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<title>
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Entry
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- *607042 - CLN3 LYSOSOMAL/ENDOSOMAL TRANSMEMBRANE PROTEIN, BATTENIN; CLN3
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- OMIM
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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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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<p>
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<span class="h4">*607042</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/607042">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=ENSG00000188603;t=ENST00000636147" 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=1201" 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=607042" 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=ENSG00000188603;t=ENST00000636147" 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_000086,NM_001042432,NM_001286104,NM_001286105,NM_001286109,NM_001286110" 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_001042432" 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=607042" 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=08450&isoform_id=08450_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/CLN3" 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/1039423,1834482,2498243,2947055,3337387,4102729,4102731,4102733,4102735,4102737,4102739,4102741,4102743,4102745,4102747,4502889,5730392,5730394,5801831,5801833,5801835,5801837,5801839,5801841,5801843,5801845,5801847,5801849,5801851,5801853,5801855,5801857,5801859,5801861,5801863,5801865,12803177,13325228,50834236,53987836,83405778,109698601,119572666,119572667,119572668,119572669,119572670,119572671,119572672,119572673,119572674,119572675,119572676,119572677,119572678,119572679,119572680,119572681,119572682,119572683,119572684,157931184,157931186,189066588,194376536,194376800,194378520,194378694,194380534,194387368,554790410,554790412,554790414,554790416,2462552165,2462552167,2462552170,2462552172,2462552174,2462552176" 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/Q13286" 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=1201" 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=ENSG00000188603;t=ENST00000636147" 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=CLN3" 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=CLN3" 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+1201" 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/CLN3" 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:1201" 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/1201" 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=chr16&hgg_gene=ENST00000636147.2&hgg_start=28466653&hgg_end=28492082&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:2074" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:2074" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/cln3" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=607042[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=607042[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/ENSG00000188603" 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=CLN3" 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=CLN3" 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=CLN3" 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="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://www.retina-international.org/files/sci-news/cln3mut.htm" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Mutations of the CLN3 Gene</a></div><div style="margin-left: 0.5em;"><a href="http://www.ucl.ac.uk/ncl/" title="Neuronal Ceroid Lipofuscinoses; NCL Mutations" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Neuronal Ceroid Lipofuscin…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=CLN3&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/PA26601" 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:2074" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0036756.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:107537" 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/CLN3#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:107537" 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/1201/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/OMIA002432/" 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=1201" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00000539;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00000539 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00000540;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00000540 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00000541;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00000541 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-041114-174" 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:607042" 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:1201" 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=CLN3&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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<strong>SNOMEDCT:</strong> 61663001<br />
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<strong>ICD10CM:</strong> E75.4<br />
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<strong>ORPHA:</strong> 228346<br />
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">ICD+</a>
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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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607042
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CLN3 LYSOSOMAL/ENDOSOMAL TRANSMEMBRANE PROTEIN, BATTENIN; CLN3
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CLN3 GENE<br />
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BATTENIN
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=CLN3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CLN3</a></em></strong>
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Cytogenetic location: <a href="/geneMap/16/301?start=-3&limit=10&highlight=301">16p12.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr16:28466653-28492082&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'})">16:28,466,653-28,492,082</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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<strong>Gene-Phenotype Relationships</strong>
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Inheritance
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16p12.1
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Ceroid lipofuscinosis, neuronal, 3
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<a href="/entry/204200"> 204200 </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/607042" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/607042" 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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<p>The <a href="#7" class="mim-tip-reference" title="International Batten Disease Consortium. <strong>Isolation of a novel gene underlying Batten disease, CLN3.</strong> Cell 82: 949-957, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7553855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7553855</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90274-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7553855">International Batten Disease Consortium (1995)</a> isolated the CLN3 gene, which is mutated in Batten disease (CLN3; <a href="/entry/204200">204200</a>). A certain haplotype, called the '56 chromosome' haplotype, defined by the 5 allele at D16S299 and the 6 allele at D16S298, is shared by 73% of Batten disease chromosomes (<a href="#22" class="mim-tip-reference" title="Mitchison, H. M., Taschner, P. E. M., O'Rawe, A. M., de Vos, N., Phillips, H. A., Thompson, A. D., Kozman, H. M., Haines, J. L., Schlumpf, K., D'Arigo, K., Boustany, R.-M. N., Callen, D. F., Breuning, M. H., Gardiner, R. M., Mole, S. E., Lerner, T. J. <strong>Genetic mapping of the Batten disease locus (CLN3) to the interval D16S288-D16S383 by analysis of haplotypes and allelic association.</strong> Genomics 22: 465-468, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7806237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7806237</a>] [<a href="https://doi.org/10.1006/geno.1994.1412" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7806237">Mitchison et al., 1994</a>). The consortium used exon amplification of a cosmid that contained D16S298, which yielded a candidate gene that was disrupted by a 1-kb genomic deletion (<a href="#0001">607042.0001</a>) in all patients carrying the 56 chromosome. Three separate deletions and a point mutation altering a splice site in 3 unrelated families confirmed the candidate as the CLN3 gene. The disease gene encodes a deduced 438-amino acid protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7553855+7806237" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Janes, R. W., Munroe, P. B., Mitchison, H. M., Gardiner, R. M., Mole, S. E., Wallace, B. A. <strong>A model for Batten disease protein CLN3: functional implications from homology and mutations.</strong> FEBS Lett. 399: 75-77, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8980123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8980123</a>] [<a href="https://doi.org/10.1016/s0014-5793(96)01290-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8980123">Janes et al. (1996)</a> reported that the amino acid sequence of the CLN3 gene product predicts a hydrophobic protein with 6 transmembrane domains. The sequence appears to contain a putative mitochondrial targeting site at residue 11 and has 4 predicted N-glycosylation sites, all on the predicted exoplasmic surface. A homology search identified a yeast protein with 36% identity to the CLN3 protein. <a href="#24" class="mim-tip-reference" title="Munroe, P. B., Mitchison, H. M., O'Rawe, A. M., Anderson, J. W., Boustany, R.-M., Lerner, T. J., Taschner, P. E. M., de Vos, N., Breuning, M. H., Gardiner, R. M., Mole, S. E. <strong>Spectrum of mutations in the Batten disease gene, CLN3.</strong> Am. J. Hum. Genet. 61: 310-316, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9311735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9311735</a>] [<a href="https://doi.org/10.1086/514846" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9311735">Munroe et al. (1997)</a> reported that all known point mutations of CLN3 are found at sites that have identical residues in the yeast protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9311735+8980123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Lee, R. L., Johnson, K. R., Lerner, T. J. <strong>Isolation and chromosomal mapping of a mouse homolog of the Batten disease gene CLN3.</strong> Genomics 35: 617-619, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8812504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8812504</a>] [<a href="https://doi.org/10.1006/geno.1996.0410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8812504">Lee et al. (1996)</a> isolated a mouse homolog of the CLN3 gene. Like its human counterpart, the mouse cDNA encodes a predicted 438-amino acid polypeptide. The mouse and human proteins share 85% sequence identity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8812504" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using an immunoprecipitation and glycosylation mutagenesis procedure, <a href="#18" class="mim-tip-reference" title="Mao, Q., Foster, B. J., Xia, H., Davidson, B. L. <strong>Membrane topology of CLN3, the protein underlying Batten disease.</strong> FEBS Lett. 541: 40-46, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12706816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12706816</a>] [<a href="https://doi.org/10.1016/s0014-5793(03)00284-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12706816">Mao et al. (2003)</a> determined that the human CLN3 protein contains 5 transmembrane domains, an extracellular/intraluminal N terminus, and a cytoplasmic C terminus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12706816" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 Western blot analysis, <a href="#20" class="mim-tip-reference" title="Margraf, L. R., Boriack, R. L., Routheut, A. A. J., Cuppen, I., Alhilali, L., Bennett, C. J., Bennett, M. J. <strong>Tissue expression and subcellular localization of CLN3, the Batten disease protein.</strong> Molec. Genet. Metab. 66: 283-289, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10191116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10191116</a>] [<a href="https://doi.org/10.1006/mgme.1999.2830" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10191116">Margraf et al. (1999)</a> observed CLN3 at an apparent molecular mass of 48 kD in cortical brain, pancreas, spleen, and testis, with weaker expression in peripheral nerve. Gray matter showed higher CLN3 expression than white matter. No protein expression was detected in ovary, small intestine, colon, and adipose tissue. Immunocytochemical analysis localized CLN3 in islet cells of the pancreas. In brain, CLN3 was observed in nuclei and cytoplasmic processes of most astrocytes, in nuclei and cytoplasm of neurons, and in capillary endothelium. Staining was similar in all brain areas examined, and no difference in staining was found between brains of adults and noninfant children. Immunoelectron microscopy detected CLN2 lining endothelial cell membranes. CLN2 was not associated with lysosomes or mitochondria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10191116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Rakheja, D., Narayan, S. B., Pastor, J. V., Bennett, M. J. <strong>CLN3P, the Batten disease protein, localizes to membrane lipid rafts (detergent-resistant membranes).</strong> Biochem. Biophys. Res. Commun. 317: 988-991, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15094366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15094366</a>] [<a href="https://doi.org/10.1016/j.bbrc.2004.03.146" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15094366">Rakheja et al. (2004)</a> found that Cln3 resided on lipid rafts, or detergent-resistant membranes, from bovine brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15094366" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#21" class="mim-tip-reference" title="Mitchison, H. M., Munroe, P. B., O'Rawe, A. M., Taschner, P. E. M., de Vos, N., Kremmidiotis, G., Lensink, I., Munk, A. C., D'Arigo, K. L., Anderson, J. W., Lerner, T. J., Moyzis, R. K., Callen, D. F., Breuning, M. H., Doggett, N. A., Gardiner, R. M., Mole, S. E. <strong>Genomic structure and complete nucleotide sequence of the Batten disease gene, CLN3.</strong> Genomics 40: 346-350, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9119403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9119403</a>] [<a href="https://doi.org/10.1006/geno.1996.4576" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9119403">Mitchison et al. (1997)</a> reported that the CLN3 gene contains at least 15 exons and spans 15 kb. Sequence comparisons between CLN3 and homologous ESTs suggested alternative splicing of the gene and at least 1 additional upstream exon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9119403" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The <a href="#7" class="mim-tip-reference" title="International Batten Disease Consortium. <strong>Isolation of a novel gene underlying Batten disease, CLN3.</strong> Cell 82: 949-957, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7553855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7553855</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90274-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7553855">International Batten Disease Consortium (1995)</a> isolated the CLN3 gene between microsatellite markers D16S288 and D16S383 on chromosome 16p12.1-p11.2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7553855" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Lee, R. L., Johnson, K. R., Lerner, T. J. <strong>Isolation and chromosomal mapping of a mouse homolog of the Batten disease gene CLN3.</strong> Genomics 35: 617-619, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8812504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8812504</a>] [<a href="https://doi.org/10.1006/geno.1996.0410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8812504">Lee et al. (1996)</a> mapped the mouse gene to distal chromosome 7 in a region of syntenic homology with human 16p12. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8812504" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#8" class="mim-tip-reference" title="Janes, R. W., Munroe, P. B., Mitchison, H. M., Gardiner, R. M., Mole, S. E., Wallace, B. A. <strong>A model for Batten disease protein CLN3: functional implications from homology and mutations.</strong> FEBS Lett. 399: 75-77, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8980123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8980123</a>] [<a href="https://doi.org/10.1016/s0014-5793(96)01290-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8980123">Janes et al. (1996)</a> speculated that the CLN3 gene product may function as a chaperone involved in the folding/unfolding or assembly/disassembly of other proteins, specifically subunit c of the ATP synthase complex. <a href="#13" class="mim-tip-reference" title="Kremmidiotis, G., Lensink, I. L., Bilton, R. L., Woollatt, E., Chataway, T. K., Sutherland, G. R., Callen, D. F. <strong>The Batten disease gene product (CLN3p) is a Golgi integral membrane protein.</strong> Hum. Molec. Genet. 8: 523-531, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9949212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9949212</a>] [<a href="https://doi.org/10.1093/hmg/8.3.523" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9949212">Kremmidiotis et al. (1999)</a> investigated the subcellular localization of the CLN3 gene product by fusing it to green fluorescent protein (GFP) or an 8-amino acid peptide tag and transiently transfecting it into fibroblasts, HeLa cells, and COS-7 cells. A juxtanuclear, asymmetric localization that correlated with the Golgi apparatus was observed in all 3 cell types. A portion of cells exhibited a punctate vesicular distribution throughout the cytoplasm. Further studies were performed on a stably transfected cell line expressing only 1 copy of the CLN3-GFP DNA construct. Fluorescence and biochemical analyses demonstrated that the CLN3 gene product is an integral membrane protein that localizes primarily to the Golgi apparatus. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8980123+9949212" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Jarvela, I., Lehtovirta, M., Tikkanen, R., Kyttala, A., Jalanko, A. <strong>Defective intracellular transport of CLN3 is the molecular basis of Batten disease (JNCL).</strong> Hum. Molec. Genet. 8: 1091-1098, 1999. Note: Erratum: Hum. Molec. Genet. 8: 1585 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10332042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10332042</a>] [<a href="https://doi.org/10.1093/hmg/8.6.1091" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10332042">Jarvela et al. (1999)</a> confirmed the lysosomal localization of the CLN3 protein by immunoelectron microscopy by colocalizing it with soluble and membrane-associated lysosomal proteins. They analyzed the intracellular processing and localization of 2 mutants, 461-677del (<a href="#0001">607042.0001</a>), which is present in 85% of CLN3 alleles and causes the classic juvenile-onset CLN3, and glu295 to lys (E295K; <a href="#0005">607042.0005</a>), which is a rare missense mutation associated with an atypical form of JNCL. Transient expression of the 2 mutants in BHK cells showed that 461-677del was retained in the endoplasmic reticulum, whereas E295K was capable of reaching the lysosomal compartment. The CLN3 polypeptides were expressed further in mouse primary neurons where the wildtype CLN3 protein was localized both in the cell soma and in neuronal extensions, whereas the 461-677del mutation was arrested in the cell soma. Colocalization of the wildtype CLN3 and E295K proteins with a synaptic vesicle marker indicated that the CLN3 protein might participate in synaptic vesicle transport/transmission. These data provided clear evidence for a cellular distinction between classic and atypical forms of Batten disease in both neural and nonneural cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10332042" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Luiro, K., Kopra, O., Lehtovirta, M., Jalanko, A. <strong>CLN3 protein is targeted to neuronal synapses but excluded from synaptic vesicles: new clues to Batten disease.</strong> Hum. Molec. Genet. 10: 2123-2131, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11590129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11590129</a>] [<a href="https://doi.org/10.1093/hmg/10.19.2123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11590129">Luiro et al. (2001)</a> analyzed CLN3 in the mouse brain by use of in situ hybridization, immunohistochemical staining, and Western blot analysis of subcellular fractions. CLN3 was abundantly expressed in neuronal cells, especially in the cortex, hippocampus, and cerebellum of the adult mouse brain. In cultured mouse retinal cells, CLN3 was not solely localized to lysosomes, but was also found in the synaptosomes, although not targeted to the synaptic vesicles. The latter observation led the authors to hypothesize a potential role of CLN3 in neuronal transport pathways. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11590129" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using surface biotinylation and antibody trapping, <a href="#19" class="mim-tip-reference" title="Mao, Q., Xia, H., Davidson, B. L. <strong>Intracellular trafficking of CLN3, the protein underlying the childhood neurodegenerative disease, Batten disease.</strong> FEBS Lett. 555: 351-357, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14644441/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14644441</a>] [<a href="https://doi.org/10.1016/s0014-5793(03)01274-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14644441">Mao et al. (2003)</a> showed that a portion of CLN3 in a human teratocarcinoma cell line trafficked to lysosomes via the cell membrane. Inhibition of the mu-3A subunit of the AP3 adaptor protein complex (AP3M1; <a href="/entry/610366">610366</a>) increased the amount of cell surface CLN3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14644441" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Luiro, K., Yliannala, K., Ahtiainen, L., Maunu, H., Jarvela, I., Kyttala, A., Jalanko, A. <strong>Interconnections of CLN3, Hook1 and Rab proteins link Batten disease to defects in the endocytic pathway.</strong> Hum. Molec. Genet. 13: 3017-3027, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15471887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15471887</a>] [<a href="https://doi.org/10.1093/hmg/ddh321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15471887">Luiro et al. (2004)</a> found that overexpression of CLN3 induced aggregation of the microtubule binding protein Hook1 (<a href="/entry/607820">607820</a>) in HeLa cells, potentially by mediating its dissociation from the microtubules. In vitro binding assays showed a weak interaction between Hook1 and the cytoplasmic segments of CLN3. Receptor-mediated endocytosis was defective in CLN3-deficient JNCL fibroblasts, linking CLN3, Hook1 and endocytosis in the mammalian system. Coimmunoprecipitation experiments showed that Hook1 physically interacted with endocytic Rab7 (<a href="/entry/602298">602298</a>), Rab9 (<a href="/entry/300284">300284</a>), and Rab11 (<a href="/entry/605570">605570</a>), suggesting a role for Hook1 in membrane trafficking. <a href="#17" class="mim-tip-reference" title="Luiro, K., Yliannala, K., Ahtiainen, L., Maunu, H., Jarvela, I., Kyttala, A., Jalanko, A. <strong>Interconnections of CLN3, Hook1 and Rab proteins link Batten disease to defects in the endocytic pathway.</strong> Hum. Molec. Genet. 13: 3017-3027, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15471887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15471887</a>] [<a href="https://doi.org/10.1093/hmg/ddh321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15471887">Luiro et al. (2004)</a> suggested a link between CLN3 function, microtubule cytoskeleton, and endocytic membrane trafficking. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15471887" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Ramirez-Montealegre, D., Pearce, D. A. <strong>Defective lysosomal arginine transport in juvenile Batten disease.</strong> Hum. Molec. Genet. 14: 3759-3773, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16251196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16251196</a>] [<a href="https://doi.org/10.1093/hmg/ddi406" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16251196">Ramirez-Montealegre and Pearce (2005)</a> reported that lysosomes from juvenile Batten disease lymphoblast cell lines demonstrated defective transport of arginine. Furthermore, they showed that there was a depletion of arginine in cells from juvenile Batten disease patients. <a href="#28" class="mim-tip-reference" title="Ramirez-Montealegre, D., Pearce, D. A. <strong>Defective lysosomal arginine transport in juvenile Batten disease.</strong> Hum. Molec. Genet. 14: 3759-3773, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16251196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16251196</a>] [<a href="https://doi.org/10.1093/hmg/ddi406" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16251196">Ramirez-Montealegre and Pearce (2005)</a> demonstrated that lysosomal arginine transport in normal lysosomes was ATP, vacuolar ATPase (see <a href="/entry/606939">606939</a>), and cationic dependent. Thus, both arginine and lysine are transported by the same transport system, designated system c. However, lysosomes from juvenile Batten disease lymphoblasts were only defective for arginine transport. An antibody to CLN3 was able to block lysosomal arginine transport, and transient expression of CLN3 in JNCL cells restored lysosomal arginine transport. <a href="#28" class="mim-tip-reference" title="Ramirez-Montealegre, D., Pearce, D. A. <strong>Defective lysosomal arginine transport in juvenile Batten disease.</strong> Hum. Molec. Genet. 14: 3759-3773, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16251196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16251196</a>] [<a href="https://doi.org/10.1093/hmg/ddi406" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16251196">Ramirez-Montealegre and Pearce (2005)</a> suggested that the CLN3 defect in juvenile Batten disease may affect how intracellular levels of arginine are regulated or distributed throughout the cell. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16251196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In cultured human neuroblastoma cells, <a href="#25" class="mim-tip-reference" title="Narayan, S. B., Rakheja, D., Tan, L., Pastor, J. V., Bennett, M. J. <strong>CLN3P, the Batten's disease protein, is a novel palmitoyl-protein delta-9 desaturase.</strong> Ann. Neurol. 60: 570-577, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17036287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17036287</a>] [<a href="https://doi.org/10.1002/ana.20975" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17036287">Narayan et al. (2006)</a> demonstrated that the CLN3 protein is a novel palmitoyl-protein delta-9 desaturase with low affinity for free fatty acids, specifically palmitate, and high affinity for palmitoylated proteins. This specific enzyme activity was deficient in pancreatic and brain tissue from Cln3-deficient mice and was completely ablated by siRNA inhibition in cultured human neuroblastoma cells. The findings indicated that the CLN3 protein plays a role in membrane-associated proteolipid modification. <a href="#25" class="mim-tip-reference" title="Narayan, S. B., Rakheja, D., Tan, L., Pastor, J. V., Bennett, M. J. <strong>CLN3P, the Batten's disease protein, is a novel palmitoyl-protein delta-9 desaturase.</strong> Ann. Neurol. 60: 570-577, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17036287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17036287</a>] [<a href="https://doi.org/10.1002/ana.20975" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17036287">Narayan et al. (2006)</a> proposed that defects in this enzymatic activity lead to intracellular proteolipid accumulation, neuronal cell death, and neurodegeneration characteristic of Batten disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17036287" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Hobert, J. A., Dawson, G. <strong>A novel role of the Batten disease gene CLN3: association with BMP synthesis.</strong> Biochem. Biophys. Res. Commun. 358: 111-116, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17482562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17482562</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17482562[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.bbrc.2007.04.064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17482562">Hobert and Dawson (2007)</a> isolated detergent-resistant membranes from control and JNCL brains and found that JNCL-derived membranes were less buoyant than controls. Analysis of phospholipid content showed reduced bis(monoacylglycerol)phosphate (BMP) in JNCL-derived membranes and in total lipids from JNCL brains. Metabolic labeling demonstrated reduced synthesis of BMP in JNCL fibroblasts, which was restored following complementation with wildtype CLN3. Overexpression of wildtype CLN3 also increased BMP synthesis. <a href="#6" class="mim-tip-reference" title="Hobert, J. A., Dawson, G. <strong>A novel role of the Batten disease gene CLN3: association with BMP synthesis.</strong> Biochem. Biophys. Res. Commun. 358: 111-116, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17482562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17482562</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17482562[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.bbrc.2007.04.064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17482562">Hobert and Dawson (2007)</a> concluded that CLN3 has a role in BMP biosynthesis and in maintaining the lipid profile of detergent-resistant membranes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17482562" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using yeast 2-hybrid analysis, in vitro protein pull-down assays, and coimmunoprecipitation of endogenous proteins in an SH-SY5Y human neuroblastoma cell line, <a href="#2" class="mim-tip-reference" title="Chang, J.-W., Choi, H., Kim, H.-J., Jo, D.-G., Jeon, Y.-J., Noh, J.-Y., Park, W. J., Jung, Y.-K. <strong>Neuronal vulnerability of CLN3 deletion to calcium-induced cytotoxicity is mediated by calsenilin.</strong> Hum. Molec. Genet. 16: 317-326, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17189291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17189291</a>] [<a href="https://doi.org/10.1093/hmg/ddl466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17189291">Chang et al. (2007)</a> showed that calsenilin (KCNIP3; <a href="/entry/604662">604662</a>) interacted with the C terminus of CLN3. Overexpression of full-length CLN3 or the isolated CLN3 C terminus suppressed cell death triggered by pharmacologically elevated intracellular Ca(2+) concentration. Conversely, knockdown of CLN3 via antisense cDNA increased cell susceptibility to high Ca(2+)-triggered cell death. Ca(2+) reduced the interaction between calsenilin and CLN3 in vitro, and knockdown of calsenilin desensitized SH-SY5Y cells to Ca(2+)-induced cell death. <a href="#2" class="mim-tip-reference" title="Chang, J.-W., Choi, H., Kim, H.-J., Jo, D.-G., Jeon, Y.-J., Noh, J.-Y., Park, W. J., Jung, Y.-K. <strong>Neuronal vulnerability of CLN3 deletion to calcium-induced cytotoxicity is mediated by calsenilin.</strong> Hum. Molec. Genet. 16: 317-326, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17189291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17189291</a>] [<a href="https://doi.org/10.1093/hmg/ddl466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17189291">Chang et al. (2007)</a> concluded that CLN3 regulates neuronal cell death mediated by calsenilin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17189291" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#32" class="mim-tip-reference" title="Tuxworth, R. I., Vivancos, V., O'Hare, M. B., Tear, G. <strong>Interactions between the juvenile Batten disease gene, CLN3, and the Notch and JNK signalling pathways.</strong> Hum. Molec. Genet. 18: 667-678, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19028667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19028667</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19028667[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn396" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19028667">Tuxworth et al. (2009)</a> developed a genetic gain-of-function system in Drosophila to identify functional pathways and interactions for CLN3. They identified interactions between CLN3 and the Notch (NOTCH1; <a href="/entry/190198">190198</a>) and Jun (MAPK8; <a href="/entry/601158">601158</a>) N-terminal kinase signaling pathways, and described a potential role for RNA splicing and localization machinery in regulating CLN3 function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19028667" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Vitiello, S. P., Benedict, J. W., Padilla-Lopez, S., Pearce, D. A. <strong>Interaction between Sdo1p and Btn1p in the Saccharomyces cerevisiae model for Batten disease.</strong> Hum. Molec. Genet. 19: 931-942, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20015955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20015955</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20015955[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp560" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20015955">Vitiello et al. (2010)</a> demonstrated that CLN3 interacts with SBDS (<a href="/entry/607444">607444</a>), the protein mutated in Shwachman-Bodian-Diamond syndrome (<a href="/entry/260400">260400</a>) patients. The protein-protein interaction was conserved between Btn1 and Sdo1, the respective S. cerevisiae orthologs of CLN3 and SBDS. It had been shown that deletion of BTN1 results in alterations in vacuolar pH and vacuolar (H+)-ATPase (V-ATPase)-dependent H+ transport and ATP hydrolysis. <a href="#33" class="mim-tip-reference" title="Vitiello, S. P., Benedict, J. W., Padilla-Lopez, S., Pearce, D. A. <strong>Interaction between Sdo1p and Btn1p in the Saccharomyces cerevisiae model for Batten disease.</strong> Hum. Molec. Genet. 19: 931-942, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20015955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20015955</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20015955[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp560" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20015955">Vitiello et al. (2010)</a> found that an Sdo1 deletion strain had decreased vacuolar pH and V-ATPase-dependent H+ transport and ATP hydrolysis; the alterations resulted from decreased V-ATPase subunit expression. Overexpression of Btn1 or the presence of ionophore carbonyl cyanide m-chlorophenil hydrazone (CCCP) caused decreased growth in yeast lacking Sdo1. In normal cells, overexpression of Btn1 mirrored the effect of CCCP, with both resulting in increased vacuolar pH due to alterations in the coupling of V-ATPase-dependent H+ transport and ATP hydrolysis. The authors proposed that Sdo1 and SBDS work to regulate Btn1 and CLN3, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20015955" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Role in Tumorigenesis</em></strong></p><p>
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Juvenile Batten disease is a neurodegenerative disease caused by accelerated apoptotic death of photoreceptors and neurons resulting from defects in the CLN3 gene. CLN3 is antiapoptotic when overexpressed in NT2 neuronal precursor cells. Because defects in regulation of apoptosis are involved in the development of cancer, <a href="#29" class="mim-tip-reference" title="Rylova, S. N., Amalfitano, A., Persaud-Sawin, D.-A., Guo, W.-X., Chang, J., Jansen, P. J., Proia, A. D., Boustany, R.-M. <strong>The CLN3 gene is a novel molecular target for cancer drug discovery.</strong> Cancer Res. 62: 801-808, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11830536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11830536</a>]" pmid="11830536">Rylova et al. (2002)</a> evaluated the expression of CLN3 on both mRNA and protein levels in a variety of cancer cell lines and solid colon cancer tissue. They showed that CLN3 mRNA and protein are overexpressed in a variety of human cancer cell lines. It was also upregulated in mouse melanoma and breast carcinoma cancer cell lines. In 8 of 10 solid colon tumors, they found CLN3 expression 22 to 330% higher than in corresponding colon control tissue. Blocking of CLN3 expression using an adenovirus-expressing antisense CLN3 inhibited growth and viability of cancer cells. It also caused elevation in endogenous ceramide production through de novo ceramide synthesis and resulted in increased apoptosis. This suggested that antisense-CLN3 may be an option for therapy in some cancers. More importantly, these results suggested that CLN3 is a novel molecular target for cancer drug discovery. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11830536" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The <a href="#7" class="mim-tip-reference" title="International Batten Disease Consortium. <strong>Isolation of a novel gene underlying Batten disease, CLN3.</strong> Cell 82: 949-957, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7553855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7553855</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90274-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7553855">International Batten Disease Consortium (1995)</a> demonstrated that the mutation responsible for 73% of Batten disease (CLN3; <a href="/entry/204200">204200</a>) chromosomes, as identified by the 56 haplotype, is a genomic deletion of 1.02 kb (<a href="#0001">607042.0001</a>) in the CLN3 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7553855" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Munroe, P. B., Mitchison, H. M., O'Rawe, A. M., Anderson, J. W., Boustany, R.-M., Lerner, T. J., Taschner, P. E. M., de Vos, N., Breuning, M. H., Gardiner, R. M., Mole, S. E. <strong>Spectrum of mutations in the Batten disease gene, CLN3.</strong> Am. J. Hum. Genet. 61: 310-316, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9311735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9311735</a>] [<a href="https://doi.org/10.1086/514846" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9311735">Munroe et al. (1997)</a> identified homozygosity for the common 1.02-kb CLN3 deletion in 139 (74%) of 188 unrelated patients with Batten disease; 41 were compound heterozygous for the deletion and another CLN3 mutation. By SSCP analysis and direct sequencing, <a href="#24" class="mim-tip-reference" title="Munroe, P. B., Mitchison, H. M., O'Rawe, A. M., Anderson, J. W., Boustany, R.-M., Lerner, T. J., Taschner, P. E. M., de Vos, N., Breuning, M. H., Gardiner, R. M., Mole, S. E. <strong>Spectrum of mutations in the Batten disease gene, CLN3.</strong> Am. J. Hum. Genet. 61: 310-316, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9311735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9311735</a>] [<a href="https://doi.org/10.1086/514846" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9311735">Munroe et al. (1997)</a> found 19 novel mutations in the CLN3 gene: 6 missense mutations, 5 nonsense mutations, 3 small deletions, 3 small insertions, 1 intronic mutation, and 1 splice site mutation. This report brought the total number of known disease-associated mutations in CLN3 to 23. All patients homozygous for mutations predicted to give rise to truncated proteins were found to have classic juvenile-onset CLN3. However, 4 patients who were compound heterozygotes for a missense mutation and a 1.02-kb deletion were found to display an atypical phenotype that was dominated by visual failure rather than by severe neurodegeneration. All missense mutations were found to affect residues conserved between the human protein and homologs in diverse species. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9311735" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Lauronen, L., Munroe, P. B., Jarvela, I., Autti, T., Mitchison, H. M., O'Rawe, A. M., Gardiner, R. M., Mole, S. E., Puranen, J., Hakkinen, A. M., Kirveskari, E., Santavuori, P. <strong>Delayed classic and protracted phenotypes of compound heterozygous juvenile neuronal ceroid lipofuscinosis.</strong> Neurology 52: 360-365, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9932957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9932957</a>] [<a href="https://doi.org/10.1212/wnl.52.2.360" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9932957">Lauronen et al. (1999)</a> presented the phenotypes of 10 different Finnish compound heterozygotes with the common 1.02-kb deletion (<a href="#0001">607042.0001</a>) and 1 of 5 rare CLN3 mutations on the other chromosome. They identified a novel mutation, resulting in a deletion of exons 10 through 13, in 3 families with a total of 6 patients. This mutation differed from that described in <a href="#0002">607042.0002</a> in that it spared marker D16S298. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9932957" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="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 mutations that had been identified in the various CLNs; they reported 25 mutations and 2 polymorphisms associated with CLN3. <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><p><a href="#26" class="mim-tip-reference" title="Persaud-Sawin, D.-A. N. W., VanDongen, A., Boustany, R.-M. N. <strong>Motifs within the CLN3 protein: modulation of cell growth rates and apoptosis.</strong> Hum. Molec. Genet. 11: 2129-2142, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12189165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12189165</a>] [<a href="https://doi.org/10.1093/hmg/11.18.2129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12189165">Persaud-Sawin et al. (2002)</a> demonstrated that CLN3-deficient immortalization of lymphoblasts homozygous for the common 1.02-kb deletion (<a href="#0001">607042.0001</a>) grew at a slower rate, and showed increased sensitivity to etoposide-induced apoptosis, supporting the notion that CLN3 may negatively regulate apoptosis. Protection from etoposide-induced apoptosis was evident and the cell growth rate was restored following transfection of JNCL lymphoblasts with mutant CLN3 cDNA that included exons 11 or 13. Deletion of the glycosylation sites 71-74 and 310-313, and mutations within the highly conserved amino acid stretches 184-195, 291-295, or 330-337, resulted in slowed growth and susceptibility to apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12189165" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#5" class="mim-tip-reference" title="Haskell, R. E., Carr, C. J,., Pearce, D. A., Bennett, M. J., Davidson, B. L. <strong>Batten disease: evaluation of CLN3 mutations on protein localization and function.</strong> Hum. Molec. Genet. 9: 735-744, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10749980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10749980</a>] [<a href="https://doi.org/10.1093/hmg/9.5.735" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10749980">Haskell et al. (2000)</a> examined the effect of naturally occurring point mutations on the intracellular localization of CLN3, their ability to complement the CLN3-deficient yeast btn1-delta, and a putative farnesylation motif thought to be involved in CLN3 trafficking. All 6 missense mutations studied, like wildtype CLN3, were highly associated with lysosome-associated membrane protein II (<a href="/entry/309060">309060</a>) in nonneuronal cells and with synaptophysin (<a href="/entry/313475">313475</a>) in neuronal cell lines. In a yeast functional assay, point mutations correlating with a mild phenotype also demonstrated CLN3 activity, whereas the mutations associated with severe disease failed to restore CLN3 function completely. CLN3 with a mutation in the farnesylation motif trafficked normally but was functionally impaired. The authors concluded that point mutations causative of Batten disease do not affect protein trafficking but rather exert their effects by impairing protein function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10749980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#4" class="mim-tip-reference" title="Cotman, S. L., Vrbanac, V., Lebel, L.-A., Lee, R. L., Johnson, K. A., Donahue, L.-R., Teed, A. M., Antonellis, K., Bronson, R. T., Lerner, T. J., MacDonald, M. E. <strong>Cln3 (ex7/8) knock-in mice with the common JNCL mutation exhibit progressive neurologic disease that begins before birth.</strong> Hum. Molec. Genet. 11: 2709-2721, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12374761/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12374761</a>] [<a href="https://doi.org/10.1093/hmg/11.22.2709" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12374761">Cotman et al. (2002)</a> introduced the common 1-kb genomic DNA deletion into the murine CLN3 homolog to create Cln3 (ex7/8) knockin mice. This allele produced alternatively spliced mRNAs, including a variant predicting a nontruncated protein, as well as mutant battenin that was detected in the cytoplasm of cells in the periphery and CNS. Moreover, Cln3 (ex7/8) homozygotes exhibited accrual of JNCL-like membrane deposits from before birth, in proportion to battenin levels, which were high in liver and select neuronal populations. Although liver enzymes and CNS development were normal, Cln3 (ex7/8) mice displayed recessively inherited degenerative changes in retina, cerebral cortex, and cerebellum, as well as neurologic deficits and premature death. The authors concluded that the harmful impact of the common JNCL mutation on the CNS was not well correlated with membrane deposition per se, suggesting instead a specific battenin activity that is essential for the survival of CNS neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12374761" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 brains of homozygous Cln3(ex7/8) mice, <a href="#1" class="mim-tip-reference" title="Cao, Y., Espinola, J. A., Fossale, E., Massey, A. C., Cuervo, A. M., MacDonald, M. E., Cotman, S. L. <strong>Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis.</strong> J. Biol. Chem. 281: 20483-20493, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16714284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16714284</a>] [<a href="https://doi.org/10.1074/jbc.M602180200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16714284">Cao et al. (2006)</a> found upregulation of the autophagy marker Lc3 II (see <a href="/entry/601242">601242</a>) and downregulation of the autophagy inhibitor Mtor (FRAP1; <a href="/entry/601231">601231</a>). Isolated autophagic vacuoles and lysosomes from homozygous Cln3(ex7/8) mice were less mature in their ultrastructural morphology than wildtype organelles, and mitochondrial ATPase subunit c (see ATP5G1; <a href="/entry/603192">603192</a>) accumulated in autophagic vacuoles, similar to that seen in JNCL. <a href="#1" class="mim-tip-reference" title="Cao, Y., Espinola, J. A., Fossale, E., Massey, A. C., Cuervo, A. M., MacDonald, M. E., Cotman, S. L. <strong>Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis.</strong> J. Biol. Chem. 281: 20483-20493, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16714284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16714284</a>] [<a href="https://doi.org/10.1074/jbc.M602180200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16714284">Cao et al. (2006)</a> also observed mitochondrial ATPase subunit c accumulation in autophagic vacuoles in normal aging mice. Lc3-positive vesicles isolated from Cln3(ex7/8) cerebellar cells showed altered trafficking and reduced fusion of endocytic and lysosomal vesicles upon stimulation of autophagy. Stimulation of autophagy did not significantly impact cell survival in homozygous Cln3(ex7/8) cells, but inhibition of autophagy led to cell death. <a href="#1" class="mim-tip-reference" title="Cao, Y., Espinola, J. A., Fossale, E., Massey, A. C., Cuervo, A. M., MacDonald, M. E., Cotman, S. L. <strong>Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis.</strong> J. Biol. Chem. 281: 20483-20493, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16714284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16714284</a>] [<a href="https://doi.org/10.1074/jbc.M602180200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16714284">Cao et al. (2006)</a> concluded that autophagy is disrupted in JNCL, likely at the level of autophagic vacuolar maturation, and they proposed that activation of autophagy may be a prosurvival feedback response in the disease process. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16714284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=607042[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1555468634 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555468634;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=rs1555468634" 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=rs1555468634" 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=RCV000003731 OR RCV000724164 OR RCV003324482" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003731, RCV000724164, RCV003324482" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003731...</a>
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<p>The <a href="#7" class="mim-tip-reference" title="International Batten Disease Consortium. <strong>Isolation of a novel gene underlying Batten disease, CLN3.</strong> Cell 82: 949-957, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7553855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7553855</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90274-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7553855">International Batten Disease Consortium (1995)</a> demonstrated that the mutation responsible for 73% of Batten disease (CLN3; <a href="/entry/204200">204200</a>) chromosomes as identified by the 56 haplotype is a genomic deletion of 1.02 kb, including 217 bp of the open reading frame (nucleotides 598-814), corresponding to 2 exons. Deletion of these 217 bp of coding sequence produces a frameshift, generating a TAA termination codon 84 bp downstream of the deletion junction. The predicted translation product is a truncated protein of 181 amino acids consisting of the first 153 residues of the protein, followed by 28 novel amino acids before the stop codon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7553855" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 Finland, 90% of patients with Batten disease carry the 1.02-kb deletion. <a href="#11" class="mim-tip-reference" title="Jarvela, I., Mitchison, H. M., Munroe, P. B., O'Rawe, A. M., Mole, S. E., Syvanen, A.-C. <strong>Rapid diagnostic test for the major mutation underlying Batten disease.</strong> J. Med. Genet. 33: 1041-1042, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9004140/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9004140</a>] [<a href="https://doi.org/10.1136/jmg.33.12.1041" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9004140">Jarvela et al. (1996)</a> developed a rapid diagnostic solid-phase minisequencing test to detect this deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9004140" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>This 1.02-kb deletion in homozygous form always causes a severe phenotype, including blindness, epilepsy, dementia, and early death at approximately 24 years of age (<a href="#24" class="mim-tip-reference" title="Munroe, P. B., Mitchison, H. M., O'Rawe, A. M., Anderson, J. W., Boustany, R.-M., Lerner, T. J., Taschner, P. E. M., de Vos, N., Breuning, M. H., Gardiner, R. M., Mole, S. E. <strong>Spectrum of mutations in the Batten disease gene, CLN3.</strong> Am. J. Hum. Genet. 61: 310-316, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9311735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9311735</a>] [<a href="https://doi.org/10.1086/514846" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9311735">Munroe et al., 1997</a>; <a href="#9" class="mim-tip-reference" title="Jarvela, I., Autti, T., Lamminranta, S., Aberg, L., Raininko, R., Santavuori, P. <strong>Clinical and magnetic resonance imaging findings in Batten disease: analysis of the major mutation (1.02 kb deletion).</strong> Ann. Neurol. 42: 799-802, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9392580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9392580</a>] [<a href="https://doi.org/10.1002/ana.410420517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9392580">Jarvela et al., 1997</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9392580+9311735" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Kitzmuller, C., Haines, R. L., Codlin, S., Cutler, D. F., Mole, S. E. <strong>A function retained by the common mutant CLN3 protein is responsible for the late onset of juvenile neuronal ceroid lipofuscinosis.</strong> Hum. Molec. Genet. 17: 303-312, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17947292/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17947292</a>] [<a href="https://doi.org/10.1093/hmg/ddm306" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17947292">Kitzmuller et al. (2008)</a> demonstrated that the common 1.02-kb deletion retains residual function. Two mutant CLN3 transcripts were present in patient cells homozygous for the mutation: the major transcript encoded a truncated protein encoding residues 1 through 153 followed by 28 additional amino acids, and the minor transcript encoded a protein that spliced exon 6 to exon 10 with restoration of the reading frame after exon 10. When RNA silencing was used to deplete these transcripts in patients' cells, the lysosomes significantly increased in size, confirming that the protein was functional. Overexpression of mutant CLN3 transcript consistently caused lysosomes to decrease in size. Studies in mouse cell models and yeast confirmed that the corresponding mutant transcripts retained significant function. The majority of the mutant 1.02-kb deletion CLN3 protein was retained within the endoplasmic reticulum. <a href="#12" class="mim-tip-reference" title="Kitzmuller, C., Haines, R. L., Codlin, S., Cutler, D. F., Mole, S. E. <strong>A function retained by the common mutant CLN3 protein is responsible for the late onset of juvenile neuronal ceroid lipofuscinosis.</strong> Hum. Molec. Genet. 17: 303-312, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17947292/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17947292</a>] [<a href="https://doi.org/10.1093/hmg/ddm306" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17947292">Kitzmuller et al. (2008)</a> concluded that the common mutant CLN3 protein retains significant function and that JNCL is a mutation-specific disease phenotype. The residual function likely explains why this form of CLN shows later onset and less severe clinical manifestations compared to other forms of CLN. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17947292" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 Finnish patient with Batten disease (<a href="/entry/204200">204200</a>), the <a href="#7" class="mim-tip-reference" title="International Batten Disease Consortium. <strong>Isolation of a novel gene underlying Batten disease, CLN3.</strong> Cell 82: 949-957, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7553855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7553855</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90274-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7553855">International Batten Disease Consortium (1995)</a> identified compound heterozygosity for 2 deletions in the CLN3 gene: the 1.02-kb deletion (<a href="#0001">607042.0001</a>) and a 3-kb deletion resulting in a 266-bp coding sequence deletion (nucleotides 928-1193), resulting in a truncated protein with the first 263 amino acids of CLN3 followed by 28 novel amino acids before a stop codon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7553855" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 of Moroccan origin with Batten disease (<a href="/entry/204200">204200</a>), <a href="#31" class="mim-tip-reference" title="Taschner, P. E. M., de Vos, N., Thompson, A. D., Callen, D. F., Doggett, N., Mole, S. E., Dooley, T. P., Barth, P. G., Breuning, M. H. <strong>Chromosome 16 microdeletion in a patient with juvenile neuronal ceroid lipofuscinosis (Batten disease).</strong> Am. J. Hum. Genet. 56: 663-668, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7887420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7887420</a>]" pmid="7887420">Taschner et al. (1995)</a> demonstrated homozygosity for a deletion in the CLN3 gene. The <a href="#7" class="mim-tip-reference" title="International Batten Disease Consortium. <strong>Isolation of a novel gene underlying Batten disease, CLN3.</strong> Cell 82: 949-957, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7553855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7553855</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90274-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7553855">International Batten Disease Consortium (1995)</a> reported that this patient had a 6-kb deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7553855+7887420" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs386833728 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs386833728;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=rs386833728" 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=rs386833728" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>The <a href="#7" class="mim-tip-reference" title="International Batten Disease Consortium. <strong>Isolation of a novel gene underlying Batten disease, CLN3.</strong> Cell 82: 949-957, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7553855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7553855</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90274-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7553855">International Batten Disease Consortium (1995)</a> described a Finnish patient, L198Pa, with Batten disease (<a href="/entry/204200">204200</a>) who was a compound heterozygote for one '56 chromosome' (<a href="#0001">607042.0001</a>) and one '76 chromosome' (D16S988/D16S298). They found a deletion of a 73-bp exon corresponding to bases 598-670 of the cDNA. Nucleotide sequence analysis showed a G-to-C transversion at +1 of the splice donor site following the exon. The father was a heterozygous carrier of the mutation. The patient had an uneventful birth and early childhood. Progressive visual failure began at age 7. At age 9, she showed an abnormal MRI. Vacuolated lymphocytes were repeatedly observed, and electron microscopy of a rectal biopsy specimen showed inclusions typical of Batten disease. She was placed on sodium valproate medication at age 9, when she experienced her only seizure. Repeat examination at the age of 13 showed good motor function but mental decline that had been relatively fast. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7553855" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 CEROID LIPOFUSCINOSIS, NEURONAL, 3, PROTRACTED</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> rs121434286 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434286;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/rs121434286?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=rs121434286" 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=rs121434286" 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=RCV000003735 OR RCV000055839 OR RCV000811923 OR RCV001074385 OR RCV001270479 OR RCV002512720 OR RCV004791194" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003735, RCV000055839, RCV000811923, RCV001074385, RCV001270479, RCV002512720, RCV004791194" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003735...</a>
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<p>In 2 sibs with a rare, protracted form of juvenile-onset neuronal ceroid lipofuscinosis (CLN3; <a href="/entry/204200">204200</a>), <a href="#34" class="mim-tip-reference" title="Wisniewski, K. E., Zhong, N., Kaczmarski, W., Kaczmarski, A., Kida, E., Brown, W. T., Schwarz, K. O., Lazzarini, A. M., Rubin, A. J., Stenroos, E. S., Johnson, W. G., Wisniewski, T. M. <strong>Compound heterozygous genotype is associated with protracted juvenile neuronal ceroid lipofuscinosis.</strong> Ann. Neurol. 43: 106-110, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9450775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9450775</a>] [<a href="https://doi.org/10.1002/ana.410430118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9450775">Wisniewski et al. (1998)</a> identified compound heterozygosity for 2 mutations in the CLN3 gene: a 1.02-kb deletion (<a href="#0001">607042.0001</a>) and a 1020G-A transition, resulting in a glu295-to-lys (E295K) substitution. Both sibs had disease onset at age 5 years, but the sister lived until age 51 and the brother was still living at age 39. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9450775" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 CEROID LIPOFUSCINOSIS, NEURONAL, 3, PROTRACTED</strong>
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CLN3, TYR199TER
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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> rs267606737 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606737;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/rs267606737?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=rs267606737" 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=rs267606737" 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=RCV000003736 OR RCV000169443 OR RCV000760368 OR RCV000823290" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003736, RCV000169443, RCV000760368, RCV000823290" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003736...</a>
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<p>In 5 sibs, born of consanguineous Lebanese parents, with a protracted form of juvenile-onset neuronal ceroid lipofuscinosis (CLN3; <a href="/entry/204200">204200</a>), <a href="#30" class="mim-tip-reference" title="Sarpong, A., Schottmann, G., Ruther, K., Stoltenburg, G., Kohlschutter, A., Hubner, C., Schuelke, M. <strong>Protracted course of juvenile ceroid lipofuscinosis associated with a novel CLN3 mutation (p.Y199X).</strong> Clin. Genet. 76: 38-45, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19489875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19489875</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01179.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19489875">Sarpong et al. (2009)</a> identified a homozygous 597C-A transversion in exon 8 of the CLN3 gene, resulting in a tyr199-to-ter (Y199X) substitution and loss of 239 C-terminal amino acids. RT-PCR analysis detected the mutant transcript, indicating that it was not degraded by nonsense-mediated mRNA decay. The Y199X mutation was identified in heterozygosity in both parents and 4 sibs but not in 200 control alleles. In this family, onset of the disorder occurred at 4 to 5 years of age, with affected children becoming silent, taciturn, and irritable. Visual loss occurred between 6 and 9 years, epilepsy between 10 and 15 years, and insidious onset of a movement disorder soon after. However, all were able to walk independently until age 20 years. The diagnosis was confirmed by pathologic studies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19489875" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 CEROID LIPOFUSCINOSIS, NEURONAL, 3, PROTRACTED</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">rs786201028 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786201028;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=rs786201028" 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=rs786201028" 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=RCV000162326" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000162326" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000162326</a>
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<p>In 2 adult Italian brothers, whose parents were consanguineous, with a protracted form of juvenile-onset neuronal ceroid lipofuscinosis (CLN3; <a href="/entry/204200">204200</a>), <a href="#3" class="mim-tip-reference" title="Cortese, A., Tucci, A., Piccolo, G., Galimberti, C. A., Fratta, P., Marchioni, E., Grampa, G., Cereda, C., Grieco, G., Ricca, I., Pittman, A., Ciscato, P., and 9 others. <strong>Novel CLN3 mutation causing autophagic vacuolar myopathy.</strong> Neurology 82: 2072-2076, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24827497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24827497</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24827497[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/10.1212/WNL.0000000000000490" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24827497">Cortese et al. (2014)</a> identified a homozygous c.494G-A transition in the CLN3 gene, resulting in a gly165-to-glu (G165E) substitution at a highly conserved residue in the second luminal loop. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against SNP databases. The unaffected mother was heterozygous for the mutation; the father was deceased. Functional studies of the variant were not performed. Both patients had loss of vision in childhood, but no other neurologic abnormalities. Later in life, they both developed hypertrophic cardiomyopathy, seizures, and very mild cognitive impairment. Muscle biopsy showed large autophagic vacuoles and autofluorescent material. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24827497" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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Cao, Y., Espinola, J. A., Fossale, E., Massey, A. C., Cuervo, A. M., MacDonald, M. E., Cotman, S. L.
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<strong>Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis.</strong>
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J. Biol. Chem. 281: 20483-20493, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16714284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16714284</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16714284" 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.M602180200" target="_blank">Full Text</a>]
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Chang, J.-W., Choi, H., Kim, H.-J., Jo, D.-G., Jeon, Y.-J., Noh, J.-Y., Park, W. J., Jung, Y.-K.
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<strong>Neuronal vulnerability of CLN3 deletion to calcium-induced cytotoxicity is mediated by calsenilin.</strong>
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Hum. Molec. Genet. 16: 317-326, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17189291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17189291</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17189291" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddl466" target="_blank">Full Text</a>]
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Cortese, A., Tucci, A., Piccolo, G., Galimberti, C. A., Fratta, P., Marchioni, E., Grampa, G., Cereda, C., Grieco, G., Ricca, I., Pittman, A., Ciscato, P., and 9 others.
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<strong>Novel CLN3 mutation causing autophagic vacuolar myopathy.</strong>
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Neurology 82: 2072-2076, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24827497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24827497</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24827497[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=24827497" 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.0000000000000490" target="_blank">Full Text</a>]
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Cotman, S. L., Vrbanac, V., Lebel, L.-A., Lee, R. L., Johnson, K. A., Donahue, L.-R., Teed, A. M., Antonellis, K., Bronson, R. T., Lerner, T. J., MacDonald, M. E.
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<strong>Cln3 (ex7/8) knock-in mice with the common JNCL mutation exhibit progressive neurologic disease that begins before birth.</strong>
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Hum. Molec. Genet. 11: 2709-2721, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12374761/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12374761</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12374761" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/11.22.2709" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/9.5.735" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.bbrc.2007.04.064" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0092-8674(95)90274-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0014-5793(96)01290-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.410420517" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/8.6.1091" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.33.12.1041" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddm306" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/8.3.523" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1996.0410" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddh321" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0014-5793(03)00284-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0014-5793(03)01274-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1996.4576" target="_blank">Full Text</a>]
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<a id="22" class="mim-anchor"></a>
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<a id="Mitchison1994" class="mim-anchor"></a>
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<div class="">
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Mitchison, H. M., Taschner, P. E. M., O'Rawe, A. M., de Vos, N., Phillips, H. A., Thompson, A. D., Kozman, H. M., Haines, J. L., Schlumpf, K., D'Arigo, K., Boustany, R.-M. N., Callen, D. F., Breuning, M. H., Gardiner, R. M., Mole, S. E., Lerner, T. J.
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<strong>Genetic mapping of the Batten disease locus (CLN3) to the interval D16S288-D16S383 by analysis of haplotypes and allelic association.</strong>
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Genomics 22: 465-468, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7806237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7806237</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7806237" 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.1994.1412" target="_blank">Full Text</a>]
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<a id="Mole1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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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="24" class="mim-anchor"></a>
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<a id="Munroe1997" class="mim-anchor"></a>
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Munroe, P. B., Mitchison, H. M., O'Rawe, A. M., Anderson, J. W., Boustany, R.-M., Lerner, T. J., Taschner, P. E. M., de Vos, N., Breuning, M. H., Gardiner, R. M., Mole, S. E.
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<strong>Spectrum of mutations in the Batten disease gene, CLN3.</strong>
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Am. J. Hum. Genet. 61: 310-316, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9311735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9311735</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9311735" 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/10.1086/514846" target="_blank">Full Text</a>]
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<a id="25" class="mim-anchor"></a>
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<a id="Narayan2006" class="mim-anchor"></a>
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<div class="">
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Narayan, S. B., Rakheja, D., Tan, L., Pastor, J. V., Bennett, M. J.
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<strong>CLN3P, the Batten's disease protein, is a novel palmitoyl-protein delta-9 desaturase.</strong>
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Ann. Neurol. 60: 570-577, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17036287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17036287</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17036287" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.20975" target="_blank">Full Text</a>]
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<a id="Persaud-Sawin2002" class="mim-anchor"></a>
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Persaud-Sawin, D.-A. N. W., VanDongen, A., Boustany, R.-M. N.
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<strong>Motifs within the CLN3 protein: modulation of cell growth rates and apoptosis.</strong>
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Hum. Molec. Genet. 11: 2129-2142, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12189165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12189165</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12189165" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/11.18.2129" target="_blank">Full Text</a>]
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<a id="Rakheja2004" class="mim-anchor"></a>
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Rakheja, D., Narayan, S. B., Pastor, J. V., Bennett, M. J.
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<strong>CLN3P, the Batten disease protein, localizes to membrane lipid rafts (detergent-resistant membranes).</strong>
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Biochem. Biophys. Res. Commun. 317: 988-991, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15094366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15094366</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15094366" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.bbrc.2004.03.146" target="_blank">Full Text</a>]
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Ramirez-Montealegre, D., Pearce, D. A.
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<strong>Defective lysosomal arginine transport in juvenile Batten disease.</strong>
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Hum. Molec. Genet. 14: 3759-3773, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16251196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16251196</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16251196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddi406" target="_blank">Full Text</a>]
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Rylova, S. N., Amalfitano, A., Persaud-Sawin, D.-A., Guo, W.-X., Chang, J., Jansen, P. J., Proia, A. D., Boustany, R.-M.
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<strong>The CLN3 gene is a novel molecular target for cancer drug discovery.</strong>
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Cancer Res. 62: 801-808, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11830536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11830536</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11830536" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Sarpong, A., Schottmann, G., Ruther, K., Stoltenburg, G., Kohlschutter, A., Hubner, C., Schuelke, M.
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<strong>Protracted course of juvenile ceroid lipofuscinosis associated with a novel CLN3 mutation (p.Y199X).</strong>
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Clin. Genet. 76: 38-45, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19489875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19489875</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19489875" 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.1399-0004.2009.01179.x" target="_blank">Full Text</a>]
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Taschner, P. E. M., de Vos, N., Thompson, A. D., Callen, D. F., Doggett, N., Mole, S. E., Dooley, T. P., Barth, P. G., Breuning, M. H.
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<strong>Chromosome 16 microdeletion in a patient with juvenile neuronal ceroid lipofuscinosis (Batten disease).</strong>
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Am. J. Hum. Genet. 56: 663-668, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7887420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7887420</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7887420" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Tuxworth, R. I., Vivancos, V., O'Hare, M. B., Tear, G.
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<strong>Interactions between the juvenile Batten disease gene, CLN3, and the Notch and JNK signalling pathways.</strong>
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Hum. Molec. Genet. 18: 667-678, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19028667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19028667</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19028667[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=19028667" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddn396" target="_blank">Full Text</a>]
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Vitiello, S. P., Benedict, J. W., Padilla-Lopez, S., Pearce, D. A.
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<strong>Interaction between Sdo1p and Btn1p in the Saccharomyces cerevisiae model for Batten disease.</strong>
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Hum. Molec. Genet. 19: 931-942, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20015955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20015955</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20015955[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=20015955" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp560" target="_blank">Full Text</a>]
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Wisniewski, K. E., Zhong, N., Kaczmarski, W., Kaczmarski, A., Kida, E., Brown, W. T., Schwarz, K. O., Lazzarini, A. M., Rubin, A. J., Stenroos, E. S., Johnson, W. G., Wisniewski, T. M.
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<strong>Compound heterozygous genotype is associated with protracted juvenile neuronal ceroid lipofuscinosis.</strong>
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Ann. Neurol. 43: 106-110, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9450775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9450775</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9450775" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.410430118" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 6/23/2014
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<span class="mim-text-font">
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George E. Tiller - updated : 11/8/2011<br>Patricia A. Hartz - updated : 6/25/2010<br>Cassandra L. Kniffin - updated : 5/24/2010<br>George E. Tiller - updated : 8/10/2009<br>Cassandra L. Kniffin - updated : 5/1/2009<br>George E. Tiller - updated : 4/23/2009<br>Patricia A. Hartz - updated : 10/29/2008<br>Cassandra L. Kniffin - updated : 10/16/2007<br>George E. Tiller - updated : 5/21/2007<br>George E. Tiller - updated : 2/12/2004<br>George E. Tiller - updated : 9/22/2003
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Cassandra L. Kniffin : 6/18/2002
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carol : 03/17/2015<br>mcolton : 3/16/2015<br>ckniffin : 6/23/2014<br>carol : 6/5/2012<br>alopez : 11/15/2011<br>terry : 11/8/2011<br>mgross : 7/6/2010<br>terry : 6/25/2010<br>wwang : 5/26/2010<br>ckniffin : 5/24/2010<br>wwang : 8/20/2009<br>terry : 8/10/2009<br>wwang : 5/20/2009<br>ckniffin : 5/1/2009<br>wwang : 4/30/2009<br>terry : 4/23/2009<br>mgross : 11/3/2008<br>terry : 10/29/2008<br>wwang : 10/19/2007<br>ckniffin : 10/16/2007<br>wwang : 6/1/2007<br>terry : 5/21/2007<br>carol : 3/24/2006<br>carol : 3/24/2006<br>ckniffin : 3/24/2006<br>ckniffin : 3/21/2006<br>ckniffin : 3/16/2006<br>cwells : 2/12/2004<br>cwells : 9/22/2003<br>carol : 8/1/2003<br>carol : 6/21/2002<br>ckniffin : 6/21/2002<br>ckniffin : 6/18/2002<br>ckniffin : 6/18/2002
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<span class="mim-font">
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<strong>*</strong> 607042
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CLN3 LYSOSOMAL/ENDOSOMAL TRANSMEMBRANE PROTEIN, BATTENIN; CLN3
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<em>Alternative titles; symbols</em>
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CLN3 GENE<br />
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BATTENIN
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: CLN3</em></strong>
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<strong>SNOMEDCT:</strong> 61663001;
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<strong>ICD10CM:</strong> E75.4;
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<strong>ORPHA:</strong> 228346;
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Cytogenetic location: 16p12.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 16:28,466,653-28,492,082 </span>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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16p12.1
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Ceroid lipofuscinosis, neuronal, 3
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204200
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Autosomal recessive
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Cloning and Expression</strong>
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<p>The International Batten Disease Consortium (1995) isolated the CLN3 gene, which is mutated in Batten disease (CLN3; 204200). A certain haplotype, called the '56 chromosome' haplotype, defined by the 5 allele at D16S299 and the 6 allele at D16S298, is shared by 73% of Batten disease chromosomes (Mitchison et al., 1994). The consortium used exon amplification of a cosmid that contained D16S298, which yielded a candidate gene that was disrupted by a 1-kb genomic deletion (607042.0001) in all patients carrying the 56 chromosome. Three separate deletions and a point mutation altering a splice site in 3 unrelated families confirmed the candidate as the CLN3 gene. The disease gene encodes a deduced 438-amino acid protein. </p><p>Janes et al. (1996) reported that the amino acid sequence of the CLN3 gene product predicts a hydrophobic protein with 6 transmembrane domains. The sequence appears to contain a putative mitochondrial targeting site at residue 11 and has 4 predicted N-glycosylation sites, all on the predicted exoplasmic surface. A homology search identified a yeast protein with 36% identity to the CLN3 protein. Munroe et al. (1997) reported that all known point mutations of CLN3 are found at sites that have identical residues in the yeast protein. </p><p>Lee et al. (1996) isolated a mouse homolog of the CLN3 gene. Like its human counterpart, the mouse cDNA encodes a predicted 438-amino acid polypeptide. The mouse and human proteins share 85% sequence identity. </p><p>Using an immunoprecipitation and glycosylation mutagenesis procedure, Mao et al. (2003) determined that the human CLN3 protein contains 5 transmembrane domains, an extracellular/intraluminal N terminus, and a cytoplasmic C terminus. </p><p>By Western blot analysis, Margraf et al. (1999) observed CLN3 at an apparent molecular mass of 48 kD in cortical brain, pancreas, spleen, and testis, with weaker expression in peripheral nerve. Gray matter showed higher CLN3 expression than white matter. No protein expression was detected in ovary, small intestine, colon, and adipose tissue. Immunocytochemical analysis localized CLN3 in islet cells of the pancreas. In brain, CLN3 was observed in nuclei and cytoplasmic processes of most astrocytes, in nuclei and cytoplasm of neurons, and in capillary endothelium. Staining was similar in all brain areas examined, and no difference in staining was found between brains of adults and noninfant children. Immunoelectron microscopy detected CLN2 lining endothelial cell membranes. CLN2 was not associated with lysosomes or mitochondria. </p><p>Rakheja et al. (2004) found that Cln3 resided on lipid rafts, or detergent-resistant membranes, from bovine brain. </p>
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<strong>Gene Structure</strong>
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<p>Mitchison et al. (1997) reported that the CLN3 gene contains at least 15 exons and spans 15 kb. Sequence comparisons between CLN3 and homologous ESTs suggested alternative splicing of the gene and at least 1 additional upstream exon. </p>
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<strong>Mapping</strong>
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<p>The International Batten Disease Consortium (1995) isolated the CLN3 gene between microsatellite markers D16S288 and D16S383 on chromosome 16p12.1-p11.2. </p><p>Lee et al. (1996) mapped the mouse gene to distal chromosome 7 in a region of syntenic homology with human 16p12. </p>
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<strong>Gene Function</strong>
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<p>Janes et al. (1996) speculated that the CLN3 gene product may function as a chaperone involved in the folding/unfolding or assembly/disassembly of other proteins, specifically subunit c of the ATP synthase complex. Kremmidiotis et al. (1999) investigated the subcellular localization of the CLN3 gene product by fusing it to green fluorescent protein (GFP) or an 8-amino acid peptide tag and transiently transfecting it into fibroblasts, HeLa cells, and COS-7 cells. A juxtanuclear, asymmetric localization that correlated with the Golgi apparatus was observed in all 3 cell types. A portion of cells exhibited a punctate vesicular distribution throughout the cytoplasm. Further studies were performed on a stably transfected cell line expressing only 1 copy of the CLN3-GFP DNA construct. Fluorescence and biochemical analyses demonstrated that the CLN3 gene product is an integral membrane protein that localizes primarily to the Golgi apparatus. </p><p>Jarvela et al. (1999) confirmed the lysosomal localization of the CLN3 protein by immunoelectron microscopy by colocalizing it with soluble and membrane-associated lysosomal proteins. They analyzed the intracellular processing and localization of 2 mutants, 461-677del (607042.0001), which is present in 85% of CLN3 alleles and causes the classic juvenile-onset CLN3, and glu295 to lys (E295K; 607042.0005), which is a rare missense mutation associated with an atypical form of JNCL. Transient expression of the 2 mutants in BHK cells showed that 461-677del was retained in the endoplasmic reticulum, whereas E295K was capable of reaching the lysosomal compartment. The CLN3 polypeptides were expressed further in mouse primary neurons where the wildtype CLN3 protein was localized both in the cell soma and in neuronal extensions, whereas the 461-677del mutation was arrested in the cell soma. Colocalization of the wildtype CLN3 and E295K proteins with a synaptic vesicle marker indicated that the CLN3 protein might participate in synaptic vesicle transport/transmission. These data provided clear evidence for a cellular distinction between classic and atypical forms of Batten disease in both neural and nonneural cells. </p><p>Luiro et al. (2001) analyzed CLN3 in the mouse brain by use of in situ hybridization, immunohistochemical staining, and Western blot analysis of subcellular fractions. CLN3 was abundantly expressed in neuronal cells, especially in the cortex, hippocampus, and cerebellum of the adult mouse brain. In cultured mouse retinal cells, CLN3 was not solely localized to lysosomes, but was also found in the synaptosomes, although not targeted to the synaptic vesicles. The latter observation led the authors to hypothesize a potential role of CLN3 in neuronal transport pathways. </p><p>Using surface biotinylation and antibody trapping, Mao et al. (2003) showed that a portion of CLN3 in a human teratocarcinoma cell line trafficked to lysosomes via the cell membrane. Inhibition of the mu-3A subunit of the AP3 adaptor protein complex (AP3M1; 610366) increased the amount of cell surface CLN3. </p><p>Luiro et al. (2004) found that overexpression of CLN3 induced aggregation of the microtubule binding protein Hook1 (607820) in HeLa cells, potentially by mediating its dissociation from the microtubules. In vitro binding assays showed a weak interaction between Hook1 and the cytoplasmic segments of CLN3. Receptor-mediated endocytosis was defective in CLN3-deficient JNCL fibroblasts, linking CLN3, Hook1 and endocytosis in the mammalian system. Coimmunoprecipitation experiments showed that Hook1 physically interacted with endocytic Rab7 (602298), Rab9 (300284), and Rab11 (605570), suggesting a role for Hook1 in membrane trafficking. Luiro et al. (2004) suggested a link between CLN3 function, microtubule cytoskeleton, and endocytic membrane trafficking. </p><p>Ramirez-Montealegre and Pearce (2005) reported that lysosomes from juvenile Batten disease lymphoblast cell lines demonstrated defective transport of arginine. Furthermore, they showed that there was a depletion of arginine in cells from juvenile Batten disease patients. Ramirez-Montealegre and Pearce (2005) demonstrated that lysosomal arginine transport in normal lysosomes was ATP, vacuolar ATPase (see 606939), and cationic dependent. Thus, both arginine and lysine are transported by the same transport system, designated system c. However, lysosomes from juvenile Batten disease lymphoblasts were only defective for arginine transport. An antibody to CLN3 was able to block lysosomal arginine transport, and transient expression of CLN3 in JNCL cells restored lysosomal arginine transport. Ramirez-Montealegre and Pearce (2005) suggested that the CLN3 defect in juvenile Batten disease may affect how intracellular levels of arginine are regulated or distributed throughout the cell. </p><p>In cultured human neuroblastoma cells, Narayan et al. (2006) demonstrated that the CLN3 protein is a novel palmitoyl-protein delta-9 desaturase with low affinity for free fatty acids, specifically palmitate, and high affinity for palmitoylated proteins. This specific enzyme activity was deficient in pancreatic and brain tissue from Cln3-deficient mice and was completely ablated by siRNA inhibition in cultured human neuroblastoma cells. The findings indicated that the CLN3 protein plays a role in membrane-associated proteolipid modification. Narayan et al. (2006) proposed that defects in this enzymatic activity lead to intracellular proteolipid accumulation, neuronal cell death, and neurodegeneration characteristic of Batten disease. </p><p>Hobert and Dawson (2007) isolated detergent-resistant membranes from control and JNCL brains and found that JNCL-derived membranes were less buoyant than controls. Analysis of phospholipid content showed reduced bis(monoacylglycerol)phosphate (BMP) in JNCL-derived membranes and in total lipids from JNCL brains. Metabolic labeling demonstrated reduced synthesis of BMP in JNCL fibroblasts, which was restored following complementation with wildtype CLN3. Overexpression of wildtype CLN3 also increased BMP synthesis. Hobert and Dawson (2007) concluded that CLN3 has a role in BMP biosynthesis and in maintaining the lipid profile of detergent-resistant membranes. </p><p>Using yeast 2-hybrid analysis, in vitro protein pull-down assays, and coimmunoprecipitation of endogenous proteins in an SH-SY5Y human neuroblastoma cell line, Chang et al. (2007) showed that calsenilin (KCNIP3; 604662) interacted with the C terminus of CLN3. Overexpression of full-length CLN3 or the isolated CLN3 C terminus suppressed cell death triggered by pharmacologically elevated intracellular Ca(2+) concentration. Conversely, knockdown of CLN3 via antisense cDNA increased cell susceptibility to high Ca(2+)-triggered cell death. Ca(2+) reduced the interaction between calsenilin and CLN3 in vitro, and knockdown of calsenilin desensitized SH-SY5Y cells to Ca(2+)-induced cell death. Chang et al. (2007) concluded that CLN3 regulates neuronal cell death mediated by calsenilin. </p><p>Tuxworth et al. (2009) developed a genetic gain-of-function system in Drosophila to identify functional pathways and interactions for CLN3. They identified interactions between CLN3 and the Notch (NOTCH1; 190198) and Jun (MAPK8; 601158) N-terminal kinase signaling pathways, and described a potential role for RNA splicing and localization machinery in regulating CLN3 function. </p><p>Vitiello et al. (2010) demonstrated that CLN3 interacts with SBDS (607444), the protein mutated in Shwachman-Bodian-Diamond syndrome (260400) patients. The protein-protein interaction was conserved between Btn1 and Sdo1, the respective S. cerevisiae orthologs of CLN3 and SBDS. It had been shown that deletion of BTN1 results in alterations in vacuolar pH and vacuolar (H+)-ATPase (V-ATPase)-dependent H+ transport and ATP hydrolysis. Vitiello et al. (2010) found that an Sdo1 deletion strain had decreased vacuolar pH and V-ATPase-dependent H+ transport and ATP hydrolysis; the alterations resulted from decreased V-ATPase subunit expression. Overexpression of Btn1 or the presence of ionophore carbonyl cyanide m-chlorophenil hydrazone (CCCP) caused decreased growth in yeast lacking Sdo1. In normal cells, overexpression of Btn1 mirrored the effect of CCCP, with both resulting in increased vacuolar pH due to alterations in the coupling of V-ATPase-dependent H+ transport and ATP hydrolysis. The authors proposed that Sdo1 and SBDS work to regulate Btn1 and CLN3, respectively. </p><p><strong><em>Role in Tumorigenesis</em></strong></p><p>
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Juvenile Batten disease is a neurodegenerative disease caused by accelerated apoptotic death of photoreceptors and neurons resulting from defects in the CLN3 gene. CLN3 is antiapoptotic when overexpressed in NT2 neuronal precursor cells. Because defects in regulation of apoptosis are involved in the development of cancer, Rylova et al. (2002) evaluated the expression of CLN3 on both mRNA and protein levels in a variety of cancer cell lines and solid colon cancer tissue. They showed that CLN3 mRNA and protein are overexpressed in a variety of human cancer cell lines. It was also upregulated in mouse melanoma and breast carcinoma cancer cell lines. In 8 of 10 solid colon tumors, they found CLN3 expression 22 to 330% higher than in corresponding colon control tissue. Blocking of CLN3 expression using an adenovirus-expressing antisense CLN3 inhibited growth and viability of cancer cells. It also caused elevation in endogenous ceramide production through de novo ceramide synthesis and resulted in increased apoptosis. This suggested that antisense-CLN3 may be an option for therapy in some cancers. More importantly, these results suggested that CLN3 is a novel molecular target for cancer drug discovery. </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<p>The International Batten Disease Consortium (1995) demonstrated that the mutation responsible for 73% of Batten disease (CLN3; 204200) chromosomes, as identified by the 56 haplotype, is a genomic deletion of 1.02 kb (607042.0001) in the CLN3 gene. </p><p>Munroe et al. (1997) identified homozygosity for the common 1.02-kb CLN3 deletion in 139 (74%) of 188 unrelated patients with Batten disease; 41 were compound heterozygous for the deletion and another CLN3 mutation. By SSCP analysis and direct sequencing, Munroe et al. (1997) found 19 novel mutations in the CLN3 gene: 6 missense mutations, 5 nonsense mutations, 3 small deletions, 3 small insertions, 1 intronic mutation, and 1 splice site mutation. This report brought the total number of known disease-associated mutations in CLN3 to 23. All patients homozygous for mutations predicted to give rise to truncated proteins were found to have classic juvenile-onset CLN3. However, 4 patients who were compound heterozygotes for a missense mutation and a 1.02-kb deletion were found to display an atypical phenotype that was dominated by visual failure rather than by severe neurodegeneration. All missense mutations were found to affect residues conserved between the human protein and homologs in diverse species. </p><p>Lauronen et al. (1999) presented the phenotypes of 10 different Finnish compound heterozygotes with the common 1.02-kb deletion (607042.0001) and 1 of 5 rare CLN3 mutations on the other chromosome. They identified a novel mutation, resulting in a deletion of exons 10 through 13, in 3 families with a total of 6 patients. This mutation differed from that described in 607042.0002 in that it spared marker D16S298. </p><p>Mole et al. (1999) tabulated the mutations that had been identified in the various CLNs; they reported 25 mutations and 2 polymorphisms associated with CLN3. </p><p>Persaud-Sawin et al. (2002) demonstrated that CLN3-deficient immortalization of lymphoblasts homozygous for the common 1.02-kb deletion (607042.0001) grew at a slower rate, and showed increased sensitivity to etoposide-induced apoptosis, supporting the notion that CLN3 may negatively regulate apoptosis. Protection from etoposide-induced apoptosis was evident and the cell growth rate was restored following transfection of JNCL lymphoblasts with mutant CLN3 cDNA that included exons 11 or 13. Deletion of the glycosylation sites 71-74 and 310-313, and mutations within the highly conserved amino acid stretches 184-195, 291-295, or 330-337, resulted in slowed growth and susceptibility to apoptosis. </p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>Haskell et al. (2000) examined the effect of naturally occurring point mutations on the intracellular localization of CLN3, their ability to complement the CLN3-deficient yeast btn1-delta, and a putative farnesylation motif thought to be involved in CLN3 trafficking. All 6 missense mutations studied, like wildtype CLN3, were highly associated with lysosome-associated membrane protein II (309060) in nonneuronal cells and with synaptophysin (313475) in neuronal cell lines. In a yeast functional assay, point mutations correlating with a mild phenotype also demonstrated CLN3 activity, whereas the mutations associated with severe disease failed to restore CLN3 function completely. CLN3 with a mutation in the farnesylation motif trafficked normally but was functionally impaired. The authors concluded that point mutations causative of Batten disease do not affect protein trafficking but rather exert their effects by impairing protein function. </p>
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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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<p>Cotman et al. (2002) introduced the common 1-kb genomic DNA deletion into the murine CLN3 homolog to create Cln3 (ex7/8) knockin mice. This allele produced alternatively spliced mRNAs, including a variant predicting a nontruncated protein, as well as mutant battenin that was detected in the cytoplasm of cells in the periphery and CNS. Moreover, Cln3 (ex7/8) homozygotes exhibited accrual of JNCL-like membrane deposits from before birth, in proportion to battenin levels, which were high in liver and select neuronal populations. Although liver enzymes and CNS development were normal, Cln3 (ex7/8) mice displayed recessively inherited degenerative changes in retina, cerebral cortex, and cerebellum, as well as neurologic deficits and premature death. The authors concluded that the harmful impact of the common JNCL mutation on the CNS was not well correlated with membrane deposition per se, suggesting instead a specific battenin activity that is essential for the survival of CNS neurons. </p><p>In brains of homozygous Cln3(ex7/8) mice, Cao et al. (2006) found upregulation of the autophagy marker Lc3 II (see 601242) and downregulation of the autophagy inhibitor Mtor (FRAP1; 601231). Isolated autophagic vacuoles and lysosomes from homozygous Cln3(ex7/8) mice were less mature in their ultrastructural morphology than wildtype organelles, and mitochondrial ATPase subunit c (see ATP5G1; 603192) accumulated in autophagic vacuoles, similar to that seen in JNCL. Cao et al. (2006) also observed mitochondrial ATPase subunit c accumulation in autophagic vacuoles in normal aging mice. Lc3-positive vesicles isolated from Cln3(ex7/8) cerebellar cells showed altered trafficking and reduced fusion of endocytic and lysosomal vesicles upon stimulation of autophagy. Stimulation of autophagy did not significantly impact cell survival in homozygous Cln3(ex7/8) cells, but inhibition of autophagy led to cell death. Cao et al. (2006) concluded that autophagy is disrupted in JNCL, likely at the level of autophagic vacuolar maturation, and they proposed that activation of autophagy may be a prosurvival feedback response in the disease process. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>7 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, 3</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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CLN3, 1.02-KB DEL
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<br />
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SNP: rs1555468634,
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ClinVar: RCV000003731, RCV000724164, RCV003324482
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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>The International Batten Disease Consortium (1995) demonstrated that the mutation responsible for 73% of Batten disease (CLN3; 204200) chromosomes as identified by the 56 haplotype is a genomic deletion of 1.02 kb, including 217 bp of the open reading frame (nucleotides 598-814), corresponding to 2 exons. Deletion of these 217 bp of coding sequence produces a frameshift, generating a TAA termination codon 84 bp downstream of the deletion junction. The predicted translation product is a truncated protein of 181 amino acids consisting of the first 153 residues of the protein, followed by 28 novel amino acids before the stop codon. </p><p>In Finland, 90% of patients with Batten disease carry the 1.02-kb deletion. Jarvela et al. (1996) developed a rapid diagnostic solid-phase minisequencing test to detect this deletion. </p><p>This 1.02-kb deletion in homozygous form always causes a severe phenotype, including blindness, epilepsy, dementia, and early death at approximately 24 years of age (Munroe et al., 1997; Jarvela et al., 1997). </p><p>Kitzmuller et al. (2008) demonstrated that the common 1.02-kb deletion retains residual function. Two mutant CLN3 transcripts were present in patient cells homozygous for the mutation: the major transcript encoded a truncated protein encoding residues 1 through 153 followed by 28 additional amino acids, and the minor transcript encoded a protein that spliced exon 6 to exon 10 with restoration of the reading frame after exon 10. When RNA silencing was used to deplete these transcripts in patients' cells, the lysosomes significantly increased in size, confirming that the protein was functional. Overexpression of mutant CLN3 transcript consistently caused lysosomes to decrease in size. Studies in mouse cell models and yeast confirmed that the corresponding mutant transcripts retained significant function. The majority of the mutant 1.02-kb deletion CLN3 protein was retained within the endoplasmic reticulum. Kitzmuller et al. (2008) concluded that the common mutant CLN3 protein retains significant function and that JNCL is a mutation-specific disease phenotype. The residual function likely explains why this form of CLN shows later onset and less severe clinical manifestations compared to other forms of CLN. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 CEROID LIPOFUSCINOSIS, NEURONAL, 3</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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CLN3, 3-KB DEL, NT928
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<br />
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ClinVar: RCV000003732
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a Finnish patient with Batten disease (204200), the International Batten Disease Consortium (1995) identified compound heterozygosity for 2 deletions in the CLN3 gene: the 1.02-kb deletion (607042.0001) and a 3-kb deletion resulting in a 266-bp coding sequence deletion (nucleotides 928-1193), resulting in a truncated protein with the first 263 amino acids of CLN3 followed by 28 novel amino acids before a stop codon. </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, 3</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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CLN3, 6-KB DEL
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<br />
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ClinVar: RCV000003733
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient of Moroccan origin with Batten disease (204200), Taschner et al. (1995) demonstrated homozygosity for a deletion in the CLN3 gene. The International Batten Disease Consortium (1995) reported that this patient had a 6-kb deletion. </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, 3</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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CLN3, IVSDS, G-C, +1/76-BP DEL
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<br />
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SNP: rs386833728,
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ClinVar: RCV000049691, RCV001853043
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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>The International Batten Disease Consortium (1995) described a Finnish patient, L198Pa, with Batten disease (204200) who was a compound heterozygote for one '56 chromosome' (607042.0001) and one '76 chromosome' (D16S988/D16S298). They found a deletion of a 73-bp exon corresponding to bases 598-670 of the cDNA. Nucleotide sequence analysis showed a G-to-C transversion at +1 of the splice donor site following the exon. The father was a heterozygous carrier of the mutation. The patient had an uneventful birth and early childhood. Progressive visual failure began at age 7. At age 9, she showed an abnormal MRI. Vacuolated lymphocytes were repeatedly observed, and electron microscopy of a rectal biopsy specimen showed inclusions typical of Batten disease. She was placed on sodium valproate medication at age 9, when she experienced her only seizure. Repeat examination at the age of 13 showed good motor function but mental decline that had been relatively fast. </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, 3, PROTRACTED</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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CLN3, GLU295LYS
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<br />
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SNP: rs121434286,
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gnomAD: rs121434286,
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ClinVar: RCV000003735, RCV000055839, RCV000811923, RCV001074385, RCV001270479, RCV002512720, RCV004791194
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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 sibs with a rare, protracted form of juvenile-onset neuronal ceroid lipofuscinosis (CLN3; 204200), Wisniewski et al. (1998) identified compound heterozygosity for 2 mutations in the CLN3 gene: a 1.02-kb deletion (607042.0001) and a 1020G-A transition, resulting in a glu295-to-lys (E295K) substitution. Both sibs had disease onset at age 5 years, but the sister lived until age 51 and the brother was still living at age 39. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 CEROID LIPOFUSCINOSIS, NEURONAL, 3, PROTRACTED</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
CLN3, TYR199TER
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<br />
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|
|
SNP: rs267606737,
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|
|
gnomAD: rs267606737,
|
|
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|
|
ClinVar: RCV000003736, RCV000169443, RCV000760368, RCV000823290
|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 sibs, born of consanguineous Lebanese parents, with a protracted form of juvenile-onset neuronal ceroid lipofuscinosis (CLN3; 204200), Sarpong et al. (2009) identified a homozygous 597C-A transversion in exon 8 of the CLN3 gene, resulting in a tyr199-to-ter (Y199X) substitution and loss of 239 C-terminal amino acids. RT-PCR analysis detected the mutant transcript, indicating that it was not degraded by nonsense-mediated mRNA decay. The Y199X mutation was identified in heterozygosity in both parents and 4 sibs but not in 200 control alleles. In this family, onset of the disorder occurred at 4 to 5 years of age, with affected children becoming silent, taciturn, and irritable. Visual loss occurred between 6 and 9 years, epilepsy between 10 and 15 years, and insidious onset of a movement disorder soon after. However, all were able to walk independently until age 20 years. The diagnosis was confirmed by pathologic studies. </p>
|
|
</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 CEROID LIPOFUSCINOSIS, NEURONAL, 3, PROTRACTED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
CLN3, GLY165GLU
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|
|
<br />
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|
|
SNP: rs786201028,
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|
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|
|
|
|
|
ClinVar: RCV000162326
|
|
|
|
|
|
</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 adult Italian brothers, whose parents were consanguineous, with a protracted form of juvenile-onset neuronal ceroid lipofuscinosis (CLN3; 204200), Cortese et al. (2014) identified a homozygous c.494G-A transition in the CLN3 gene, resulting in a gly165-to-glu (G165E) substitution at a highly conserved residue in the second luminal loop. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against SNP databases. The unaffected mother was heterozygous for the mutation; the father was deceased. Functional studies of the variant were not performed. Both patients had loss of vision in childhood, but no other neurologic abnormalities. Later in life, they both developed hypertrophic cardiomyopathy, seizures, and very mild cognitive impairment. Muscle biopsy showed large autophagic vacuoles and autofluorescent material. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
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|
</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Cao, Y., Espinola, J. A., Fossale, E., Massey, A. C., Cuervo, A. M., MacDonald, M. E., Cotman, S. L.
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<strong>Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis.</strong>
|
|
J. Biol. Chem. 281: 20483-20493, 2006.
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[PubMed: 16714284]
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[Full Text: https://doi.org/10.1074/jbc.M602180200]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Chang, J.-W., Choi, H., Kim, H.-J., Jo, D.-G., Jeon, Y.-J., Noh, J.-Y., Park, W. J., Jung, Y.-K.
|
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<strong>Neuronal vulnerability of CLN3 deletion to calcium-induced cytotoxicity is mediated by calsenilin.</strong>
|
|
Hum. Molec. Genet. 16: 317-326, 2007.
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[PubMed: 17189291]
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[Full Text: https://doi.org/10.1093/hmg/ddl466]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Cortese, A., Tucci, A., Piccolo, G., Galimberti, C. A., Fratta, P., Marchioni, E., Grampa, G., Cereda, C., Grieco, G., Ricca, I., Pittman, A., Ciscato, P., and 9 others.
|
|
<strong>Novel CLN3 mutation causing autophagic vacuolar myopathy.</strong>
|
|
Neurology 82: 2072-2076, 2014.
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[PubMed: 24827497]
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[Full Text: https://doi.org/10.1212/WNL.0000000000000490]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Cotman, S. L., Vrbanac, V., Lebel, L.-A., Lee, R. L., Johnson, K. A., Donahue, L.-R., Teed, A. M., Antonellis, K., Bronson, R. T., Lerner, T. J., MacDonald, M. E.
|
|
<strong>Cln3 (ex7/8) knock-in mice with the common JNCL mutation exhibit progressive neurologic disease that begins before birth.</strong>
|
|
Hum. Molec. Genet. 11: 2709-2721, 2002.
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[PubMed: 12374761]
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[Full Text: https://doi.org/10.1093/hmg/11.22.2709]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Haskell, R. E., Carr, C. J,., Pearce, D. A., Bennett, M. J., Davidson, B. L.
|
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<strong>Batten disease: evaluation of CLN3 mutations on protein localization and function.</strong>
|
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Hum. Molec. Genet. 9: 735-744, 2000.
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[PubMed: 10749980]
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[Full Text: https://doi.org/10.1093/hmg/9.5.735]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Hobert, J. A., Dawson, G.
|
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<strong>A novel role of the Batten disease gene CLN3: association with BMP synthesis.</strong>
|
|
Biochem. Biophys. Res. Commun. 358: 111-116, 2007.
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[PubMed: 17482562]
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[Full Text: https://doi.org/10.1016/j.bbrc.2007.04.064]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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|
International Batten Disease Consortium.
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<strong>Isolation of a novel gene underlying Batten disease, CLN3.</strong>
|
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Cell 82: 949-957, 1995.
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[PubMed: 7553855]
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[Full Text: https://doi.org/10.1016/0092-8674(95)90274-0]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Janes, R. W., Munroe, P. B., Mitchison, H. M., Gardiner, R. M., Mole, S. E., Wallace, B. A.
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<strong>A model for Batten disease protein CLN3: functional implications from homology and mutations.</strong>
|
|
FEBS Lett. 399: 75-77, 1996.
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[PubMed: 8980123]
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[Full Text: https://doi.org/10.1016/s0014-5793(96)01290-2]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Jarvela, I., Autti, T., Lamminranta, S., Aberg, L., Raininko, R., Santavuori, P.
|
|
<strong>Clinical and magnetic resonance imaging findings in Batten disease: analysis of the major mutation (1.02 kb deletion).</strong>
|
|
Ann. Neurol. 42: 799-802, 1997.
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[PubMed: 9392580]
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[Full Text: https://doi.org/10.1002/ana.410420517]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Jarvela, I., Lehtovirta, M., Tikkanen, R., Kyttala, A., Jalanko, A.
|
|
<strong>Defective intracellular transport of CLN3 is the molecular basis of Batten disease (JNCL).</strong>
|
|
Hum. Molec. Genet. 8: 1091-1098, 1999. Note: Erratum: Hum. Molec. Genet. 8: 1585 only, 1999.
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Narayan, S. B., Rakheja, D., Tan, L., Pastor, J. V., Bennett, M. J.
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<strong>CLN3P, the Batten's disease protein, is a novel palmitoyl-protein delta-9 desaturase.</strong>
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Persaud-Sawin, D.-A. N. W., VanDongen, A., Boustany, R.-M. N.
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Rakheja, D., Narayan, S. B., Pastor, J. V., Bennett, M. J.
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<strong>CLN3P, the Batten disease protein, localizes to membrane lipid rafts (detergent-resistant membranes).</strong>
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