, K. <strong>Catalytic residues and substrate specificity of recombinant human tripeptidyl peptidase I (CLN2).</strong> J. Biochem. 138: 127-134, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16091586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16091586</a>] [<a href="https://doi.org/10.1093/jb/mvi110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16091586">Oyama et al. (2005)</a> identified ser280, glu77, and asp81 (numbering of the mature enzyme) as catalytic residues by mutational analysis, inhibition studies, and sequence similarity with other family members. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16091586" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Neuronal Ceroid Lipofuscinosis 2</em></strong>
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<p>In patients with late-infantile onset of CLN2 (<a href="/entry/204500">204500</a>), <a href="#13" class="mim-tip-reference" title="Sleat, D. E., Donnelly, R. J., Lackland, H., Liu, C.-G., Sohar, I., Pullarkat, R. K., Lobel, P. <strong>Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid lipofuscinosis.</strong> Science 277: 1802-1805, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9295267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9295267</a>] [<a href="https://doi.org/10.1126/science.277.5333.1802" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9295267">Sleat et al. (1997)</a> identified mutations in the CLN2 gene (<a href="#0001">607998.0001</a>-<a href="#0004">607998.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9295267" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 2 unrelated patients, originally diagnosed with juvenile-onset CLN3 (<a href="/entry/204200">204200</a>) on the basis of age at onset, age at death, and inclusion morphology, <a href="#15" class="mim-tip-reference" title="Sleat, D. E., Gin, R. M., Sohar, I., Wisniewski, K., Sklower-Brooks, S., Pullarkat, R. K., Palmer, D. N., Lerner, T. J., Boustany, R.-M., Uldall, P., Siakotos, A. N., Donnelly, R. J., Lobel, P. <strong>Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder.</strong> Am. J. Hum. Genet. 64: 1511-1523, 1999. Note: Erratum: Am. J. Hum. Genet. 75: 1158 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10330339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10330339</a>] [<a href="https://doi.org/10.1086/302427" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10330339">Sleat et al. (1999)</a> identified a rare monoallelic mutation that resulted in an arg447-to-his (R447H) substitution in the CLN2 gene (<a href="#0005">607998.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10330339" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Defects in the CLN2 gene do not appear to be responsible for adult NCL (CLN4; <a href="/entry/204300">204300</a>), or Kufs disease, as CLN2 protease activities are the same as or higher than controls in adult NCL lymphoblasts (<a href="#17" class="mim-tip-reference" title="Sohar, I., Sleat, D. E., Jadot, M., Lobel, P. <strong>Biochemical characterization of a lysosomal protease deficient in classical late infantile neuronal ceroid lipofuscinosis (LINCL) and development of an enzyme-based assay for diagnosis and exclusion of LINCL in human specimens and animal models.</strong> J. Neurochem. 73: 700-711, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10428067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10428067</a>] [<a href="https://doi.org/10.1046/j.1471-4159.1999.0730700.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10428067">Sohar et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10428067" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#10" class="mim-tip-reference" title="Mole, S. E., Mitchison, H. M., Munroe, P. B. <strong>Molecular basis of the neuronal ceroid lipofuscinoses: mutations in CLN1, CLN2, CLN3, and CLN5.</strong> Hum. Mutat. 14: 199-215, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10477428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10477428</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)14:3<199::AID-HUMU3>3.0.CO;2-A" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10477428">Mole et al. (1999)</a> tabulated the reported mutations and polymorphisms in the CLN genes. The largest number of mutations, 26, had been identified in the CLN2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10477428" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#11" class="mim-tip-reference" title="Moore, S. J., Buckley, D. J., MacMillan, A., Marshall, H. D., Steele, L., Ray, P. N., Nawaz, Z., Baskin, B., Frecker, M., Carr, S. M., Ives, E., Parfrey, P. S. <strong>The clinical and genetic epidemiology of neuronal ceroid lipofuscinosis in Newfoundland.</strong> Clin. Genet. 74: 213-222, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18684116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18684116</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.01054.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18684116">Moore et al. (2008)</a> identified 5 different mutations in the CLN2 gene (see, e.g., <a href="#0007">607998.0007</a>) in affected members of 18 CLN2 families from Newfoundland. Among a total of 28 CLN families in this population, CLN2 showed the highest incidence of 1 in 11,161 live births. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18684116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#22" class="mim-tip-reference" title="Walus, M., Kida, E., Golabek, A. A. <strong>Functional consequences and rescue potential of pathogenic missense mutations in tripeptidyl peptidase I.</strong> Hum. Mutat. 31: 710-721, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20340139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20340139</a>] [<a href="https://doi.org/10.1002/humu.21251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20340139">Walus et al. (2010)</a> expressed 14 disease-associated missense TPP1 mutations (see, e.g., C365R, <a href="#0001">607998.0001</a>; R447H, <a href="#0005">607998.0005</a>; R206C, <a href="#0006">607998.0006</a>; G284V, <a href="#0007">607998.0007</a>; N286S, <a href="#0008">607998.0008</a>), into Chinese hamster ovary cells. Most variants showed folding abnormalities, resulting in obstructed transport to the lysosomes, prolonged half-life of the proenzyme, and significantly reduced or no enzymatic activity. Many of the mutant proteins were retained in the ER. The routes of removal of misfolded proteins by the cells varied, ranging from efficient degradation by the ubiquitin/proteasome system to abundant secretion. Two TPPI variants (V277M and R447H) demonstrated enhanced processing in response to folding improvement with molecular chaperones, and R447H showed a 5-fold increase in activity under permissive temperature conditions, suggesting that folding improvement strategies may ameliorate the function of some misfolding TPPI mutant proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20340139" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="mim-changed mim-change"><p>In 2 sibs, born to consanguineous parents, with CLN2, <a href="#18" class="mim-tip-reference" title="Steigerwald, C., Borsuk, J., Pappas, J., Galey, M., Scott, A., Devaney, J. M., Miller, D. E., Abreu, N. J. <strong>CLN2 disease resulting from a novel homozygous deep intronic splice variant in TPP1 discovered using long-read sequencing.</strong> Molec. Genet. Metab. 140: 107713, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37922835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37922835</a>] [<a href="https://doi.org/10.1016/j.ymgme.2023.107713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37922835">Steigerwald et al. (2023)</a> identified a homozygous splice site mutation in the TPP1 gene (c.1146-199G-A, <a href="#0012">607998.0012</a>). The mutation was identified by long-read sequencing (LRS) of the TPP1 gene. TPP1 enzyme activity was absent in leukocytes from one of the sibs and in a CVS sample and blood spot from the other sib. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37922835" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<p><strong><em>Spinocerebellar Ataxia 7, Autosomal Recessive</em></strong>
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<p>In affected members of a Dutch family with autosomal recessive spinocerebellar ataxia-7 (SCAR7; <a href="/entry/609270">609270</a>), originally reported by <a href="#3" class="mim-tip-reference" title="Breedveld, G. J., van Wetten, B., te Raa, G. D., Brusse, E., van Swieten, J. C., Oostra, B. A., Maat-Kievit, J. A. <strong>A new locus for a childhood onset, slowly progressive autosomal recessive spinocerebellar ataxia maps to chromosome 11p15. (Letter)</strong> J. Med. Genet. 41: 858-866, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15520412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15520412</a>] [<a href="https://doi.org/10.1136/jmg.2004.019232" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15520412">Breedveld et al. (2004)</a>, <a href="#20" class="mim-tip-reference" title="Sun, Y., Almomani, R., Breedveld, G. J., Santen, G. W. E., Aten, E., Lefeber, D. J., Hoff, J. I., Brusse, E., Verheijen, F. W., Verdijk, R. M., Kriek, M., Oostra, B., Breuning, M. H., Losekoot, M., den Dunnen, J. T., van de Warrenburg, B. P., Maat-Kievit, A. J. A. <strong>Autosomal recessive spinocerebellar ataxia 7 (SCAR7) is caused by variants in TPP1, the gene involved in classic late-infantile neuronal ceroid lipofuscinosis 2 disease (CLN2 disease).</strong> Hum. Mutat. 34: 706-713, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23418007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23418007</a>] [<a href="https://doi.org/10.1002/humu.22292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23418007">Sun et al. (2013)</a> identified compound heterozygous mutations in the TPP1 gene: a splice site mutation resulting in premature termination (<a href="#0004">607998.0004</a>) and a missense mutation (V466G; <a href="#0010">607998.0010</a>). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. An unrelated Dutch woman with the disorder was also found to be compound heterozygous for these 2 mutations, although a founder effect could not be confirmed. Residual TPP1 activity in patient lymphocytes was 10 to 15% that of controls, with 5% activity in patient fibroblasts. Electron microscopic analysis of 1 patient's skin fibroblasts showed some granular osmiophilic deposits (GROD) and fingerprint profiles, but no curvilinear profiles. Analysis of the unrelated Dutch woman's fibroblasts showed no abnormalities. <a href="#20" class="mim-tip-reference" title="Sun, Y., Almomani, R., Breedveld, G. J., Santen, G. W. E., Aten, E., Lefeber, D. J., Hoff, J. I., Brusse, E., Verheijen, F. W., Verdijk, R. M., Kriek, M., Oostra, B., Breuning, M. H., Losekoot, M., den Dunnen, J. T., van de Warrenburg, B. P., Maat-Kievit, A. J. A. <strong>Autosomal recessive spinocerebellar ataxia 7 (SCAR7) is caused by variants in TPP1, the gene involved in classic late-infantile neuronal ceroid lipofuscinosis 2 disease (CLN2 disease).</strong> Hum. Mutat. 34: 706-713, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23418007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23418007</a>] [<a href="https://doi.org/10.1002/humu.22292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23418007">Sun et al. (2013)</a> suggested that V466G yields a hypomorphic allele with residual functional TPP1 activity, which likely resulted in a later age at onset and less severe phenotype in patients with SCAR7 compared to patients with CLN2. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15520412+23418007" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 an 11-year-old girl with SCAR7, <a href="#4" class="mim-tip-reference" title="Dy, M. E., Sims, K. B., Friedman, J. <strong>TPP1 deficiency: rare cause of isolated childhood-onset progressive ataxia.</strong> Neurology 85: 1259-1261, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26224725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26224725</a>] [<a href="https://doi.org/10.1212/WNL.0000000000001876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26224725">Dy et al. (2015)</a> identified compound heterozygous mutations in the TPP1 gene: the common splice site mutation (<a href="#0004">607998.0004</a>) and a missense mutation (E343D; <a href="#0011">607998.0011</a>). The mutations were found by whole-exome sequencing. TPP1 activity in patient cells was significantly decreased (3 to 15%) compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26224725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Bessa, C, Teixeira, C. A., Dias, A., Alves, M., Rocha, S., Lacerda, L., Loureiro, L., Guimaraes, A., Ribeiro, M. G. <strong>CLN2/TPP1 deficiency: the novel mutation IVS7-10A-G causes intron retention and is associated with a mild disease phenotype.</strong> Molec. Genet. Metab. 93: 66-73, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17959406/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17959406</a>] [<a href="https://doi.org/10.1016/j.ymgme.2007.08.124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17959406">Bessa et al. (2008)</a> reported a 40-year-old Portuguese man with a mild protracted form of CLN2 who was homozygous for a mutation that created a potential acceptor site in intron 7 of the TPP1 gene (IVS7AS-10A-G; <a href="#0009">607998.0009</a>), predicted to result in a protein with 3 extra amino acids between codons 295 and 296 and not affecting the wildtype splice site. The patient had onset at age 10 years of progressive cognitive and motor dysfunction and seizures. Western blot analysis detected a 60% reduction in overall TPP1 protein levels, suggesting that the mutant protein had decreased stability. <a href="#2" class="mim-tip-reference" title="Bessa, C, Teixeira, C. A., Dias, A., Alves, M., Rocha, S., Lacerda, L., Loureiro, L., Guimaraes, A., Ribeiro, M. G. <strong>CLN2/TPP1 deficiency: the novel mutation IVS7-10A-G causes intron retention and is associated with a mild disease phenotype.</strong> Molec. Genet. Metab. 93: 66-73, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17959406/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17959406</a>] [<a href="https://doi.org/10.1016/j.ymgme.2007.08.124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17959406">Bessa et al. (2008)</a> concluded that the mutant protein retained enzyme activity, which was consistent with the milder phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17959406" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#16" class="mim-tip-reference" title="Sleat, D. E., Wiseman, J. A., El-Banna, M., Kim, K.-H., Mao, Q., Price, S., Macauley, S. L., Sidman, R. L., Shen, M. M., Zhao, Q., Passini, M. A., Davidson, B. L., Stewart, G. R., Lobel, P. <strong>A mouse model of classical late-infantile neuronal ceroid lipofuscinosis based on targeted disruption of the CLN2 gene results in a loss of tripeptidyl-peptidase I activity and progressive neurodegeneration.</strong> J. Neurosci. 24: 9117-9126, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15483130/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15483130</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15483130[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1523/JNEUROSCI.2729-04.2004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15483130">Sleat et al. (2004)</a> found that mice with targeted homozygous disruption of the Tpp1 gene were viable and healthy at birth, but developed progressive neurologic deterioration around 7 weeks of age. Clinical features included tremor and ataxia, and neuropathologic examination showed extensive neuronal pathology with accumulation of autofluorescent cytoplasmic storage material within the lysosomal-endosomal compartment, loss of cerebellar Purkinje cells, and widespread axonal degeneration. The life span of mutant mice was significantly decreased compared to wildtype. The findings recapitulated the features of human CLN2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15483130" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Sleat, D. E., El-Banna, M., Sohar, I., Kim, K.-H., Dobrenis, K., Walkley, S. U., Lobel, P. <strong>Residual levels of tripeptidyl-peptidase I activity dramatically ameliorate disease in late-infantile neuronal ceroid lipofuscinosis.</strong> Molec. Genet. Metab. 94: 222-233, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18343701/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18343701</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18343701[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ymgme.2008.01.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18343701">Sleat et al. (2008)</a> generated mouse models of CLN2 with different hypomorphic Tpp1 mutations. Mice who were homozygous for R446H, which is analogous to human R447H (<a href="#0005">607998.0005</a>), had approximately 6% residual brain activity of Tpp1. Mice who were compound heterozygous for the R446H allele and a null allele had about 3% residual Tpp1 activity and showed delayed disease onset and longer survival compared to homozygous-null mice. Homozygosity for R446H resulted in dramatic attenuation of disease, with even further expanded life span. The findings indicated that residual levels of Tpp1 can ameliorate disease, which has potential therapeutic implications for humans with the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18343701" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs119455953 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119455953;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/rs119455953?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=rs119455953" 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=rs119455953" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 unrelated patients with late-infantile onset of neuronal ceroid lipofuscinosis-2 (CLN2; <a href="/entry/204500">204500</a>), <a href="#13" class="mim-tip-reference" title="Sleat, D. E., Donnelly, R. J., Lackland, H., Liu, C.-G., Sohar, I., Pullarkat, R. K., Lobel, P. <strong>Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid lipofuscinosis.</strong> Science 277: 1802-1805, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9295267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9295267</a>] [<a href="https://doi.org/10.1126/science.277.5333.1802" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9295267">Sleat et al. (1997)</a> identified different mutation at the cys365 codon in the CLN2 gene. In 1 patient, a monoallelic T-to-C transition resulted in a cys365-to-arg substitution (C365R); presumably, the defect in this patient was compound heterozygous and there was an additional, unidentified mutation. In the second patient the mutation was homozygous (<a href="#0002">607998.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9295267" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 patient with late-infantile onset of neuronal ceroid lipofuscinosis-2 (CLN2; <a href="/entry/204500">204500</a>), <a href="#13" class="mim-tip-reference" title="Sleat, D. E., Donnelly, R. J., Lackland, H., Liu, C.-G., Sohar, I., Pullarkat, R. K., Lobel, P. <strong>Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid lipofuscinosis.</strong> Science 277: 1802-1805, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9295267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9295267</a>] [<a href="https://doi.org/10.1126/science.277.5333.1802" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9295267">Sleat et al. (1997)</a> identified homozygosity for a G-to-A transition in the TPP1 gene that resulted in a cys365-to-tyr (C365Y) amino acid substitution. The authors identified a different mutation at the same codon in heterozygosity in another patient (<a href="#0002">607998.0002</a>). Since this cysteine proved to be involved in disulfide bonding, <a href="#13" class="mim-tip-reference" title="Sleat, D. E., Donnelly, R. J., Lackland, H., Liu, C.-G., Sohar, I., Pullarkat, R. K., Lobel, P. <strong>Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid lipofuscinosis.</strong> Science 277: 1802-1805, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9295267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9295267</a>] [<a href="https://doi.org/10.1126/science.277.5333.1802" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9295267">Sleat et al. (1997)</a> predicted that these mutations are probably highly disruptive given the role of disulfide bonds in establishing and maintaining protein structure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9295267" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs119455955 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119455955;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/rs119455955?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=rs119455955" 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=rs119455955" 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=RCV000002762 OR RCV000189769 OR RCV000210605 OR RCV000230952 OR RCV000763267 OR RCV001813939 OR RCV004554580" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002762, RCV000189769, RCV000210605, RCV000230952, RCV000763267, RCV001813939, RCV004554580" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002762...</a>
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<p>In 2 sibs with late-infantile onset of neuronal ceroid lipofuscinosis-2 (CLN2; <a href="/entry/204500">204500</a>), <a href="#13" class="mim-tip-reference" title="Sleat, D. E., Donnelly, R. J., Lackland, H., Liu, C.-G., Sohar, I., Pullarkat, R. K., Lobel, P. <strong>Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid lipofuscinosis.</strong> Science 277: 1802-1805, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9295267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9295267</a>] [<a href="https://doi.org/10.1126/science.277.5333.1802" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9295267">Sleat et al. (1997)</a> found compound heterozygosity for a C-to-T transition that resulted in the conversion of codon 208 (CGA) to a stop codon (TGA). In the other allele, the conserved AG of the intronic 3-prime splice junction sequence was changed to AC, which was predicted to result in intron splicing (<a href="#0004">607998.0004</a>). Each parent possessed a single different mutant allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9295267" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs56144125 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs56144125;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/rs56144125?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=rs56144125" 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=rs56144125" 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=RCV000002763 OR RCV000074608 OR RCV000189765 OR RCV000210689 OR RCV000228119 OR RCV000763268 OR RCV004554581" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002763, RCV000074608, RCV000189765, RCV000210689, RCV000228119, RCV000763268, RCV004554581" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002763...</a>
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<p><a href="#13" class="mim-tip-reference" title="Sleat, D. E., Donnelly, R. J., Lackland, H., Liu, C.-G., Sohar, I., Pullarkat, R. K., Lobel, P. <strong>Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid lipofuscinosis.</strong> Science 277: 1802-1805, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9295267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9295267</a>] [<a href="https://doi.org/10.1126/science.277.5333.1802" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9295267">Sleat et al. (1997)</a> described compound heterozygosity in 2 sibs with late-infantile onset of neuronal ceroid lipofuscinosis-2 (CLN2; <a href="/entry/204500">204500</a>). One allele of the CLN2 gene carried the R208X nonsense mutation (<a href="#0003">607998.0003</a>); the other allele showed a splice site mutation, a G-to-C transversion of the consensus AG 3-prime splice acceptor site immediately preceding 523T of the cDNA sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9295267" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a Dutch family with autosomal recessive spinocerebellar ataxia-7 (SCAR7; <a href="/entry/609270">609270</a>), originally reported by <a href="#3" class="mim-tip-reference" title="Breedveld, G. J., van Wetten, B., te Raa, G. D., Brusse, E., van Swieten, J. C., Oostra, B. A., Maat-Kievit, J. A. <strong>A new locus for a childhood onset, slowly progressive autosomal recessive spinocerebellar ataxia maps to chromosome 11p15. (Letter)</strong> J. Med. Genet. 41: 858-866, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15520412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15520412</a>] [<a href="https://doi.org/10.1136/jmg.2004.019232" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15520412">Breedveld et al. (2004)</a>, <a href="#20" class="mim-tip-reference" title="Sun, Y., Almomani, R., Breedveld, G. J., Santen, G. W. E., Aten, E., Lefeber, D. J., Hoff, J. I., Brusse, E., Verheijen, F. W., Verdijk, R. M., Kriek, M., Oostra, B., Breuning, M. H., Losekoot, M., den Dunnen, J. T., van de Warrenburg, B. P., Maat-Kievit, A. J. A. <strong>Autosomal recessive spinocerebellar ataxia 7 (SCAR7) is caused by variants in TPP1, the gene involved in classic late-infantile neuronal ceroid lipofuscinosis 2 disease (CLN2 disease).</strong> Hum. Mutat. 34: 706-713, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23418007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23418007</a>] [<a href="https://doi.org/10.1002/humu.22292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23418007">Sun et al. (2013)</a> identified compound heterozygous mutations in the TPP1 gene: a G-to-C transversion in intron 5 (c.509-1G-C) resulting in a frameshift and premature termination (Val170GlyfsTer29), and V466G (<a href="#0010">607998.0010</a>). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. An unrelated Dutch woman with the disorder was also found to be compound heterozygous for these 2 mutations, although a founder effect could not be confirmed. Residual TPP1 activity in patient lymphocytes was 10 to 15% that of controls, with 5% activity in patient fibroblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15520412+23418007" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 an 11-year-old girl with SCAR7, <a href="#4" class="mim-tip-reference" title="Dy, M. E., Sims, K. B., Friedman, J. <strong>TPP1 deficiency: rare cause of isolated childhood-onset progressive ataxia.</strong> Neurology 85: 1259-1261, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26224725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26224725</a>] [<a href="https://doi.org/10.1212/WNL.0000000000001876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26224725">Dy et al. (2015)</a> identified compound heterozygous mutations in the TPP1 gene: c.509-1G-C, and a missense mutation (E343D; <a href="#0011">607998.0011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26224725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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TPP1, ARG447HIS
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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> rs119455956 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119455956;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/rs119455956?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=rs119455956" 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=rs119455956" 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=RCV000002764 OR RCV000189790 OR RCV005049313" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002764, RCV000189790, RCV005049313" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002764...</a>
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<p>In 2 unrelated patients with juvenile-onset neuronal ceroid lipofuscinosis-2 (CLN2; <a href="/entry/204500">204500</a>), <a href="#15" class="mim-tip-reference" title="Sleat, D. E., Gin, R. M., Sohar, I., Wisniewski, K., Sklower-Brooks, S., Pullarkat, R. K., Palmer, D. N., Lerner, T. J., Boustany, R.-M., Uldall, P., Siakotos, A. N., Donnelly, R. J., Lobel, P. <strong>Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder.</strong> Am. J. Hum. Genet. 64: 1511-1523, 1999. Note: Erratum: Am. J. Hum. Genet. 75: 1158 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10330339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10330339</a>] [<a href="https://doi.org/10.1086/302427" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10330339">Sleat et al. (1999)</a> identified a rare monoallelic mutation that resulted in an arg447-to-his (R447H) substitution in the CLN2 gene. Both of these patients were compound heterozygous, with either a monoallelic common splice junction mutation (<a href="#0004">607998.0004</a>) or the arg208-to-ter mutation (R208X; <a href="#0003">607998.0003</a>). Both patients were originally diagnosed with juvenile-onset CLN3 (<a href="/entry/204200">204200</a>) on the basis of age at onset, age at death, and inclusion morphology. <a href="#15" class="mim-tip-reference" title="Sleat, D. E., Gin, R. M., Sohar, I., Wisniewski, K., Sklower-Brooks, S., Pullarkat, R. K., Palmer, D. N., Lerner, T. J., Boustany, R.-M., Uldall, P., Siakotos, A. N., Donnelly, R. J., Lobel, P. <strong>Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder.</strong> Am. J. Hum. Genet. 64: 1511-1523, 1999. Note: Erratum: Am. J. Hum. Genet. 75: 1158 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10330339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10330339</a>] [<a href="https://doi.org/10.1086/302427" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10330339">Sleat et al. (1999)</a> considered it likely that the R447H mutation caused incomplete loss of function of the CLN2 protease, resulting in the protracted phenotype. The findings indicated that an attenuated form of CLN2 (i.e., with juvenile onset) may not be correctly diagnosed or may be confused with other later-onset neurodegenerative disorders. Such observations are not uncommon with other lysosomal storage diseases, in which missense mutations result in a partial dysfunction and subsequent mild or protracted phenotype. The possible phenotype of an individual homozygous for the R447H allele remained unknown. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10330339" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs28940573 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940573;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/rs28940573?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=rs28940573" 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=rs28940573" 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=RCV000002765 OR RCV001382645" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002765, RCV001382645" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002765...</a>
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<p>In a family with first-cousin parents, <a href="#1" class="mim-tip-reference" title="Berry-Kravis, E., Sleat, D. E., Sohar, I., Meyer, P., Donnelly, R., Lobel, P. <strong>Prenatal testing for late infantile neuronal ceroid lipofuscinosis.</strong> Ann. Neurol. 47: 254-257, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10665500/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10665500</a>]" pmid="10665500">Berry-Kravis et al. (2000)</a> demonstrated a 3664C-T transition in the CLN2 gene, resulting in an arg206-to-cys mutation (R206C), as the cause of late-infantile onset of neuronal ceroid lipofuscinosis-2 (CLN2; <a href="/entry/204500">204500</a>) and used the mutation successfully for prenatal diagnosis, demonstrating that the fetus at risk was homozygous for the wildtype alleles. The homozygous proband had developed seizures at age 3 years and was unable to ambulate independently by age 5. Electron microscopy performed on a skin biopsy demonstrated curvilinear bodies typical of CLN2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10665500" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs119455957 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119455957;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/rs119455957?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=rs119455957" 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=rs119455957" 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=RCV000002766 OR RCV000531153 OR RCV000763266" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002766, RCV000531153, RCV000763266" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002766...</a>
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<p>In affected members of 11 of 20 Canadian families with late-infantile onset of neuronal ceroid lipofuscinosis-2 (CLN2; <a href="/entry/204500">204500</a>), <a href="#8" class="mim-tip-reference" title="Ju, W., Zhong, R., Moore, S., Moroziewicz, D., Currie, J. R., Parfrey, P., Brown, W. T., Zhong, N. <strong>Identification of novel CLN2 mutations shows Canadian specific NCL2 alleles.</strong> J. Med. Genet. 39: 822-825, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12414822/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12414822</a>] [<a href="https://doi.org/10.1136/jmg.39.11.822" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12414822">Ju et al. (2002)</a> identified a gly284-to-val (G284V) mutation in the CLN2 gene, which represented 55% and 32.5% of families and alleles, respectively, in this study. The authors referred to this mutation as the Canadian mutation, noting that it had not been found in any other population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12414822" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Moore, S. J., Buckley, D. J., MacMillan, A., Marshall, H. D., Steele, L., Ray, P. N., Nawaz, Z., Baskin, B., Frecker, M., Carr, S. M., Ives, E., Parfrey, P. S. <strong>The clinical and genetic epidemiology of neuronal ceroid lipofuscinosis in Newfoundland.</strong> Clin. Genet. 74: 213-222, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18684116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18684116</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.01054.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18684116">Moore et al. (2008)</a> identified a homozygous G284V mutation in affected members from 5 families from Newfoundland with CLN2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18684116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs119455958 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119455958;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/rs119455958?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=rs119455958" 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=rs119455958" 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=RCV000002767 OR RCV001851588" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002767, RCV001851588" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002767...</a>
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<p>In 2 unrelated female patients of Kurdish ethnicity with late infantile neuronal ceroid lipofuscinosis-2 (CLN2; <a href="/entry/204500">204500</a>), <a href="#19" class="mim-tip-reference" title="Steinfeld, R., Heim, P., von Gregory, H., Meyer, K., Ullrich, K., Goebel, H. H., Kohlschutter, A. <strong>Late infantile neuronal ceroid lipofuscinosis: quantitative description of the clinical course in patients with CLN2 mutations.</strong> Am. J. Med. Genet. 112: 347-354, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12376936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12376936</a>] [<a href="https://doi.org/10.1002/ajmg.10660" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12376936">Steinfeld et al. (2002)</a> identified a homozygous A-to-G transition at nucleotide 857 in exon 7 of the TPP1 gene. The mutation resulted in an asn286-to-ser (N286S) substitution that altered 1 of 5 N-glycosylation sites in the TPP1 protein. Both patients had a more protracted clinical course compared with patients with typical disease progression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12376936" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 transient transfection analysis in human embryonic kidney cells, <a href="#21" class="mim-tip-reference" title="Tsiakas, K., Steinfeld, R., Storch, S., Ezaki, J., Lukacs, Z., Kominami, E., Kohlschutter, A., Ullrich, K., Braulke, T. <strong>Mutation of the glycosylated asparagine residue 286 in human CLN2 protein results in loss of enzymatic activity.</strong> Glycobiology 14: 1C-5C, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14736728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14736728</a>] [<a href="https://doi.org/10.1093/glycob/cwh054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14736728">Tsiakas et al. (2004)</a> found that TPP1 containing the N286S mutation was synthesized and sorted in the Golgi like wildtype TPP1, but it was expressed at a lower level and was enzymatically inactive. TPP1 with the N286 mutation had an apparent molecular mass 2 kD lower than that of wildtype TPP1, whereas deglycosylation of mutant and wildtype TPP1 led to proteins of the same size. <a href="#21" class="mim-tip-reference" title="Tsiakas, K., Steinfeld, R., Storch, S., Ezaki, J., Lukacs, Z., Kominami, E., Kohlschutter, A., Ullrich, K., Braulke, T. <strong>Mutation of the glycosylated asparagine residue 286 in human CLN2 protein results in loss of enzymatic activity.</strong> Glycobiology 14: 1C-5C, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14736728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14736728</a>] [<a href="https://doi.org/10.1093/glycob/cwh054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14736728">Tsiakas et al. (2004)</a> concluded that TPP1 with the N286S mutation lacks 1 oligosaccharide chain, resulting in enzymatic inactivation and possibly prelysosomal protein degradation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14736728" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs755445790 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs755445790;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/rs755445790?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=rs755445790" 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=rs755445790" 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=RCV000002768 OR RCV000359791 OR RCV005049314" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002768, RCV000359791, RCV005049314" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002768...</a>
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<p>In a 40-year-old Portuguese man with a mild protracted form of neuronal ceroid lipofuscinosis-2 (CLN2; <a href="/entry/204500">204500</a>), <a href="#2" class="mim-tip-reference" title="Bessa, C, Teixeira, C. A., Dias, A., Alves, M., Rocha, S., Lacerda, L., Loureiro, L., Guimaraes, A., Ribeiro, M. G. <strong>CLN2/TPP1 deficiency: the novel mutation IVS7-10A-G causes intron retention and is associated with a mild disease phenotype.</strong> Molec. Genet. Metab. 93: 66-73, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17959406/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17959406</a>] [<a href="https://doi.org/10.1016/j.ymgme.2007.08.124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17959406">Bessa et al. (2008)</a> identified a homozygous A-to-G transition in intron 7 (IVS7AS-10A-G) of the TPP1 gene, which created a potential acceptor site predicted to result in 3 extra amino acids between codons 295 and 296 and not affecting the wildtype splice site. At age 10 years, the patient had onset of progressive cognitive and motor dysfunction and seizures. Leukocytes and fibroblasts showed decreased TPP1 activity compared to controls, but activity was about 2-fold higher than that associated with TPP1-null mutations. Northern blot analysis found normal levels of correctly spliced CLN2 mRNA in patient fibroblasts, but cDNA sequencing showed the retention of 9 nucleotides from intron 7, showing that the alternative splice site was used. Western blot analysis detected a 60% reduction in overall TPP1 protein levels, suggesting that the mutant protein had decreased stability. Each unaffected parent was heterozygous for the mutation, which was not found in 100 control chromosomes. <a href="#2" class="mim-tip-reference" title="Bessa, C, Teixeira, C. A., Dias, A., Alves, M., Rocha, S., Lacerda, L., Loureiro, L., Guimaraes, A., Ribeiro, M. G. <strong>CLN2/TPP1 deficiency: the novel mutation IVS7-10A-G causes intron retention and is associated with a mild disease phenotype.</strong> Molec. Genet. Metab. 93: 66-73, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17959406/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17959406</a>] [<a href="https://doi.org/10.1016/j.ymgme.2007.08.124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17959406">Bessa et al. (2008)</a> concluded that the mutant protein retained enzyme activity, which was consistent with the milder phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17959406" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 7</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> rs398122959 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122959;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/rs398122959?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=rs398122959" 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=rs398122959" 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=RCV000074609 OR RCV001529105" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000074609, RCV001529105" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000074609...</a>
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<p>In affected members of a Dutch family with autosomal recessive spinocerebellar ataxia-7 (SCAR7; <a href="/entry/609270">609270</a>), originally reported by <a href="#3" class="mim-tip-reference" title="Breedveld, G. J., van Wetten, B., te Raa, G. D., Brusse, E., van Swieten, J. C., Oostra, B. A., Maat-Kievit, J. A. <strong>A new locus for a childhood onset, slowly progressive autosomal recessive spinocerebellar ataxia maps to chromosome 11p15. (Letter)</strong> J. Med. Genet. 41: 858-866, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15520412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15520412</a>] [<a href="https://doi.org/10.1136/jmg.2004.019232" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15520412">Breedveld et al. (2004)</a>, <a href="#20" class="mim-tip-reference" title="Sun, Y., Almomani, R., Breedveld, G. J., Santen, G. W. E., Aten, E., Lefeber, D. J., Hoff, J. I., Brusse, E., Verheijen, F. W., Verdijk, R. M., Kriek, M., Oostra, B., Breuning, M. H., Losekoot, M., den Dunnen, J. T., van de Warrenburg, B. P., Maat-Kievit, A. J. A. <strong>Autosomal recessive spinocerebellar ataxia 7 (SCAR7) is caused by variants in TPP1, the gene involved in classic late-infantile neuronal ceroid lipofuscinosis 2 disease (CLN2 disease).</strong> Hum. Mutat. 34: 706-713, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23418007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23418007</a>] [<a href="https://doi.org/10.1002/humu.22292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23418007">Sun et al. (2013)</a> identified compound heterozygous mutations in the TPP1 gene: a c.1397T-G transversion, resulting in a val466-to-gly (V466G) substitution at a highly conserved residue, and splice site mutation (c.509-1G-C; <a href="#0004">607998.0004</a>), resulting in a frameshift and premature termination (Val170GlyfsTer29). The mutations were found by whole-exome sequencing, confirmed by Sanger sequencing, and segregated with the disorder in the family. An unrelated Dutch woman with the disorder was also found to be compound heterozygous for these 2 mutations, although a founder effect could not be confirmed. Residual TPP1 activity in patient lymphocytes was 10 to 15% that of controls, with 5% activity in patient fibroblasts. Electron microscopic analysis of 1 of the affected family member's skin fibroblasts showed some granular osmiophilic deposits (GROD) and fingerprint profiles, but no curvilinear profiles. Analysis of the unrelated Dutch woman's fibroblasts showed no abnormalities. <a href="#20" class="mim-tip-reference" title="Sun, Y., Almomani, R., Breedveld, G. J., Santen, G. W. E., Aten, E., Lefeber, D. J., Hoff, J. I., Brusse, E., Verheijen, F. W., Verdijk, R. M., Kriek, M., Oostra, B., Breuning, M. H., Losekoot, M., den Dunnen, J. T., van de Warrenburg, B. P., Maat-Kievit, A. J. A. <strong>Autosomal recessive spinocerebellar ataxia 7 (SCAR7) is caused by variants in TPP1, the gene involved in classic late-infantile neuronal ceroid lipofuscinosis 2 disease (CLN2 disease).</strong> Hum. Mutat. 34: 706-713, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23418007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23418007</a>] [<a href="https://doi.org/10.1002/humu.22292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23418007">Sun et al. (2013)</a> suggested that V466G yields a hypomorphic allele with residual functional TPP1 activity, which likely resulted in a later age at onset and less severe phenotype in patients with SCAR7 compared to patients with neuronal ceroid lipofuscinosis-2 (CLN2; <a href="/entry/204500">204500</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15520412+23418007" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs886037833 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886037833;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=rs886037833" 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=rs886037833" 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=RCV000211004 OR RCV002509307" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000211004, RCV002509307" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000211004...</a>
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<p>In an 11-year-old girl with autosomal recessive spinocerebellar ataxia-7 (SCAR7; <a href="/entry/609270">609270</a>), <a href="#4" class="mim-tip-reference" title="Dy, M. E., Sims, K. B., Friedman, J. <strong>TPP1 deficiency: rare cause of isolated childhood-onset progressive ataxia.</strong> Neurology 85: 1259-1261, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26224725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26224725</a>] [<a href="https://doi.org/10.1212/WNL.0000000000001876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26224725">Dy et al. (2015)</a> identified compound heterozygous mutations in the TPP1 gene: a c.1029G-C transversion resulting in a glu343-to-asp (E343D) substitution at a highly conserved residue, and the common splice site mutation (c.509-1G-C; <a href="#0004">607998.0004</a>). The mutations were found by whole-exome sequencing. TPP1 activity in patient cells was significantly decreased (3 to 15%) compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26224725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0012 CEROID LIPOFUSCINOSIS, NEURONAL, 2</strong>
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TPP1, IVS9AS, G-A, -199
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003486538" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003486538" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003486538</a>
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<div class="mim-changed mim-change"><p>In 2 sibs, born to consanguineous parents, with neuronal ceroid lipofuscinosis-2 (CLN2; <a href="/entry/204500">204500</a>), <a href="#18" class="mim-tip-reference" title="Steigerwald, C., Borsuk, J., Pappas, J., Galey, M., Scott, A., Devaney, J. M., Miller, D. E., Abreu, N. J. <strong>CLN2 disease resulting from a novel homozygous deep intronic splice variant in TPP1 discovered using long-read sequencing.</strong> Molec. Genet. Metab. 140: 107713, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37922835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37922835</a>] [<a href="https://doi.org/10.1016/j.ymgme.2023.107713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37922835">Steigerwald et al. (2023)</a> identified a homozygous splice site mutation (c.1146-199G-A, NM_000391.3) in intron 9 of the TPP1 gene, resulting in abnormal splicing. The mutation, which was identified by long-read sequencing of the TPP1 gene, was present in heterozygous state in the unaffected parents. TPP1 enzyme activity was absent in leukocytes from one of the sibs and in a CVS sample and blood spot from the other sib. RNA sequencing in blood from one of the sibs demonstrated that the mutation resulted in retention of 84 basepairs from intron 9. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37922835" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="Berry-Kravis2000" class="mim-anchor"></a>
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Berry-Kravis, E., Sleat, D. E., Sohar, I., Meyer, P., Donnelly, R., Lobel, P.
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<strong>Prenatal testing for late infantile neuronal ceroid lipofuscinosis.</strong>
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<a id="Bessa2008" class="mim-anchor"></a>
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Bessa, C, Teixeira, C. A., Dias, A., Alves, M., Rocha, S., Lacerda, L., Loureiro, L., Guimaraes, A., Ribeiro, M. G.
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<strong>CLN2/TPP1 deficiency: the novel mutation IVS7-10A-G causes intron retention and is associated with a mild disease phenotype.</strong>
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Molec. Genet. Metab. 93: 66-73, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17959406/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17959406</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17959406" 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.ymgme.2007.08.124" target="_blank">Full Text</a>]
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Breedveld, G. J., van Wetten, B., te Raa, G. D., Brusse, E., van Swieten, J. C., Oostra, B. A., Maat-Kievit, J. A.
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<strong>A new locus for a childhood onset, slowly progressive autosomal recessive spinocerebellar ataxia maps to chromosome 11p15. (Letter)</strong>
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J. Med. Genet. 41: 858-866, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15520412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15520412</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15520412" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.2004.019232" target="_blank">Full Text</a>]
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<a id="Dy2015" class="mim-anchor"></a>
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<p class="mim-text-font">
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Dy, M. E., Sims, K. B., Friedman, J.
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<strong>TPP1 deficiency: rare cause of isolated childhood-onset progressive ataxia.</strong>
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Neurology 85: 1259-1261, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26224725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26224725</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26224725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0000000000001876" target="_blank">Full Text</a>]
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<a id="Golabek2003" class="mim-anchor"></a>
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Golabek, A. A., Kida, E., Walus, M., Wujek, P., Mehta, P., Wisniewski, K. E.
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<strong>Biosynthesis, glycosylation, and enzymatic processing in vivo of human tripeptidyl-peptidase I.</strong>
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J. Biol. Chem. 278: 7135-7145, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12488460/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12488460</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12488460" 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.M211872200" target="_blank">Full Text</a>]
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<a id="Golabek2005" class="mim-anchor"></a>
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Golabek, A. A., Walus, M., Wisniewski, K. E., Kida, E.
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<strong>Glycosaminoglycans modulate activation, activity, and stability of tripeptidyl-peptidase I in vitro and in vivo.</strong>
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J. Biol. Chem. 280: 7550-7561, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15582991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15582991</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15582991" 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.M412047200" target="_blank">Full Text</a>]
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<a id="Haines1998" class="mim-anchor"></a>
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<div class="">
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Haines, J. L., Boustany, R.-M., N., Alroy, J., Auger, K. J., Shook, K. S., Terwedow, H., Lerner, T. J.
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<strong>Chromosomal localization of two genes underlying late-infantile neuronal ceroid lipofuscinosis.</strong>
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Neurogenetics 1: 217-222, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10737126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10737126</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10737126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s100480050032" target="_blank">Full Text</a>]
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<a id="Ju2002" class="mim-anchor"></a>
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Ju, W., Zhong, R., Moore, S., Moroziewicz, D., Currie, J. R., Parfrey, P., Brown, W. T., Zhong, N.
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<strong>Identification of novel CLN2 mutations shows Canadian specific NCL2 alleles.</strong>
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J. Med. Genet. 39: 822-825, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12414822/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12414822</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12414822" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.39.11.822" target="_blank">Full Text</a>]
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<a id="Liu1998" class="mim-anchor"></a>
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Liu, C.-G., Sleat, D. E., Donnelly, R. J., Lobel, P.
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<strong>Structural organization and sequence of CLN2, the defective gene in classical late infantile neuronal ceroid lipofuscinosis.</strong>
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Genomics 50: 206-212, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9653647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9653647</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9653647" 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.1998.5328" target="_blank">Full Text</a>]
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<a id="Mole1999" class="mim-anchor"></a>
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Mole, S. E., Mitchison, H. M., Munroe, P. B.
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<strong>Molecular basis of the neuronal ceroid lipofuscinoses: mutations in CLN1, CLN2, CLN3, and CLN5.</strong>
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Hum. Mutat. 14: 199-215, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10477428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10477428</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10477428" 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/(SICI)1098-1004(1999)14:3<199::AID-HUMU3>3.0.CO;2-A" target="_blank">Full Text</a>]
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<a id="Moore2008" class="mim-anchor"></a>
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Moore, S. J., Buckley, D. J., MacMillan, A., Marshall, H. D., Steele, L., Ray, P. N., Nawaz, Z., Baskin, B., Frecker, M., Carr, S. M., Ives, E., Parfrey, P. S.
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<strong>The clinical and genetic epidemiology of neuronal ceroid lipofuscinosis in Newfoundland.</strong>
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Clin. Genet. 74: 213-222, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18684116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18684116</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18684116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2008.01054.x" target="_blank">Full Text</a>]
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Oyama, H., Fujisawa, T., Suzuki, T., Dunn, B. M., Wlodawer, A., Oda, K.
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<strong>Catalytic residues and substrate specificity of recombinant human tripeptidyl peptidase I (CLN2).</strong>
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J. Biochem. 138: 127-134, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16091586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16091586</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16091586" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/jb/mvi110" target="_blank">Full Text</a>]
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<a id="Sleat1997" class="mim-anchor"></a>
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Sleat, D. E., Donnelly, R. J., Lackland, H., Liu, C.-G., Sohar, I., Pullarkat, R. K., Lobel, P.
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<strong>Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid lipofuscinosis.</strong>
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Science 277: 1802-1805, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9295267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9295267</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9295267" 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.277.5333.1802" target="_blank">Full Text</a>]
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<a id="Sleat2008" class="mim-anchor"></a>
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Sleat, D. E., El-Banna, M., Sohar, I., Kim, K.-H., Dobrenis, K., Walkley, S. U., Lobel, P.
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<strong>Residual levels of tripeptidyl-peptidase I activity dramatically ameliorate disease in late-infantile neuronal ceroid lipofuscinosis.</strong>
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Molec. Genet. Metab. 94: 222-233, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18343701/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18343701</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18343701[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=18343701" 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.ymgme.2008.01.014" target="_blank">Full Text</a>]
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<a id="Sleat1999" class="mim-anchor"></a>
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Sleat, D. E., Gin, R. M., Sohar, I., Wisniewski, K., Sklower-Brooks, S., Pullarkat, R. K., Palmer, D. N., Lerner, T. J., Boustany, R.-M., Uldall, P., Siakotos, A. N., Donnelly, R. J., Lobel, P.
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<strong>Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder.</strong>
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Am. J. Hum. Genet. 64: 1511-1523, 1999. Note: Erratum: Am. J. Hum. Genet. 75: 1158 only, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10330339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10330339</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10330339" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/302427" target="_blank">Full Text</a>]
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Sleat, D. E., Wiseman, J. A., El-Banna, M., Kim, K.-H., Mao, Q., Price, S., Macauley, S. L., Sidman, R. L., Shen, M. M., Zhao, Q., Passini, M. A., Davidson, B. L., Stewart, G. R., Lobel, P.
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<strong>A mouse model of classical late-infantile neuronal ceroid lipofuscinosis based on targeted disruption of the CLN2 gene results in a loss of tripeptidyl-peptidase I activity and progressive neurodegeneration.</strong>
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J. Neurosci. 24: 9117-9126, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15483130/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15483130</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15483130[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=15483130" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1523/JNEUROSCI.2729-04.2004" target="_blank">Full Text</a>]
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Sohar, I., Sleat, D. E., Jadot, M., Lobel, P.
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<strong>Biochemical characterization of a lysosomal protease deficient in classical late infantile neuronal ceroid lipofuscinosis (LINCL) and development of an enzyme-based assay for diagnosis and exclusion of LINCL in human specimens and animal models.</strong>
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J. Neurochem. 73: 700-711, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10428067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10428067</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10428067" 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/10.1046/j.1471-4159.1999.0730700.x" target="_blank">Full Text</a>]
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Steigerwald, C., Borsuk, J., Pappas, J., Galey, M., Scott, A., Devaney, J. M., Miller, D. E., Abreu, N. J.
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<strong>CLN2 disease resulting from a novel homozygous deep intronic splice variant in TPP1 discovered using long-read sequencing.</strong>
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Molec. Genet. Metab. 140: 107713, 2023.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37922835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37922835</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37922835" 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.ymgme.2023.107713" target="_blank">Full Text</a>]
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Steinfeld, R., Heim, P., von Gregory, H., Meyer, K., Ullrich, K., Goebel, H. H., Kohlschutter, A.
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<strong>Late infantile neuronal ceroid lipofuscinosis: quantitative description of the clinical course in patients with CLN2 mutations.</strong>
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Am. J. Med. Genet. 112: 347-354, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12376936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12376936</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12376936" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.10660" target="_blank">Full Text</a>]
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Sun, Y., Almomani, R., Breedveld, G. J., Santen, G. W. E., Aten, E., Lefeber, D. J., Hoff, J. I., Brusse, E., Verheijen, F. W., Verdijk, R. M., Kriek, M., Oostra, B., Breuning, M. H., Losekoot, M., den Dunnen, J. T., van de Warrenburg, B. P., Maat-Kievit, A. J. A.
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<strong>Autosomal recessive spinocerebellar ataxia 7 (SCAR7) is caused by variants in TPP1, the gene involved in classic late-infantile neuronal ceroid lipofuscinosis 2 disease (CLN2 disease).</strong>
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Hum. Mutat. 34: 706-713, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23418007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23418007</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23418007" 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/humu.22292" target="_blank">Full Text</a>]
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Tsiakas, K., Steinfeld, R., Storch, S., Ezaki, J., Lukacs, Z., Kominami, E., Kohlschutter, A., Ullrich, K., Braulke, T.
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<strong>Mutation of the glycosylated asparagine residue 286 in human CLN2 protein results in loss of enzymatic activity.</strong>
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Glycobiology 14: 1C-5C, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14736728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14736728</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14736728" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/glycob/cwh054" target="_blank">Full Text</a>]
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Walus, M., Kida, E., Golabek, A. A.
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<strong>Functional consequences and rescue potential of pathogenic missense mutations in tripeptidyl peptidase I.</strong>
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Hum. Mutat. 31: 710-721, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20340139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20340139</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20340139" 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/humu.21251" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 01/24/2024
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Cassandra L. Kniffin - updated : 4/27/2016<br>Cassandra L. Kniffin - updated : 12/9/2013<br>Cassandra L. Kniffin - updated : 3/5/2013<br>Cassandra L. Kniffin - updated : 3/19/2010<br>Cassandra L. Kniffin - updated : 4/28/2009<br>Patricia A. Hartz - updated : 3/12/2008<br>Victor A. McKusick - updated : 5/4/2004
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Cassandra L. Kniffin : 7/30/2003
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carol : 02/07/2025
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carol : 01/24/2024<br>alopez : 05/04/2016<br>ckniffin : 4/27/2016<br>carol : 1/7/2016<br>alopez : 4/30/2015<br>mcolton : 4/17/2015<br>carol : 12/12/2013<br>carol : 12/12/2013<br>ckniffin : 12/9/2013<br>alopez : 7/22/2013<br>carol : 3/11/2013<br>ckniffin : 3/5/2013<br>alopez : 2/6/2013<br>terry : 1/29/2013<br>terry : 9/7/2012<br>carol : 7/30/2010<br>wwang : 3/29/2010<br>ckniffin : 3/19/2010<br>wwang : 5/11/2009<br>ckniffin : 4/28/2009<br>mgross : 3/12/2008<br>mgross : 3/12/2008<br>mgross : 3/12/2008<br>mgross : 3/11/2008<br>ckniffin : 3/21/2006<br>ckniffin : 3/16/2006<br>tkritzer : 6/2/2004<br>tkritzer : 5/21/2004<br>terry : 5/4/2004<br>carol : 8/1/2003<br>carol : 7/31/2003<br>ckniffin : 7/30/2003
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TRIPEPTIDYL PEPTIDASE I; TPP1
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TPP I<br />
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CLN2 GENE; CLN2
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: TPP1</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 785301002;
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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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<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: 11p15.4
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Genomic coordinates <span class="small">(GRCh38)</span> : 11:6,612,768-6,619,422 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="2">
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<span class="mim-font">
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11p15.4
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</span>
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</td>
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<td>
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<span class="mim-font">
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Ceroid lipofuscinosis, neuronal, 2
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</span>
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</td>
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<td>
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<span class="mim-font">
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204500
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Spinocerebellar ataxia, autosomal recessive 7
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</span>
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</td>
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<td>
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<span class="mim-font">
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609270
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>TPP1 (EC 3.4.14.9) is a lysosomal exopeptidase that sequentially removes tripeptides from the N termini of proteins. It also has a minor endoprotease activity (Golabek et al., 2005). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Sleat et al. (1997) used an approach applicable to other lysosomal storage diseases to identify the molecular basis of 'late infantile neuronal ceroid lipofuscinosis' (LINCL, or CLN2; 204500). By purifying mannose 6-phosphate-containing glycoproteins, which are present on newly synthesized lysosomal enzymes, from normal brain by affinity chromatography and fractionation by SDS-polyacrylamide gel electrophoresis, they identified a single protein absent in CLN2 specimens. Comparisons with EST databases resulted in the assembly of a nearly complete sequence for the human CLN2 gene. Northern blot analysis showed 2 transcripts, and mRNA was detected in all tissues examined with highest levels in heart and placenta. The CLN2 transcript encodes a 563-residue protein with a molecular mass of 46 kD. Sequence comparisons suggested that this protein is a pepstatin-insensitive lysosomal peptidase. </p><p>Liu et al. (1998) reported the complete sequence of the CLN2 gene. </p><p>Golabek et al. (2003) stated that TPP1 encodes a 563-amino acid preproenzyme with a 19-amino acid signal peptide and a 176-amino acid prodomain that are removed during maturation, yielding a 368-amino acid mature enzyme. TPP1 also contains 5 N-glycosylation sites. The proenzyme has an apparent molecular mass of 66 kD, and the mature enzyme has an apparent molecular mass of 46 to 48 kD. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Liu et al. (1998) determined that the CLN2 gene contains 13 exons and spans 6.65 kb. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By genomewide analysis, Haines et al. (1998) mapped the CLN2 gene to chromosome 11p15.5. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using immunostaining and confocal microscopy, Golabek et al. (2003) found that TPP1 was present in lysosomes of Chinese hamster ovary cells expressing human TPP1, similar to the endogenous enzyme in human cells. Immunoblot analysis of cell lysates revealed a 68-kD precursor that was converted to a mature 48-kD enzyme. Compounds affecting the pH of intracellular acidic compartments and those interfering with intracellular vesicular transport, as well as inhibition of fusion between late endosomes and lysosomes, hampered conversion of TPP1 proenzyme into the mature form, suggesting that this process takes place in lysosomes. Digestion of immunoprecipitated TPP1 with glycosidases or chemical inhibition of N-glycosylation in cells reduced the molecular mass of TPP1 proenzyme by about 10 kD, indicating that all 5 N-glycosylation sites of TPP1 are used. Further analysis showed that a serine protease sensitive to the inhibitor AEBSF participated in processing the TPP1 proenzyme to the mature form in vivo. </p><p>TPP1 proenzyme autoactivates in vitro via an unimolecular mechanism. Golabek et al. (2005) found that high ionic strength and glycosaminoglycans (GAGs) increased yield (ionic strength) or yield and rate (GAGs) of TPP1 activation, enhanced degradation of liberated TPP1 prosegment fragments, and increased the pH of autoactivation up to 6.0. Although ionic strength and GAGs also inhibited TPP1 activity in vitro and in living cells, the degree of inhibition (from 20 to 60%) appeared to be of limited functional significance. Binding of TPP1 to GAGs improved its thermal stability and protected the enzyme against alkaline pH-induced denaturation in vitro and in vivo. Golabek et al. (2005) concluded that TPP1 can be autoactivated in vivo at lysosomal pH and that GAGs can regulate this process. </p><p>Oyama et al. (2005) purified recombinant human TPP1 from virus-TPP1-infected silkworm pupae and found that it had been processed to the mature enzyme. Using a synthetic substrate, they showed that mature TPP1 was stable in a pH range of 2.5 to 5.0, with an optimum pH for activity of 4.0; activity was lost above pH 7. Oyama et al. (2005) identified ser280, glu77, and asp81 (numbering of the mature enzyme) as catalytic residues by mutational analysis, inhibition studies, and sequence similarity with other family members. </p>
|
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</span>
|
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<div>
|
|
<br />
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
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</span>
|
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</h4>
|
|
</div>
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<span class="mim-text-font">
|
|
<p><strong><em>Neuronal Ceroid Lipofuscinosis 2</em></strong></p><p>
|
|
In patients with late-infantile onset of CLN2 (204500), Sleat et al. (1997) identified mutations in the CLN2 gene (607998.0001-607998.0004). </p><p>In 2 unrelated patients, originally diagnosed with juvenile-onset CLN3 (204200) on the basis of age at onset, age at death, and inclusion morphology, Sleat et al. (1999) identified a rare monoallelic mutation that resulted in an arg447-to-his (R447H) substitution in the CLN2 gene (607998.0005). </p><p>Defects in the CLN2 gene do not appear to be responsible for adult NCL (CLN4; 204300), or Kufs disease, as CLN2 protease activities are the same as or higher than controls in adult NCL lymphoblasts (Sohar et al., 1999). </p><p>Mole et al. (1999) tabulated the reported mutations and polymorphisms in the CLN genes. The largest number of mutations, 26, had been identified in the CLN2 gene. </p><p>Moore et al. (2008) identified 5 different mutations in the CLN2 gene (see, e.g., 607998.0007) in affected members of 18 CLN2 families from Newfoundland. Among a total of 28 CLN families in this population, CLN2 showed the highest incidence of 1 in 11,161 live births. </p><p>Walus et al. (2010) expressed 14 disease-associated missense TPP1 mutations (see, e.g., C365R, 607998.0001; R447H, 607998.0005; R206C, 607998.0006; G284V, 607998.0007; N286S, 607998.0008), into Chinese hamster ovary cells. Most variants showed folding abnormalities, resulting in obstructed transport to the lysosomes, prolonged half-life of the proenzyme, and significantly reduced or no enzymatic activity. Many of the mutant proteins were retained in the ER. The routes of removal of misfolded proteins by the cells varied, ranging from efficient degradation by the ubiquitin/proteasome system to abundant secretion. Two TPPI variants (V277M and R447H) demonstrated enhanced processing in response to folding improvement with molecular chaperones, and R447H showed a 5-fold increase in activity under permissive temperature conditions, suggesting that folding improvement strategies may ameliorate the function of some misfolding TPPI mutant proteins. </p><p>In 2 sibs, born to consanguineous parents, with CLN2, Steigerwald et al. (2023) identified a homozygous splice site mutation in the TPP1 gene (c.1146-199G-A, 607998.0012). The mutation was identified by long-read sequencing (LRS) of the TPP1 gene. TPP1 enzyme activity was absent in leukocytes from one of the sibs and in a CVS sample and blood spot from the other sib. </p><p><strong><em>Spinocerebellar Ataxia 7, Autosomal Recessive</em></strong></p><p>
|
|
In affected members of a Dutch family with autosomal recessive spinocerebellar ataxia-7 (SCAR7; 609270), originally reported by Breedveld et al. (2004), Sun et al. (2013) identified compound heterozygous mutations in the TPP1 gene: a splice site mutation resulting in premature termination (607998.0004) and a missense mutation (V466G; 607998.0010). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. An unrelated Dutch woman with the disorder was also found to be compound heterozygous for these 2 mutations, although a founder effect could not be confirmed. Residual TPP1 activity in patient lymphocytes was 10 to 15% that of controls, with 5% activity in patient fibroblasts. Electron microscopic analysis of 1 patient's skin fibroblasts showed some granular osmiophilic deposits (GROD) and fingerprint profiles, but no curvilinear profiles. Analysis of the unrelated Dutch woman's fibroblasts showed no abnormalities. Sun et al. (2013) suggested that V466G yields a hypomorphic allele with residual functional TPP1 activity, which likely resulted in a later age at onset and less severe phenotype in patients with SCAR7 compared to patients with CLN2. </p><p>In an 11-year-old girl with SCAR7, Dy et al. (2015) identified compound heterozygous mutations in the TPP1 gene: the common splice site mutation (607998.0004) and a missense mutation (E343D; 607998.0011). The mutations were found by whole-exome sequencing. TPP1 activity in patient cells was significantly decreased (3 to 15%) compared to controls. </p>
|
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</span>
|
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<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Genotype/Phenotype Correlations</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Bessa et al. (2008) reported a 40-year-old Portuguese man with a mild protracted form of CLN2 who was homozygous for a mutation that created a potential acceptor site in intron 7 of the TPP1 gene (IVS7AS-10A-G; 607998.0009), predicted to result in a protein with 3 extra amino acids between codons 295 and 296 and not affecting the wildtype splice site. The patient had onset at age 10 years of progressive cognitive and motor dysfunction and seizures. Western blot analysis detected a 60% reduction in overall TPP1 protein levels, suggesting that the mutant protein had decreased stability. Bessa et al. (2008) concluded that the mutant protein retained enzyme activity, which was consistent with the milder phenotype. </p>
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</span>
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<div>
|
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<br />
|
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Animal Model</strong>
|
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</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
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<p>Sleat et al. (2004) found that mice with targeted homozygous disruption of the Tpp1 gene were viable and healthy at birth, but developed progressive neurologic deterioration around 7 weeks of age. Clinical features included tremor and ataxia, and neuropathologic examination showed extensive neuronal pathology with accumulation of autofluorescent cytoplasmic storage material within the lysosomal-endosomal compartment, loss of cerebellar Purkinje cells, and widespread axonal degeneration. The life span of mutant mice was significantly decreased compared to wildtype. The findings recapitulated the features of human CLN2. </p><p>Sleat et al. (2008) generated mouse models of CLN2 with different hypomorphic Tpp1 mutations. Mice who were homozygous for R446H, which is analogous to human R447H (607998.0005), had approximately 6% residual brain activity of Tpp1. Mice who were compound heterozygous for the R446H allele and a null allele had about 3% residual Tpp1 activity and showed delayed disease onset and longer survival compared to homozygous-null mice. Homozygosity for R446H resulted in dramatic attenuation of disease, with even further expanded life span. The findings indicated that residual levels of Tpp1 can ameliorate disease, which has potential therapeutic implications for humans with the disorder. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>ALLELIC VARIANTS</strong>
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</span>
|
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<strong>12 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 CEROID LIPOFUSCINOSIS, NEURONAL, 2</strong>
|
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</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TPP1, CYS365ARG
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<br />
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SNP: rs119455953,
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gnomAD: rs119455953,
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|
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ClinVar: RCV000002760, RCV001248011, RCV004554579, RCV004579515
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 unrelated patients with late-infantile onset of neuronal ceroid lipofuscinosis-2 (CLN2; 204500), Sleat et al. (1997) identified different mutation at the cys365 codon in the CLN2 gene. In 1 patient, a monoallelic T-to-C transition resulted in a cys365-to-arg substitution (C365R); presumably, the defect in this patient was compound heterozygous and there was an additional, unidentified mutation. In the second patient the mutation was homozygous (607998.0002). </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>.0002 CEROID LIPOFUSCINOSIS, NEURONAL, 2</strong>
|
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</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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|
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TPP1, CYS365TYR
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<br />
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|
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SNP: rs119455954,
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gnomAD: rs119455954,
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|
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ClinVar: RCV000002761, RCV000189781, RCV000526403, RCV002496238, RCV004758587
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient with late-infantile onset of neuronal ceroid lipofuscinosis-2 (CLN2; 204500), Sleat et al. (1997) identified homozygosity for a G-to-A transition in the TPP1 gene that resulted in a cys365-to-tyr (C365Y) amino acid substitution. The authors identified a different mutation at the same codon in heterozygosity in another patient (607998.0002). Since this cysteine proved to be involved in disulfide bonding, Sleat et al. (1997) predicted that these mutations are probably highly disruptive given the role of disulfide bonds in establishing and maintaining protein structure. </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 CEROID LIPOFUSCINOSIS, NEURONAL, 2</strong>
|
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</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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TPP1, ARG208TER
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<br />
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SNP: rs119455955,
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gnomAD: rs119455955,
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ClinVar: RCV000002762, RCV000189769, RCV000210605, RCV000230952, RCV000763267, RCV001813939, RCV004554580
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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 2 sibs with late-infantile onset of neuronal ceroid lipofuscinosis-2 (CLN2; 204500), Sleat et al. (1997) found compound heterozygosity for a C-to-T transition that resulted in the conversion of codon 208 (CGA) to a stop codon (TGA). In the other allele, the conserved AG of the intronic 3-prime splice junction sequence was changed to AC, which was predicted to result in intron splicing (607998.0004). Each parent possessed a single different mutant allele. </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 CEROID LIPOFUSCINOSIS, NEURONAL, 2</strong>
|
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</span>
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|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
|
|
SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 7, INCLUDED
|
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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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TPP1, IVS5AS, G-C, -1
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<br />
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SNP: rs56144125,
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gnomAD: rs56144125,
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|
|
ClinVar: RCV000002763, RCV000074608, RCV000189765, RCV000210689, RCV000228119, RCV000763268, RCV004554581
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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>Sleat et al. (1997) described compound heterozygosity in 2 sibs with late-infantile onset of neuronal ceroid lipofuscinosis-2 (CLN2; 204500). One allele of the CLN2 gene carried the R208X nonsense mutation (607998.0003); the other allele showed a splice site mutation, a G-to-C transversion of the consensus AG 3-prime splice acceptor site immediately preceding 523T of the cDNA sequence. </p><p>In affected members of a Dutch family with autosomal recessive spinocerebellar ataxia-7 (SCAR7; 609270), originally reported by Breedveld et al. (2004), Sun et al. (2013) identified compound heterozygous mutations in the TPP1 gene: a G-to-C transversion in intron 5 (c.509-1G-C) resulting in a frameshift and premature termination (Val170GlyfsTer29), and V466G (607998.0010). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. An unrelated Dutch woman with the disorder was also found to be compound heterozygous for these 2 mutations, although a founder effect could not be confirmed. Residual TPP1 activity in patient lymphocytes was 10 to 15% that of controls, with 5% activity in patient fibroblasts. </p><p>In an 11-year-old girl with SCAR7, Dy et al. (2015) identified compound heterozygous mutations in the TPP1 gene: c.509-1G-C, and a missense mutation (E343D; 607998.0011). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0005 CEROID LIPOFUSCINOSIS, NEURONAL, 2</strong>
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</span>
|
|
</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TPP1, ARG447HIS
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<br />
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SNP: rs119455956,
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gnomAD: rs119455956,
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ClinVar: RCV000002764, RCV000189790, RCV005049313
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|
|
</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 unrelated patients with juvenile-onset neuronal ceroid lipofuscinosis-2 (CLN2; 204500), Sleat et al. (1999) identified a rare monoallelic mutation that resulted in an arg447-to-his (R447H) substitution in the CLN2 gene. Both of these patients were compound heterozygous, with either a monoallelic common splice junction mutation (607998.0004) or the arg208-to-ter mutation (R208X; 607998.0003). Both patients were originally diagnosed with juvenile-onset CLN3 (204200) on the basis of age at onset, age at death, and inclusion morphology. Sleat et al. (1999) considered it likely that the R447H mutation caused incomplete loss of function of the CLN2 protease, resulting in the protracted phenotype. The findings indicated that an attenuated form of CLN2 (i.e., with juvenile onset) may not be correctly diagnosed or may be confused with other later-onset neurodegenerative disorders. Such observations are not uncommon with other lysosomal storage diseases, in which missense mutations result in a partial dysfunction and subsequent mild or protracted phenotype. The possible phenotype of an individual homozygous for the R447H allele remained unknown. </p>
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
<div>
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|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 CEROID LIPOFUSCINOSIS, NEURONAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
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TPP1, ARG206CYS
|
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|
|
<br />
|
|
|
|
SNP: rs28940573,
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|
|
|
|
|
gnomAD: rs28940573,
|
|
|
|
|
|
ClinVar: RCV000002765, RCV001382645
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
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|
<span class="mim-text-font">
|
|
<p>In a family with first-cousin parents, Berry-Kravis et al. (2000) demonstrated a 3664C-T transition in the CLN2 gene, resulting in an arg206-to-cys mutation (R206C), as the cause of late-infantile onset of neuronal ceroid lipofuscinosis-2 (CLN2; 204500) and used the mutation successfully for prenatal diagnosis, demonstrating that the fetus at risk was homozygous for the wildtype alleles. The homozygous proband had developed seizures at age 3 years and was unable to ambulate independently by age 5. Electron microscopy performed on a skin biopsy demonstrated curvilinear bodies typical of CLN2. </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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|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 CEROID LIPOFUSCINOSIS, NEURONAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
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<div>
|
|
<span class="mim-text-font">
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|
|
|
TPP1, GLY284VAL
|
|
|
|
|
|
<br />
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|
|
SNP: rs119455957,
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|
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|
|
gnomAD: rs119455957,
|
|
|
|
|
|
ClinVar: RCV000002766, RCV000531153, RCV000763266
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 11 of 20 Canadian families with late-infantile onset of neuronal ceroid lipofuscinosis-2 (CLN2; 204500), Ju et al. (2002) identified a gly284-to-val (G284V) mutation in the CLN2 gene, which represented 55% and 32.5% of families and alleles, respectively, in this study. The authors referred to this mutation as the Canadian mutation, noting that it had not been found in any other population. </p><p>Moore et al. (2008) identified a homozygous G284V mutation in affected members from 5 families from Newfoundland with CLN2. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 CEROID LIPOFUSCINOSIS, NEURONAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
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|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TPP1, ASN286SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs119455958,
|
|
|
|
|
|
gnomAD: rs119455958,
|
|
|
|
|
|
ClinVar: RCV000002767, RCV001851588
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated female patients of Kurdish ethnicity with late infantile neuronal ceroid lipofuscinosis-2 (CLN2; 204500), Steinfeld et al. (2002) identified a homozygous A-to-G transition at nucleotide 857 in exon 7 of the TPP1 gene. The mutation resulted in an asn286-to-ser (N286S) substitution that altered 1 of 5 N-glycosylation sites in the TPP1 protein. Both patients had a more protracted clinical course compared with patients with typical disease progression. </p><p>By transient transfection analysis in human embryonic kidney cells, Tsiakas et al. (2004) found that TPP1 containing the N286S mutation was synthesized and sorted in the Golgi like wildtype TPP1, but it was expressed at a lower level and was enzymatically inactive. TPP1 with the N286 mutation had an apparent molecular mass 2 kD lower than that of wildtype TPP1, whereas deglycosylation of mutant and wildtype TPP1 led to proteins of the same size. Tsiakas et al. (2004) concluded that TPP1 with the N286S mutation lacks 1 oligosaccharide chain, resulting in enzymatic inactivation and possibly prelysosomal protein degradation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 CEROID LIPOFUSCINOSIS, NEURONAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TPP1, IVS7AS, A-G, -10
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs755445790,
|
|
|
|
|
|
gnomAD: rs755445790,
|
|
|
|
|
|
ClinVar: RCV000002768, RCV000359791, RCV005049314
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 40-year-old Portuguese man with a mild protracted form of neuronal ceroid lipofuscinosis-2 (CLN2; 204500), Bessa et al. (2008) identified a homozygous A-to-G transition in intron 7 (IVS7AS-10A-G) of the TPP1 gene, which created a potential acceptor site predicted to result in 3 extra amino acids between codons 295 and 296 and not affecting the wildtype splice site. At age 10 years, the patient had onset of progressive cognitive and motor dysfunction and seizures. Leukocytes and fibroblasts showed decreased TPP1 activity compared to controls, but activity was about 2-fold higher than that associated with TPP1-null mutations. Northern blot analysis found normal levels of correctly spliced CLN2 mRNA in patient fibroblasts, but cDNA sequencing showed the retention of 9 nucleotides from intron 7, showing that the alternative splice site was used. Western blot analysis detected a 60% reduction in overall TPP1 protein levels, suggesting that the mutant protein had decreased stability. Each unaffected parent was heterozygous for the mutation, which was not found in 100 control chromosomes. Bessa et al. (2008) concluded that the mutant protein retained enzyme activity, which was consistent with the milder phenotype. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 7</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TPP1, VAL466GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs398122959,
|
|
|
|
|
|
gnomAD: rs398122959,
|
|
|
|
|
|
ClinVar: RCV000074609, RCV001529105
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a Dutch family with autosomal recessive spinocerebellar ataxia-7 (SCAR7; 609270), originally reported by Breedveld et al. (2004), Sun et al. (2013) identified compound heterozygous mutations in the TPP1 gene: a c.1397T-G transversion, resulting in a val466-to-gly (V466G) substitution at a highly conserved residue, and splice site mutation (c.509-1G-C; 607998.0004), resulting in a frameshift and premature termination (Val170GlyfsTer29). The mutations were found by whole-exome sequencing, confirmed by Sanger sequencing, and segregated with the disorder in the family. An unrelated Dutch woman with the disorder was also found to be compound heterozygous for these 2 mutations, although a founder effect could not be confirmed. Residual TPP1 activity in patient lymphocytes was 10 to 15% that of controls, with 5% activity in patient fibroblasts. Electron microscopic analysis of 1 of the affected family member's skin fibroblasts showed some granular osmiophilic deposits (GROD) and fingerprint profiles, but no curvilinear profiles. Analysis of the unrelated Dutch woman's fibroblasts showed no abnormalities. Sun et al. (2013) suggested that V466G yields a hypomorphic allele with residual functional TPP1 activity, which likely resulted in a later age at onset and less severe phenotype in patients with SCAR7 compared to patients with neuronal ceroid lipofuscinosis-2 (CLN2; 204500). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 7</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TPP1, GLU343ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs886037833,
|
|
|
|
|
|
|
|
ClinVar: RCV000211004, RCV002509307
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 11-year-old girl with autosomal recessive spinocerebellar ataxia-7 (SCAR7; 609270), Dy et al. (2015) identified compound heterozygous mutations in the TPP1 gene: a c.1029G-C transversion resulting in a glu343-to-asp (E343D) substitution at a highly conserved residue, and the common splice site mutation (c.509-1G-C; 607998.0004). The mutations were found by whole-exome sequencing. TPP1 activity in patient cells was significantly decreased (3 to 15%) compared to controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 CEROID LIPOFUSCINOSIS, NEURONAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TPP1, IVS9AS, G-A, -199
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV003486538
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In 2 sibs, born to consanguineous parents, with neuronal ceroid lipofuscinosis-2 (CLN2; 204500), Steigerwald et al. (2023) identified a homozygous splice site mutation (c.1146-199G-A, NM_000391.3) in intron 9 of the TPP1 gene, resulting in abnormal splicing. The mutation, which was identified by long-read sequencing of the TPP1 gene, was present in heterozygous state in the unaffected parents. TPP1 enzyme activity was absent in leukocytes from one of the sibs and in a CVS sample and blood spot from the other sib. RNA sequencing in blood from one of the sibs demonstrated that the mutation resulted in retention of 84 basepairs from intron 9. </p></div>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
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</div>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Berry-Kravis, E., Sleat, D. E., Sohar, I., Meyer, P., Donnelly, R., Lobel, P.
|
|
<strong>Prenatal testing for late infantile neuronal ceroid lipofuscinosis.</strong>
|
|
Ann. Neurol. 47: 254-257, 2000.
|
|
|
|
|
|
[PubMed: 10665500]
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|
|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bessa, C, Teixeira, C. A., Dias, A., Alves, M., Rocha, S., Lacerda, L., Loureiro, L., Guimaraes, A., Ribeiro, M. G.
|
|
<strong>CLN2/TPP1 deficiency: the novel mutation IVS7-10A-G causes intron retention and is associated with a mild disease phenotype.</strong>
|
|
Molec. Genet. Metab. 93: 66-73, 2008.
|
|
|
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|
|
[PubMed: 17959406]
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|
|
[Full Text: https://doi.org/10.1016/j.ymgme.2007.08.124]
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|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Breedveld, G. J., van Wetten, B., te Raa, G. D., Brusse, E., van Swieten, J. C., Oostra, B. A., Maat-Kievit, J. A.
|
|
<strong>A new locus for a childhood onset, slowly progressive autosomal recessive spinocerebellar ataxia maps to chromosome 11p15. (Letter)</strong>
|
|
J. Med. Genet. 41: 858-866, 2004.
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|
|
[PubMed: 15520412]
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|
[Full Text: https://doi.org/10.1136/jmg.2004.019232]
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</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Dy, M. E., Sims, K. B., Friedman, J.
|
|
<strong>TPP1 deficiency: rare cause of isolated childhood-onset progressive ataxia.</strong>
|
|
Neurology 85: 1259-1261, 2015.
|
|
|
|
|
|
[PubMed: 26224725]
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|
|
[Full Text: https://doi.org/10.1212/WNL.0000000000001876]
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|
</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Golabek, A. A., Kida, E., Walus, M., Wujek, P., Mehta, P., Wisniewski, K. E.
|
|
<strong>Biosynthesis, glycosylation, and enzymatic processing in vivo of human tripeptidyl-peptidase I.</strong>
|
|
J. Biol. Chem. 278: 7135-7145, 2003.
|
|
|
|
|
|
[PubMed: 12488460]
|
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|
|
[Full Text: https://doi.org/10.1074/jbc.M211872200]
|
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|
|
</p>
|
|
</li>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Golabek, A. A., Walus, M., Wisniewski, K. E., Kida, E.
|
|
<strong>Glycosaminoglycans modulate activation, activity, and stability of tripeptidyl-peptidase I in vitro and in vivo.</strong>
|
|
J. Biol. Chem. 280: 7550-7561, 2005.
|
|
|
|
|
|
[PubMed: 15582991]
|
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