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Entry
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- *138945 - GRANULIN PRECURSOR; GRN
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*138945</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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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#nomenclature">Nomenclature</a>
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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/138945">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel 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=ENSG00000030582;t=ENST00000053867" 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=2896" 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=138945" 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="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=ENSG00000030582;t=ENST00000053867" 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_002087" 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_002087" 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=138945" 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=00733&isoform_id=00733_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/GRN" 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/31193,183613,3005730,4504151,10435244,12653115,14714851,22252940,30582527,62896603,77416865,119571984,119571985,119571986,194382178,194383612" 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/P28799" 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=2896" 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=ENSG00000030582;t=ENST00000053867" 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=GRN" 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=GRN" 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+2896" 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/GRN" 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:2896" 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/2896" 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=chr17&hgg_gene=ENST00000053867.8&hgg_start=44345302&hgg_end=44353106&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:4601" 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/grn" 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=138945[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=138945[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/ENSG00000030582" 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=GRN" 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=GRN" 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=GRN" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.molgen.ua.ac.be/ADMutations/" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=GRN&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/PA28998" 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:4601" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:95832" 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/GRN#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:95832" 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/2896/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://www.orthodb.org/?ncbi=2896" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00011936;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-7393" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
|
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</div>
|
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=GRN&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 230270009<br />
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<strong>ICD10CM:</strong> G31.0, G31.01<br />
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<strong>ICD9CM:</strong> 331.1<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
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138945
|
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
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GRANULIN PRECURSOR; GRN
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</span>
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</h3>
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</div>
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<div>
|
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
PROGRANULIN; PGRN<br />
|
|
EPITHELIN PRECURSOR<br />
|
|
PROEPITHELIN; PEPI<br />
|
|
GRANULIN-EPITHELIN PRECURSOR; GEP<br />
|
|
PC CELL-DERIVED GROWTH FACTOR; PCDGF<br />
|
|
ACROGRANIN<br />
|
|
GLYCOPROTEIN, 88-KD; GP88
|
|
</span>
|
|
</h4>
|
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</div>
|
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</div>
|
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="includedTitles" class="mim-anchor"></a>
|
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<div>
|
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<p>
|
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<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
GRANULINS, INCLUDED
|
|
</span>
|
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</div>
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<div>
|
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<span class="h4 mim-font">
|
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|
|
EPITHELINS, INCLUDED
|
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</span>
|
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</div>
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</div>
|
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=GRN" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">GRN</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/17/638?start=-3&limit=10&highlight=638">17q21.31</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr17:44345302-44353106&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'})">17:44,345,302-44,353,106</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=607485,614706,607485" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/17/638?start=-3&limit=10&highlight=638">
|
|
17q21.31
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Aphasia, primary progressive
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/607485"> 607485 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
|
</span>
|
|
</td>
|
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</tr>
|
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|
|
|
|
|
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|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Ceroid lipofuscinosis, neuronal, 11
|
|
|
|
</span>
|
|
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<p>Progranulin is an 88-kD glycoprotein that functions as an autocrine growth factor. It can also be processed into several 6-kD growth-modulating peptides called granulins or epithelins, which are characterized by a highly conserved motif containing 12 cysteines (summary by <a href="#48" class="mim-tip-reference" title="Serrero, G. <strong>Autocrine growth factor revisited: PC-cell-derived growth factor (progranulin), a critical player in breast cancer tumorigenesis.</strong> Biochem. Biophys. Res. Commun. 308: 409-413, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12914763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12914763</a>] [<a href="https://doi.org/10.1016/s0006-291x(03)01452-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12914763">Serrero, 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12914763" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>From a human bone marrow cDNA library, <a href="#8" class="mim-tip-reference" title="Bhandari, V., Palfree, R. G. E., Bateman, A. <strong>Isolation and sequence of the granulin precursor cDNA from human bone marrow reveals tandem cysteine-rich granulin domains.</strong> Proc. Nat. Acad. Sci. 89: 1715-1719, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1542665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1542665</a>] [<a href="https://doi.org/10.1073/pnas.89.5.1715" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1542665">Bhandari et al. (1992)</a> isolated GRN. The deduced 593-residue protein contains a 56-residue GrnA sequence, as well as 6 other cysteine-rich granulin-like domains, including GrnB, GrnC, and GrnD, which had previously been known only from N-terminal sequences. The results indicated that 4 known human granulin-like peptides are produced by the precursor protein, progranulin, which has a highly conserved 12-cysteine backbone defining a consensus sequence that is repeated 7 times. Northern blot analysis detected a 2.3-kb transcript with highest expression in epithelial cell lines, myelogenous leukemic cell lines, and kidney. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1542665" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#19" class="mim-tip-reference" title="He, Z., Bateman, A. <strong>Progranulin gene expression regulates epithelial cell growth and promotes tumor growth in vivo.</strong> Cancer Res. 59: 3222-3229, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10397269/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10397269</a>]" pmid="10397269">He and Bateman (1999)</a> demonstrated that overexpression of the progranulin gene in SW-13 adrenal carcinoma cells and MDCK nontransformed renal epithelia resulted in transfection-specific secretion of progranulin, acquired clonogenicity in semisolid agar, and increased mitosis in monolayer culture, whereas diminution of progranulin gene expression impaired growth of these cells. They proposed that the rate of growth of some epithelia is proportional to the level of intrinsic progranulin gene expression, and that elevated progranulin gene expression confers a transformed phenotype on epithelial cells including anchorage independence in vitro and growth as tumors in nude mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10397269" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Liau, L. M., Lallone, R. L., Seitz, R. S., Buznikov, A., Gregg, J. P., Kornblum, H. I., Nelson, S. F., Bronstein, J. M. <strong>Identification of a human glioma-associated growth factor gene, granulin, using differential immuno-absorption.</strong> Cancer Res. 60: 1353-1360, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10728698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10728698</a>]" pmid="10728698">Liau et al. (2000)</a> found that the 2.1-kb granulin mRNA is expressed predominantly in glial tumors of the brain, with lower levels in spleen, kidney, and testis, whereas expression was not detected in nontumor brain tissues. The differential expression pattern, tissue distribution, and implication of this glioma-associated molecule in growth regulation suggested a potentially important role for granulin in the pathogenesis and/or malignant progression of primary brain neoplasms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10728698" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="He, Z., Ong, C. H. P., Halper, J., Bateman, A. <strong>Progranulin is a mediator of the wound response.</strong> Nature Med. 9: 225-229, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12524533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12524533</a>] [<a href="https://doi.org/10.1038/nm816" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12524533">He et al. (2003)</a> reported that in murine transcutaneous puncture wounds, progranulin mRNA is expressed in the inflammatory infiltrate and is highly induced in dermal fibroblasts and endothelia following injury. When applied to a cutaneous wound, progranulin increased the accumulation of neutrophils, macrophages, blood vessels, and fibroblasts in the wound. It acted directly on isolated dermal fibroblasts and endothelial cells to promote division, migration, and the formation of capillary-like tubule structures. They concluded that progranulin is, therefore, probably a wound-related growth factor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12524533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Increased leukocyte elastase (<a href="/entry/130130">130130</a>) activity in mice lacking secretory leukocyte protease inhibitor (SLPI; <a href="/entry/107285">107285</a>) leads to impaired wound healing due to enhanced activity of transforming growth factor-beta (<a href="/entry/190180">190180</a>) and perhaps additional mechanisms (<a href="#2" class="mim-tip-reference" title="Ashcroft, G. S., Lei, K., Jin, W., Longenecker, G., Kulkarni, A. B., Greenwell-Wild, T., Hale-Donze, H., McGrady, G., Song, X.-Y., Wahl, S. M. <strong>Secretory leukocyte protease inhibitor mediates non-redundant functions necessary for normal wound healing.</strong> Nature Med. 6: 1147-1153, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017147</a>] [<a href="https://doi.org/10.1038/80489" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017147">Ashcroft et al., 2000</a>). Proepithelin (PEPI), also known as progranulin, an epithelial growth factor, can be converted to epithelins (EPIs) in vivo. <a href="#57" class="mim-tip-reference" title="Zhu, J., Nathan, C., Jin, W., Sim, D., Ashcroft, G. S., Wahl, S. M., Lacomis, L., Erdjument-Bromage, H., Tempst, P., Wright, C. D., Ding, A. <strong>Conversion of proepithelin to epithelins: roles of SLPI and elastase in host defense and wound repair.</strong> Cell 111: 867-878, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12526812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12526812</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)01141-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12526812">Zhu et al. (2002)</a> found that PEPI and EPIs exert opposing activities. EPIs inhibited the growth of epithelial cells but induced them to secrete the neutrophil attractant interleukin-8 (IL8; <a href="/entry/146930">146930</a>), while PEPI blocked neutrophil activation by tumor necrosis factor (TNF; <a href="/entry/191160">191160</a>), preventing release of oxidants and proteases. SLPI and PEPI formed complexes, preventing elastase from converting PEPI to EPIs. Supplying PEPI corrected the wound-healing defect in Slpi null mice. The authors concluded that SLPI/elastase act via PEPI/EPIs to operate a switch at the interface between innate immunity and wound healing. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11017147+12526812" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#53" class="mim-tip-reference" title="Tangkeangsirisin, W., Serrero, G. <strong>PC cell-derived growth factor (PCDGF/GP88, progranulin) stimulates migration, invasiveness and VEGF expression in breast cancer cells.</strong> Carcinogenesis 25: 1587-1592, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15117809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15117809</a>] [<a href="https://doi.org/10.1093/carcin/bgh171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15117809">Tangkeangsirisin and Serrero (2004)</a> stated that progranulin stimulates growth in mesenchymal and epithelial cells via the MAP kinase (see MAPK1, <a href="/entry/176948">176948</a>), PI3 kinase (see PIK3CA, <a href="/entry/171834">171834</a>), and FAK (PTK2; <a href="/entry/600758">600758</a>) pathways, and that its overexpression in breast cancer cells correlates positively with acquisition of estrogen-independent growth, tamoxifen resistance, and tumorigenicity. They showed that overexpression of progranulin in MCF-7 cells, an estrogen receptor (see ESR1; <a href="/entry/133430">133430</a>)-positive human breast cancer cell line, stimulated anchorage-independent cell growth and accelerated cell migration in a 3-dimensional gel. Exogenous treatment of MCF-7 cells with progranulin gave similar results. Gelatin zymographs and Western blot analysis revealed that progranulin upregulated expression of matrix metalloprotease-9 (MMP9; <a href="/entry/120361">120361</a>) expression. Progranulin also upregulated VEGF (<a href="/entry/192240">192240</a>) expression. <a href="#53" class="mim-tip-reference" title="Tangkeangsirisin, W., Serrero, G. <strong>PC cell-derived growth factor (PCDGF/GP88, progranulin) stimulates migration, invasiveness and VEGF expression in breast cancer cells.</strong> Carcinogenesis 25: 1587-1592, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15117809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15117809</a>] [<a href="https://doi.org/10.1093/carcin/bgh171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15117809">Tangkeangsirisin and Serrero (2004)</a> concluded that progranulin expression can promote angiogenesis and metastasis in human breast cancer cells, in addition to stimulating cell proliferation and survival. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15117809" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#45" class="mim-tip-reference" title="Rademakers, R., Eriksen, J. L., Baker, M., Robinson, T., Ahmed, Z., Lincoln, S. J., Finch, N., Rutherford, N. J., Crook, R. J., Josephs, K. A., Boeve, B. F., Knopman, D. S., and 10 others. <strong>Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia.</strong> Hum. Molec. Genet. 17: 3631-3642, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18723524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18723524</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18723524[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/ddn257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18723524">Rademakers et al. (2008)</a> identified a predicted binding site for microRNA-659 (MIR659; <a href="/entry/613556">613556</a>) within the 3-prime UTR of GRN. They showed that transfected MIR659 inhibited expression of endogenous GRN in M17 human neuroblastoma cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18723524" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Hu, F., Padukkavidana, T., Vaegter, C. B., Brady, O. A., Zheng, Y., Mackenzie, I. R., Feldman, H. H., Nykjaer, A., Strittmatter, S. M. <strong>Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin.</strong> Neuron 68: 654-667, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21092856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21092856</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21092856[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2010.09.034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21092856">Hu et al. (2010)</a> showed in cellular studies that SORT1 (<a href="/entry/602458">602458</a>) is a cell surface binding site for PGRN. PGRN binds to SORT1 on cortical neurons via its C terminus, and the complex undergoes endocytosis, with delivery of PGRN to lysosomes. PGRN was induced in activated microglia cells surrounding motor neurons after murine spinal cord injury. Sort1-null mice had 5-fold increased levels of Pgrn in brain and serum, suggesting that SORT1 can control PGRN levels in vivo. <a href="#21" class="mim-tip-reference" title="Hu, F., Padukkavidana, T., Vaegter, C. B., Brady, O. A., Zheng, Y., Mackenzie, I. R., Feldman, H. H., Nykjaer, A., Strittmatter, S. M. <strong>Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin.</strong> Neuron 68: 654-667, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21092856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21092856</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21092856[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2010.09.034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21092856">Hu et al. (2010)</a> suggested a role for the endosomal/autophagosomal/lysosomal pathway in the pathogenesis of GRN-related frontotemporal lobar dementia (<a href="/entry/607485">607485</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21092856" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Jiao, J., Herl, L. D., Farese, R. V., Jr., Gao, F.-B. <strong>MicroRNA-29b regulates the expression level of human progranulin, a secreted glycoprotein implicated in frontotemporal dementia.</strong> PLoS One 5: e10551, 2010. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20479936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20479936</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20479936[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pone.0010551" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20479936">Jiao et al. (2010)</a> noted that expression of microRNA-29B (MIR29B; see <a href="/entry/610783">610783</a>) overlaps with that of progranulin. They found that MIR29B suppressed production and secretion of human progranulin by binding directly to the 3-prime UTR of progranulin mRNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20479936" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#52" class="mim-tip-reference" title="Tang, W., Lu, Y., Tian, Q.-Y., Zhang, Y., Guo, F.-J., Liu, G.-Y., Syed, N. M., Lai, Y., Lin, E. A., Kong, L., Su, J., Yin, F., and 10 others. <strong>The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice.</strong> Science 332: 478-484, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21393509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21393509</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21393509[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1199214" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21393509">Tang et al. (2011)</a> reported that PGRN bound directly to tumor necrosis factor receptors (TNFR1, <a href="/entry/191190">191190</a> and TNFR2, <a href="/entry/191191">191191</a>) and disturbed the TNFA-TNFR interaction. Pgrn-deficient mice were susceptible to collagen-induced arthritis, and administration of PGRN reversed inflammatory arthritis. Atsttrin, an engineered protein composed of 3 PGRN fragments, exhibited selective TNFR binding. PGRN and Atsttrin prevented inflammation in multiple arthritis mouse models and inhibited TNFA-activated intracellular signaling. <a href="#52" class="mim-tip-reference" title="Tang, W., Lu, Y., Tian, Q.-Y., Zhang, Y., Guo, F.-J., Liu, G.-Y., Syed, N. M., Lai, Y., Lin, E. A., Kong, L., Su, J., Yin, F., and 10 others. <strong>The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice.</strong> Science 332: 478-484, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21393509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21393509</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21393509[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1199214" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21393509">Tang et al. (2011)</a> concluded that PGRN is a ligand of TNFR, an antagonist of TNFA signaling, and plays a critical role in the pathogenesis of inflammatory arthritis in mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21393509" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Toll-like receptors, such as TLR9 (<a href="/entry/605474">605474</a>), recognize different components of microbial cells and play critical roles in innate and adaptive immunity. TLR9 belongs to a group of TLRs that detect nucleic acids and are found in endolysosomal compartments. By immunoprecipitation analysis of mouse macrophages, <a href="#41" class="mim-tip-reference" title="Park, B., Buti, L., Lee, S., Matsuwaki, T., Spooner, E., Brinkmann, M. M., Nishihara, M., Ploegh, H. L. <strong>Granulin is a soluble cofactor for Toll-like receptor 9 signaling.</strong> Immunity 34: 505-513, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21497117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21497117</a>] [<a href="https://doi.org/10.1016/j.immuni.2011.01.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21497117">Park et al. (2011)</a> found that granulin interacted with Tlr9. Exposure of mouse macrophages to TLR agonists and inhibitors of elastase, which is required for conversion of granulin from its precursor, blocked CpG-elicited Tnf production via Tlr9 signaling, but it did not interfere with signaling through other TLRs. Inhibitors of elastase had no effect on Tlr9 cleavage. Depletion of granulin in mouse cells impaired Tlr9 responses to CpG, whereas addition of granulin potentiated Tlr9 responses to CpG. In the absence of serum, macrophages from mice lacking granulin were also unable to generate Tlr9-mediated responses. Addition of exogenous granulin restored responses to CpG. Confocal microscopy demonstrated binding of CpG to Tlr9 from wildtype macrophages, but not from granulin -/- macrophages. <a href="#41" class="mim-tip-reference" title="Park, B., Buti, L., Lee, S., Matsuwaki, T., Spooner, E., Brinkmann, M. M., Nishihara, M., Ploegh, H. L. <strong>Granulin is a soluble cofactor for Toll-like receptor 9 signaling.</strong> Immunity 34: 505-513, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21497117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21497117</a>] [<a href="https://doi.org/10.1016/j.immuni.2011.01.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21497117">Park et al. (2011)</a> proposed that granulin contributes to innate immunity by functioning as a critical soluble cofactor for TLR9 signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21497117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 immunohistochemical analysis, <a href="#22" class="mim-tip-reference" title="Huang, K., Chen, A., Zhang, X., Song, Z., Xu, H., Cao, J., Yin, Y. <strong>Progranulin is preferentially expressed in patients with psoriasis vulgaris and protects mice form psoriasis-like skin inflammation.</strong> Immunology 145: 279-287, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25626394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25626394</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25626394[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/10.1111/imm.12446" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25626394">Huang et al. (2015)</a> demonstrated marked expression of PGRN in epidermal keratinocytes of psoriasis (see <a href="/entry/177900">177900</a>) patients, but no expression in nearly all controls. RT-PCR detected significantly higher PGRN levels in psoriatic lesions compared with normal skin. Serum PGRN levels were significantly higher in patients compared with controls, but they were at the same level as healthy controls after treatment. Serum levels of TNF were also significantly higher in untreated patients compared with controls. Psoriasis severity was negatively correlated with PGRN/TNF ratio. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25626394" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Reviews</em></strong></p><p>
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<a href="#48" class="mim-tip-reference" title="Serrero, G. <strong>Autocrine growth factor revisited: PC-cell-derived growth factor (progranulin), a critical player in breast cancer tumorigenesis.</strong> Biochem. Biophys. Res. Commun. 308: 409-413, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12914763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12914763</a>] [<a href="https://doi.org/10.1016/s0006-291x(03)01452-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12914763">Serrero (2003)</a> reviewed the role of progranulin in breast cancer tumorigenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12914763" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#7" class="mim-tip-reference" title="Bhandari, V., Bateman, A. <strong>Structure and chromosomal location of the human granulin gene.</strong> Biochem. Biophys. Res. Commun. 188: 57-63, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1417868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1417868</a>] [<a href="https://doi.org/10.1016/0006-291x(92)92349-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1417868">Bhandari and Bateman (1992)</a> showed that the protein-coding region of the GRN gene comprises 12 exons covering about 3,700 bp. Each tandem granulin repeat is encoded by 2 nonequivalent exons, a configuration unique to the granulins that would permit the formation of hybrid granulin-like proteins by alternate splicing. <a href="#13" class="mim-tip-reference" title="Cruts, M., Gijselinck, I., van der Zee, J., Engelborghs, S., Wils, H., Pirici, D., Rademakers, R., Vandenberghe, R., Dermaut, B., Martin, J.-J., van Duijn, C., Peeters, K., and 10 others. <strong>Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.</strong> Nature 442: 920-924, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16862115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16862115</a>] [<a href="https://doi.org/10.1038/nature05017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16862115">Cruts et al. (2006)</a> stated that the GRN gene comprises a total of 13 exons, including a noncoding exon 0. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16862115+1417868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using DNA from human-hamster somatic cell hybrids, <a href="#7" class="mim-tip-reference" title="Bhandari, V., Bateman, A. <strong>Structure and chromosomal location of the human granulin gene.</strong> Biochem. Biophys. Res. Commun. 188: 57-63, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1417868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1417868</a>] [<a href="https://doi.org/10.1016/0006-291x(92)92349-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1417868">Bhandari and Bateman (1992)</a> assigned the granulin precursor gene to chromosome 17. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1417868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 the course of studying the relationship between the ITGA2B (<a href="/entry/607759">607759</a>) and ITGB3 (<a href="/entry/173470">173470</a>) genes, which are both located on 17q21.32, <a href="#54" class="mim-tip-reference" title="Thornton, M. A., Poncz, M., Korostishevsky, M., Yakobson, E., Usher, S., Seligsohn, U., Peretz, H. <strong>The human platelet alpha-IIb gene is not closely linked to its integrin partner beta-3.</strong> Blood 94: 2039-2047, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10477733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10477733</a>]" pmid="10477733">Thornton et al. (1999)</a> found that the GRN gene is located approximately 18 kb downstream to ITGA2B. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10477733" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#4" class="mim-tip-reference" title="Baker, M., Mackenzie, I. R., Pickering-Brown, S. M., Gass, J., Rademakers, R., Lindholm, C., Snowden, J., Adamson, J., Sadovnick, A. D., Rollinson, S., Cannon, A., Dwosh, E., and 15 others. <strong>Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.</strong> Nature 442: 916-919, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16862116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16862116</a>] [<a href="https://doi.org/10.1038/nature05016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16862116">Baker et al. (2006)</a> and <a href="#13" class="mim-tip-reference" title="Cruts, M., Gijselinck, I., van der Zee, J., Engelborghs, S., Wils, H., Pirici, D., Rademakers, R., Vandenberghe, R., Dermaut, B., Martin, J.-J., van Duijn, C., Peeters, K., and 10 others. <strong>Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.</strong> Nature 442: 920-924, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16862115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16862115</a>] [<a href="https://doi.org/10.1038/nature05017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16862115">Cruts et al. (2006)</a> demonstrated that mutations in progranulin that create null alleles cause tau-negative frontotemporal lobar degeneration with ubiquitin (UBB; <a href="/entry/191339">191339</a>)-positive inclusions (<a href="/entry/607485">607485</a>). Patients with frontotemporal dementia caused by mutations in progranulin exhibit ubiquitin-immunoreactive nuclear cytoplasmic inclusions and characteristic lentiform ubiquitin-immunoreactive neuronal intranuclear inclusions. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16862115+16862116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a large 4-generation kindred with autosomal dominant ubiquitin-positive frontotemporal dementia, originally described as having 'hereditary dysphasic disinhibition dementia' (<a href="#32" class="mim-tip-reference" title="Lendon, C. L., Lynch, T., Norton, J., McKeel, D. W., Jr., Busfield, F., Craddock, N., Chakraverty, S., Gopalakrishnan, G., Shears, S. D., Grimmett, W., Wilhelmsen, K. C., Hansen, L., Morris, J. C., Goate, A. M. <strong>Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21-22.</strong> Neurology 50: 1546-1555, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9633693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9633693</a>] [<a href="https://doi.org/10.1212/wnl.50.6.1546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9633693">Lendon et al., 1998</a>), <a href="#38" class="mim-tip-reference" title="Mukherjee, O., Pastor, P., Cairns, N. J., Chakraverty, S., Kauwe, J. S. K., Shears, S., Behrens, M. I., Budde, J., Hinrichs, A. L., Norton, J., Levitch, D., Taylor-Reinwald, L., Gitcho, M., Tu, P.-H., Grinberg, L. T., Liscic, R. M., Armendariz, J., Morris, J. C., Goate, A. M. <strong>HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin.</strong> Ann. Neurol. 60: 314-322, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16983685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16983685</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16983685[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.20963" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16983685">Mukherjee et al. (2006)</a> identified a heterozygous mutation in the GRN gene (<a href="#0008">138945.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16983685+9633693" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#31" class="mim-tip-reference" title="Le Ber, I., van der Zee, J., Hannequin, D., Gijselinck, I., Campion, D., Puel, M., Laquerriere, A., De Pooter, T., Camuzat, A., Van den Broeck, M., Dubois, B., Sellal, F., and 13 others. <strong>Progranulin null mutations in both sporadic and familial frontotemporal dementia.</strong> Hum. Mutat. 28: 846-855, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436289</a>] [<a href="https://doi.org/10.1002/humu.20520" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436289">Le Ber et al. (2007)</a> identified 9 novel null mutations in the GRN gene in 10 (4.8%) of 210 unrelated patients with frontotemporal dementia. The frequency was 12.8% (5 of 39) in familial cases and 3.2% (5 of 158) in sporadic cases. The phenotype was heterogeneous with age at onset ranging from 45 to 74 years and frequent occurrence of early apraxia (50%), visual hallucinations (30%), and parkinsonism (30%). No GRN mutations were identified in 43 patients with a dementia and motor neuron disease. <a href="#31" class="mim-tip-reference" title="Le Ber, I., van der Zee, J., Hannequin, D., Gijselinck, I., Campion, D., Puel, M., Laquerriere, A., De Pooter, T., Camuzat, A., Van den Broeck, M., Dubois, B., Sellal, F., and 13 others. <strong>Progranulin null mutations in both sporadic and familial frontotemporal dementia.</strong> Hum. Mutat. 28: 846-855, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436289</a>] [<a href="https://doi.org/10.1002/humu.20520" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436289">Le Ber et al. (2007)</a> stated that 31 GRN mutations had been identified in patients worldwide. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17436289" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Bruni, A. C., Momeni, P., Bernardi, L., Tomaino, C., Frangipane, F., Elder, J., Kawarai, T., Sato, C., Pradella, S., Wakutani, Y., Anfossi, M., Gallo, M., and 12 others. <strong>Heterogeneity within a large kindred with frontotemporal dementia: a novel progranulin mutation.</strong> Neurology 69: 140-147, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17620546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17620546</a>] [<a href="https://doi.org/10.1212/01.wnl.0000265220.64396.b4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17620546">Bruni et al. (2007)</a> identified a mutation in the GRN gene (<a href="#0011">138945.0011</a>) in 1 of 78 unrelated families with frontotemporal dementia. They noted that incidence of 1.3% was lower than in a previously published series (about 10%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17620546" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 quantitative analysis of PGRN in a series of 103 Belgian patients with frontotemporal dementia, <a href="#18" class="mim-tip-reference" title="Gijselinck, I., van der Zee, J., Engelborghs, S., Goossens, D., Peeters, K., Mattheijssens, M., Corsmit, E., Del-Favero, J., De Deyn, P. P., Van Broeckhoven, C., Cruts, M. <strong>Progranulin locus deletion in frontotemporal dementia.</strong> Hum. Mutat. 29: 53-58, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18157829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18157829</a>] [<a href="https://doi.org/10.1002/humu.20651" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18157829">Gijselinck et al. (2008)</a> identified 1 (1%) patient with a heterozygous 54 to 69-kb genomic deletion encompassing the PGRN gene and 2 centromeric neighboring genes: RUNDC3A (<a href="/entry/605448">605448</a>) and SLC25A39 (<a href="/entry/610820">610820</a>). The patient developed classic frontotemporal dementia at age 71 years without additional symptoms and died 3 years later. The findings confirmed that PGRN haploinsufficiency results in the disease phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18157829" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Most progranulin mutations are nonsense mutations, resulting in nonsense-mediated mRNA decay and reduced protein levels. <a href="#49" class="mim-tip-reference" title="Shankaran, S. S., Capell, A., Hruscha, A. T., Fellerer, K., Neumann, M., Schmid, B., Haass, C. <strong>Missense mutations in the progranulin gene linked to frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions reduce progranulin production and secretion.</strong> J. Biol. Chem. 283: 1744-1753, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17984093/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17984093</a>] [<a href="https://doi.org/10.1074/jbc.M705115200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17984093">Shankaran et al. (2008)</a> demonstrated that missense mutations in the PGRN gene (see, e.g., A9D; <a href="#0008">138945.0008</a>) resulted in decreased protein expression or secretion, consistent with haploinsufficiency. Downregulation of PGRN in human cells did not result in a major redistribution of TDP43 (TARDBP; <a href="/entry/605078">605078</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17984093" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Gijselinck, I., Van Broeckhoven, C., Cruts, M. <strong>Granulin mutations associated with frontotemporal lobar degeneration and related disorders: an update.</strong> Hum. Mutat. 29: 1373-1386, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18543312/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18543312</a>] [<a href="https://doi.org/10.1002/humu.20785" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18543312">Gijselinck et al. (2008)</a> provided a detailed review of granulin mutations associated with frontotemporal lobar degeneration (FTLD). They noted that 63 heterozygous loss-of-function mutations had been identified in 163 families worldwide, representing about 5 to 10% of FTLD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18543312" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a population-based study of 59 patients with pathologically confirmed FTLDU and 433 controls, <a href="#45" class="mim-tip-reference" title="Rademakers, R., Eriksen, J. L., Baker, M., Robinson, T., Ahmed, Z., Lincoln, S. J., Finch, N., Rutherford, N. J., Crook, R. J., Josephs, K. A., Boeve, B. F., Knopman, D. S., and 10 others. <strong>Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia.</strong> Hum. Molec. Genet. 17: 3631-3642, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18723524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18723524</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18723524[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/ddn257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18723524">Rademakers et al. (2008)</a> identified a C-to-T SNP in the 3-prime untranslated region of the GRN gene (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs5848;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs5848</a>; <a href="#0018">138945.0018</a>) that conferred increased risk for the development of FTLDU when present in the homozygous state. Functional studies showed that the T allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs5848;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs5848</a> increased binding of MIR659, a translation suppressor, this providing a novel mechanism for loss of GRN function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18723524" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#56" class="mim-tip-reference" title="Yu, C.-E., Bird, T. D., Bekris, L. M., Montine, T. J., Leverenz, J. B., Steinbart, E., Galloway, N. M., Feldman, H., Woltjer, R., Miller, C. A., Wood, E. M., Grossman, M., and 13 others. <strong>The spectrum of mutations in progranulin: a collaborative study screening 545 cases of neurodegeneration.</strong> Arch. Neurol. 67: 161-170, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20142524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20142524</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20142524[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/10.1001/archneurol.2009.328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20142524">Yu et al. (2010)</a> reported the results of a large collaborative study of GRN mutations involving 8 academic centers. Twenty-four pathogenic GRN mutations, including 8 novel mutations, were found among 434 patients with various forms of cognitive neurodegenerative diseases. Approximately 55% of the patients with FTD for whom information was available had a family history of the disorder. Overall, the frequency of GRN mutations was 6.9% (30 of 434) of all FTD-spectrum cases. The frequency was 21.4% (9 of 42) in those with a pathologically confirmed diagnosis of FTLD-U; 16.0% (28 of 175) of FTD-spectrum cases with a family history; and 56.2% (9 of 16) of FTLD-U with a family history. The authors noted that GRN mutations were found only in FTD-spectrum cases and not in other related neurodegenerative diseases, such as Pick disease (<a href="/entry/172700">172700</a>) or progressive supranuclear palsy (PSNP1; <a href="/entry/601104">601104</a>). In addition, GRN mutations were not found in patients with ALS (<a href="/entry/105400">105400</a>) or multiple system atrophy (MSA; <a href="/entry/146500">146500</a>) in whom TDP43 deposits were a neuropathologic feature. <a href="#56" class="mim-tip-reference" title="Yu, C.-E., Bird, T. D., Bekris, L. M., Montine, T. J., Leverenz, J. B., Steinbart, E., Galloway, N. M., Feldman, H., Woltjer, R., Miller, C. A., Wood, E. M., Grossman, M., and 13 others. <strong>The spectrum of mutations in progranulin: a collaborative study screening 545 cases of neurodegeneration.</strong> Arch. Neurol. 67: 161-170, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20142524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20142524</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20142524[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/10.1001/archneurol.2009.328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20142524">Yu et al. (2010)</a> concluded that haploinsufficiency of GRN is the predominant mechanism leading to FTD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20142524" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Kuang, L., Hashimoto, K., Huang, E. J., Gentry, M. S., Zhu, H. <strong>Frontotemporal dementia non-sense mutation of progranulin rescued by aminoglycosides.</strong> Hum. Molec. Genet. 29: 624-634, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31913476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31913476</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31913476[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/ddz280" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31913476">Kuang et al. (2020)</a> evaluated whether aminoglycosides could facilitate the readthrough of nonsense mutations in the GRN gene by transfecting N2A cells with plasmids with wildtype GRN, one of 3 mutations associated with FTD (R493X, <a href="#0009">138945.0009</a>; Q125X, <a href="#0002">138945.0002</a>; or Y229X), or a mutation associated with juvenile-onset amyotrophic lateral sclerosis (R495X), and testing the readthrough effects of 11 aminoglycosides and a clinically approved readthrough small molecule, PTC124. Both G418 and gentamicin induced the readthrough of GRN with the R493X mutation, but not the other GRN mutants, in a time- and dose-dependent manner. G418 had a stronger effect on readthrough than gentamicin. The readthrough product of the R493X GRN mutant had similar subcellular localization as wildtype GRN, and partially colocalized with the lysosomal marker Lamp1 (<a href="/entry/153330">153330</a>) and the Golgi marker GM130 (<a href="/entry/602580">602580</a>). G418 also led to increased mRNA expression of the R493X mutant, which suggested that G418 also stabilized the mutant mRNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31913476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Autosomal Recessive Frontotemporal Dementia 2</em></strong></p><p>
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In 3 patients from 2 unrelated French families with autosomal recessive FTD2, <a href="#24" class="mim-tip-reference" title="Huin, V., Barbier, M., Bottani, A., Lobrinus, J. A., Clot, F., Lamari, F., Chat, L., Rucheton, B., Fluchere, F., Auvin, S., Myers, P., Gelot, A., and 9 others. <strong>Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms.</strong> Brain 143: 303-319, 2020. Note: Erratum: Brain 143: e24, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31855245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31855245</a>] [<a href="https://doi.org/10.1093/brain/awz377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31855245">Huin et al. (2020)</a> identified homozygous mutations in the GRN gene: a splice site mutation (<a href="#0024">138945.0024</a>) and a frameshift (<a href="#0025">138945.0025</a>). Aside from the 2 sibs in 1 family, additional family segregation studies could not be performed. <a href="#24" class="mim-tip-reference" title="Huin, V., Barbier, M., Bottani, A., Lobrinus, J. A., Clot, F., Lamari, F., Chat, L., Rucheton, B., Fluchere, F., Auvin, S., Myers, P., Gelot, A., and 9 others. <strong>Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms.</strong> Brain 143: 303-319, 2020. Note: Erratum: Brain 143: e24, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31855245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31855245</a>] [<a href="https://doi.org/10.1093/brain/awz377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31855245">Huin et al. (2020)</a> noted that both mutations have been detected in the heterozygous state in patients with autosomal dominant FTD2, suggesting the presence of additional modifying factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31855245" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Autosomal Recessive Neuronal Ceroid Lipofuscinosis-11</em></strong></p><p>
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<a href="#51" class="mim-tip-reference" title="Smith, K. R., Damiano, J., Franceschetti, S., Carpenter, S., Canafoglia, L., Morbin, M., Rossi, G., Pareyson, D., Mole, S. E., Staropoli, J. F., Sims, K. B., Lewis, J., Lin, W.-L., Dickson, D. W., Dahl, H.-H., Bahlo, M., Berkovic, S. F. <strong>Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage.</strong> Am. J. Hum. Genet. 90: 1102-1107, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22608501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22608501</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22608501[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.ajhg.2012.04.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22608501">Smith et al. (2012)</a> identified a homozygous c.813_816 deletion in the GRN gene (<a href="#0015">138945.0015</a>) in 2 Italian sibs with young-adult onset of neuronal ceroid lipofuscinosis-11 (CLN11; <a href="/entry/614706">614706</a>). The patients developed rapidly progressive visual failure in their early twenties, followed by retinal dystrophy, seizures, cerebellar ataxia, and cerebellar hypoplasia. One had cognitive decline. Skin biopsy of 1 patient showed numerous fingerprint profiles in membrane-bound structures in eccrine secretory cells and endothelium. Plasma progranulin levels in the homozygous patients were undetectable and were about 50% decreased in the heterozygous parents. Family history revealed 3 cases of late-onset dementia in both sides of the family, but DNA was not available from these patients. The healthy parents were in their fifties; the molecular findings suggested that they may be at risk for later-onset dementia. <a href="#51" class="mim-tip-reference" title="Smith, K. R., Damiano, J., Franceschetti, S., Carpenter, S., Canafoglia, L., Morbin, M., Rossi, G., Pareyson, D., Mole, S. E., Staropoli, J. F., Sims, K. B., Lewis, J., Lin, W.-L., Dickson, D. W., Dahl, H.-H., Bahlo, M., Berkovic, S. F. <strong>Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage.</strong> Am. J. Hum. Genet. 90: 1102-1107, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22608501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22608501</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22608501[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.ajhg.2012.04.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22608501">Smith et al. (2012)</a> commented on the remarkable phenotypic differences between heterozygous and homozygous GRN mutations, and suggested that progranulin may have a lysosomal function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22608501" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 14-year-old Indian girl, born of consanguineous parents, with CLN11, <a href="#26" class="mim-tip-reference" title="Kamate, M., Detroja, M., Hattiholi, V. <strong>Neuronal ceroid lipofuscinosis type-11 in an adolescent.</strong> Brain Dev. 41: 542-545, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30922528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30922528</a>] [<a href="https://doi.org/10.1016/j.braindev.2019.03.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30922528">Kamate et al. (2019)</a> identified a homozygous nonsense mutation in the GRN gene (W304X; <a href="#0020">138945.0020</a>). The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each unaffected parent and an unaffected sib. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a complete loss of GRN. Serum GRN levels were not assessed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30922528" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 patients from 2 unrelated families with CLN11, <a href="#24" class="mim-tip-reference" title="Huin, V., Barbier, M., Bottani, A., Lobrinus, J. A., Clot, F., Lamari, F., Chat, L., Rucheton, B., Fluchere, F., Auvin, S., Myers, P., Gelot, A., and 9 others. <strong>Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms.</strong> Brain 143: 303-319, 2020. Note: Erratum: Brain 143: e24, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31855245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31855245</a>] [<a href="https://doi.org/10.1093/brain/awz377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31855245">Huin et al. (2020)</a> identified homozygous putative loss-of-function mutations in the GRN gene: a frameshift (<a href="#0021">138945.0021</a>) and a mutation affecting the initiation codon (Met1?; <a href="#0022">138945.0022</a>). The mutations, which were found by exome sequencing or molecular screening of a CLN panel and confirmed by Sanger sequencing, segregated with the disorder in both families. Functional studies of the mutations were not performed, but plasma progranulin was undetectable in the patients, suggesting a complete loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31855245" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 6 patients from 5 unrelated families with CLN11, <a href="#40" class="mim-tip-reference" title="Neuray, C., Sultan, T., Alvi, J. R., Franca, M. C., Jr., Assmann, B., Wagner, M., Canafoglia, L., Franceschetti, S., Rossi, G., Santana, I., Macario, M. C., Almeida, M. R., Kamate, M., Parikh, S., Elloumi, H. Z., Murphy, D., Efthymiou, S., Maroofian, R., Houlden, H. <strong>Early-onset phenotype of bi-allelic GRN mutations.</strong> Brain 144: e22, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33351065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33351065</a>] [<a href="https://doi.org/10.1093/brain/awaa414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33351065">Neuray et al. (2021)</a> identified homozygous putative loss-of-function mutations in the GRN gene (R493X, <a href="#0009">138945.0009</a>; c.813delCACT, <a href="#0015">138945.0015</a>; and c.768dupCC, <a href="#0021">138945.0021</a>). One of the mutations was a deletion of the entire GRN coding sequence. Functional studies of the variants were not performed. Of note, some of these mutations caused FTD2 in the heterozygous state. However, all of the carrier parents, who ranged from 36 to 72 years of age, were healthy and unaffected, although the authors noted that some may have been too young to manifest dementia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33351065" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#42" class="mim-tip-reference" title="Plowman, G. D., Green, J. M., Neubauer, M. G., Buckley, S. D., McDonald, V. L., Todaro, G. J., Shoyab, M. <strong>The epithelin precursor encodes two proteins with opposing activities on epithelial cell growth.</strong> J. Biol. Chem. 267: 13073-13078, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1618805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1618805</a>]" pmid="1618805">Plowman et al. (1992)</a> referred to progranulin as epithelin precursor. <a href="#3" class="mim-tip-reference" title="Baba, T., Hoff, H. B., III, Nemoto, H., Lee, H., Orth, J., Arai, Y., Gerton, G. L. <strong>Acrogranin, an acrosomal cysteine-rich glycoprotein, is the precursor of the growth-modulating peptides, granulins, and epithelins, and is expressed in somatic as well as male germ cells.</strong> Molec. Reprod. Dev. 34: 233-243, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8471244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8471244</a>] [<a href="https://doi.org/10.1002/mrd.1080340302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8471244">Baba et al. (1993)</a> referred to it as acrogranin. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1618805+8471244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#48" class="mim-tip-reference" title="Serrero, G. <strong>Autocrine growth factor revisited: PC-cell-derived growth factor (progranulin), a critical player in breast cancer tumorigenesis.</strong> Biochem. Biophys. Res. Commun. 308: 409-413, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12914763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12914763</a>] [<a href="https://doi.org/10.1016/s0006-291x(03)01452-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12914763">Serrero (2003)</a> noted that progranulin has also been called PC cell-derived growth factor (PCDGF). She suggested that the names progranulin and granulin/epithelin precursor do not reflect the true biologic function of the 88-kD glycoprotein and proposed renaming the protein GP88 to recognize its unique role as a cell growth promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12914763" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#49" class="mim-tip-reference" title="Shankaran, S. S., Capell, A., Hruscha, A. T., Fellerer, K., Neumann, M., Schmid, B., Haass, C. <strong>Missense mutations in the progranulin gene linked to frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions reduce progranulin production and secretion.</strong> J. Biol. Chem. 283: 1744-1753, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17984093/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17984093</a>] [<a href="https://doi.org/10.1074/jbc.M705115200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17984093">Shankaran et al. (2008)</a> demonstrated that downregulation of Pgrn in zebrafish did not affect the subcellular localization of Tdp43 homologs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17984093" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Ahmed, Z., Sheng, H., Xu, Y., Lin, W.-L., Innes, A. E., Gass, J., Yu, X., Wuertzer, C. A., Hou, H., Chiba, S., Yamanouchi, K., Leissring, M., Petrucelli, L., Nishihara, M., Hutton, M. L., McGowan, E., Dickson, D. W., Lewis, J. <strong>Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging.</strong> Am. J. Path. 177: 311-324, 2010. Note: Erratum: Am. J. Path. 177: 2146 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20522652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20522652</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20522652[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/10.2353/ajpath.2010.090915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20522652">Ahmed et al. (2010)</a> found that Grn-null mice were viable, although produced at lower than predicted frequency. Heterozygous Grn (+/-) mice were neuropathologically indistinguishable from controls. In contrast, Grn-null mice developed age-associated, abnormal accumulation of intraneuronal ubiquitin-positive autofluorescent lipofuscin. Lipofuscin was noted in aged wildtype mice at levels comparable with those of young Grn-null mice. Grn-null mice developed microgliosis, astrogliosis, and tissue vacuolation, with focal neuronal loss and severe gliosis becoming apparent with age. <a href="#1" class="mim-tip-reference" title="Ahmed, Z., Sheng, H., Xu, Y., Lin, W.-L., Innes, A. E., Gass, J., Yu, X., Wuertzer, C. A., Hou, H., Chiba, S., Yamanouchi, K., Leissring, M., Petrucelli, L., Nishihara, M., Hutton, M. L., McGowan, E., Dickson, D. W., Lewis, J. <strong>Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging.</strong> Am. J. Path. 177: 311-324, 2010. Note: Erratum: Am. J. Path. 177: 2146 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20522652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20522652</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20522652[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/10.2353/ajpath.2010.090915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20522652">Ahmed et al. (2010)</a> suggested that Grn may play a role in maintaining neuronal function during aging, consistent with it being a trophic factor essential for long-term neuronal survival. Using electron microscopy in fixed brain tissue of Grn-null mice, <a href="#51" class="mim-tip-reference" title="Smith, K. R., Damiano, J., Franceschetti, S., Carpenter, S., Canafoglia, L., Morbin, M., Rossi, G., Pareyson, D., Mole, S. E., Staropoli, J. F., Sims, K. B., Lewis, J., Lin, W.-L., Dickson, D. W., Dahl, H.-H., Bahlo, M., Berkovic, S. F. <strong>Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage.</strong> Am. J. Hum. Genet. 90: 1102-1107, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22608501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22608501</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22608501[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.ajhg.2012.04.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22608501">Smith et al. (2012)</a> found abundant rectilinear profiles diagnostic of neuronal ceroid lipofuscinosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20522652+22608501" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 repeated topical application of the TPA mitogen to mouse ears, <a href="#22" class="mim-tip-reference" title="Huang, K., Chen, A., Zhang, X., Song, Z., Xu, H., Cao, J., Yin, Y. <strong>Progranulin is preferentially expressed in patients with psoriasis vulgaris and protects mice form psoriasis-like skin inflammation.</strong> Immunology 145: 279-287, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25626394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25626394</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25626394[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/10.1111/imm.12446" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25626394">Huang et al. (2015)</a> induced psoriasis-like inflammation in mouse skin and observed increased expression of Pgrn in epidermis and infiltrating inflammatory cells. RT-PCR also detected increased Pgrn expression. Unexpectedly, Pgrn -/- mice had an enhanced inflammatory response to the TPA mitogen in skin compared with wildtype mice. The exacerbated response was associated with lower percentages of regulatory T cells, but not helper T cells, in skin and cervical lymph node. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25626394" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 gene ontology analysis, <a href="#28" class="mim-tip-reference" title="Klein, Z. A., Takahashi, H., Ma, M., Stagi, M., Zhou, M., Lam, T. T., Strittmatter, S. M. <strong>Loss of TMEM106B ameliorates lysosomal and frontotemporal dementia-related phenotypes in progranulin-deficient mice.</strong> Neuron 95: 281-296, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28728022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28728022</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28728022[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2017.06.026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28728022">Klein et al. (2017)</a> found that lysosomal enzymes and markers were upregulated in maturing Grn -/- mouse brain. Elevated lysosomal enzyme activities followed elevated protein content, suggesting that lysosomal enzymes were properly folded and functional in Grn -/- brain. In contrast, Tmem106b (<a href="/entry/613413">613413</a>) -/- mice showed downregulation of multiple lysosomal enzymes upregulated in Grn -/- brain. Deletion of Tmem1206b in Grn -/- mice corrected lysosomal enzyme protein levels and activities, with concomitant correction of FLD-related behaviors and retinal degeneration, but did not improve lipofuscin, C1q (see <a href="/entry/120550">120550</a>), and microglial accumulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28728022" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 8 families with autosomal dominant ubiquitin-positive frontotemporal dementia-2 (FTD2; <a href="/entry/607485">607485</a>) all segregating the same haplotype, presumably from the same Belgian founder (<a href="#55" class="mim-tip-reference" title="van der Zee, J., Rademakers, R., Engelborghs, S., Gijselinck, I., Bogaerts, V., Vandenberghe, R., Santens, P., Caekebeke, J., De Pooter, T., Peeters, K., Lubke, U., Van den Broeck, M., Martin, J.-J., Cruts, M., De Deyn, P. P., Van Broeckhoven, C., Dermaut, B. <strong>A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD.</strong> Brain 129: 841-852, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16495329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16495329</a>] [<a href="https://doi.org/10.1093/brain/awl029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16495329">van der Zee et al., 2006</a>), <a href="#13" class="mim-tip-reference" title="Cruts, M., Gijselinck, I., van der Zee, J., Engelborghs, S., Wils, H., Pirici, D., Rademakers, R., Vandenberghe, R., Dermaut, B., Martin, J.-J., van Duijn, C., Peeters, K., and 10 others. <strong>Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.</strong> Nature 442: 920-924, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16862115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16862115</a>] [<a href="https://doi.org/10.1038/nature05017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16862115">Cruts et al. (2006)</a> identified a heterozygous G-to-C transversion at the +5 position of the intron following the first noncoding exon of the GRN gene (IVS0+5G-C). In silico analysis predicted a marked drop in binding efficiency of the U1 snRNP complex (see <a href="/entry/180680">180680</a>). Furthermore, analysis of full-length progranulin cDNA in lymphoblasts and brain of 2 probands did not identify aberrant transcripts. However, these 2 probands, who were heterozygous for a C/T single-nucleotide polymorphism (SNP) in the 3-prime untranslated sequence, with the C allele segregating on the disease haplotype, showed only the T allele when their lymphoblast and/or brain progranulin cDNAs were sequenced. These data suggested that the mutation results in absent granulin mRNA and protein. This mutation was not identified in 436 control individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16862115+16495329" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Brouwers, N., Nuytemans, K., van der Zee, J., Gijselinck, I., Engelborghs, S., Theuns, J., Kumar-Singh, S., Pickut, B. A., Pals, P., Dermaut, B., Bogaerts, V., De Pooter, T., and 14 others. <strong>Alzheimer and Parkinson diagnoses in progranulin null mutation carriers in an extended founder family.</strong> Arch. Neurol. 64: 1436-1446, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17923627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17923627</a>] [<a href="https://doi.org/10.1001/archneur.64.10.1436" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17923627">Brouwers et al. (2007)</a> identified the IVS0+5G-C mutation in 2 of 666 Belgian patients with a clinical diagnosis of Alzheimer disease (see <a href="/entry/104300">104300</a>). Clinical features of 1 of the cases included memory loss, disorientation, and loss of spontaneous speech. The other patient was shown to be a member of 1 of the families reported by <a href="#13" class="mim-tip-reference" title="Cruts, M., Gijselinck, I., van der Zee, J., Engelborghs, S., Wils, H., Pirici, D., Rademakers, R., Vandenberghe, R., Dermaut, B., Martin, J.-J., van Duijn, C., Peeters, K., and 10 others. <strong>Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.</strong> Nature 442: 920-924, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16862115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16862115</a>] [<a href="https://doi.org/10.1038/nature05017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16862115">Cruts et al. (2006)</a>, reported as having FTLDU. Thus, the phenotype in both patients was also consistent with FTLDU. <a href="#10" class="mim-tip-reference" title="Brouwers, N., Nuytemans, K., van der Zee, J., Gijselinck, I., Engelborghs, S., Theuns, J., Kumar-Singh, S., Pickut, B. A., Pals, P., Dermaut, B., Bogaerts, V., De Pooter, T., and 14 others. <strong>Alzheimer and Parkinson diagnoses in progranulin null mutation carriers in an extended founder family.</strong> Arch. Neurol. 64: 1436-1446, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17923627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17923627</a>] [<a href="https://doi.org/10.1001/archneur.64.10.1436" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17923627">Brouwers et al. (2007)</a> also identified the IVS0+5G-C mutation in 1 of 255 Belgian patients with a clinical diagnosis of Parkinson disease (see <a href="/entry/168600">168600</a>). Although the man presented with parkinsonism, he later developed progressive memory problems, apathy, hypophonia, and frontotemporal dementia. All 3 patients had the same haplotype reported by <a href="#13" class="mim-tip-reference" title="Cruts, M., Gijselinck, I., van der Zee, J., Engelborghs, S., Wils, H., Pirici, D., Rademakers, R., Vandenberghe, R., Dermaut, B., Martin, J.-J., van Duijn, C., Peeters, K., and 10 others. <strong>Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.</strong> Nature 442: 920-924, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16862115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16862115</a>] [<a href="https://doi.org/10.1038/nature05017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16862115">Cruts et al. (2006)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16862115+17923627" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 the large Dutch family with 19 individuals segregating autosomal dominant ubiquitin-positive frontotemporal dementia-2 (FTD2; <a href="/entry/607485">607485</a>) originally reported by <a href="#44" class="mim-tip-reference" title="Rademakers, R., Cruts, M., Dermaut, B., Sleegers, K., Rosso, S. M., Van den Broeck, M., Backhovens, H., van Swieten, J., van Duijn, C. M., Van Broeckhoven, C. <strong>Tau negative frontal lobe dementia at 17q21: significant finemapping of the candidate region to a 4.8 cM interval.</strong> Molec. Psychiat. 7: 1064-1074, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12476321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12476321</a>] [<a href="https://doi.org/10.1038/sj.mp.4001198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12476321">Rademakers et al. (2002)</a>, <a href="#4" class="mim-tip-reference" title="Baker, M., Mackenzie, I. R., Pickering-Brown, S. M., Gass, J., Rademakers, R., Lindholm, C., Snowden, J., Adamson, J., Sadovnick, A. D., Rollinson, S., Cannon, A., Dwosh, E., and 15 others. <strong>Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.</strong> Nature 442: 916-919, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16862116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16862116</a>] [<a href="https://doi.org/10.1038/nature05016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16862116">Baker et al. (2006)</a> and <a href="#13" class="mim-tip-reference" title="Cruts, M., Gijselinck, I., van der Zee, J., Engelborghs, S., Wils, H., Pirici, D., Rademakers, R., Vandenberghe, R., Dermaut, B., Martin, J.-J., van Duijn, C., Peeters, K., and 10 others. <strong>Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.</strong> Nature 442: 920-924, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16862115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16862115</a>] [<a href="https://doi.org/10.1038/nature05017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16862115">Cruts et al. (2006)</a> found a C-to-T transition at nucleotide 373 (c.373C-T, NM_002087.2) of the GRN gene, resulting in a substitution of a termination codon for glutamine-125 (Q125X). <a href="#4" class="mim-tip-reference" title="Baker, M., Mackenzie, I. R., Pickering-Brown, S. M., Gass, J., Rademakers, R., Lindholm, C., Snowden, J., Adamson, J., Sadovnick, A. D., Rollinson, S., Cannon, A., Dwosh, E., and 15 others. <strong>Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.</strong> Nature 442: 916-919, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16862116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16862116</a>] [<a href="https://doi.org/10.1038/nature05016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16862116">Baker et al. (2006)</a> found the mean age of onset in this family to be 65 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16862115+16862116+12476321" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In an American proband with autosomal dominant ubiquitin-positive frontotemporal dementia-2 (FTD2; <a href="/entry/607485">607485</a>), <a href="#4" class="mim-tip-reference" title="Baker, M., Mackenzie, I. R., Pickering-Brown, S. M., Gass, J., Rademakers, R., Lindholm, C., Snowden, J., Adamson, J., Sadovnick, A. D., Rollinson, S., Cannon, A., Dwosh, E., and 15 others. <strong>Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.</strong> Nature 442: 916-919, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16862116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16862116</a>] [<a href="https://doi.org/10.1038/nature05016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16862116">Baker et al. (2006)</a> found a T-to-C transition of the second nucleotide in exon 1 of the GRN gene, which altered the initiating methionine codon (c.2T-C). RT-PCR analysis showed a substantial reduction of mutant mRNA in brain. Another alteration at this codon was found by <a href="#13" class="mim-tip-reference" title="Cruts, M., Gijselinck, I., van der Zee, J., Engelborghs, S., Wils, H., Pirici, D., Rademakers, R., Vandenberghe, R., Dermaut, B., Martin, J.-J., van Duijn, C., Peeters, K., and 10 others. <strong>Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.</strong> Nature 442: 920-924, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16862115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16862115</a>] [<a href="https://doi.org/10.1038/nature05017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16862115">Cruts et al. (2006)</a> (<a href="#0004">138945.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16862115+16862116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 Belgian patient with ubiquitin-positive frontotemporal dementia-2 (FTD2; <a href="/entry/607485">607485</a>), <a href="#13" class="mim-tip-reference" title="Cruts, M., Gijselinck, I., van der Zee, J., Engelborghs, S., Wils, H., Pirici, D., Rademakers, R., Vandenberghe, R., Dermaut, B., Martin, J.-J., van Duijn, C., Peeters, K., and 10 others. <strong>Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.</strong> Nature 442: 920-924, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16862115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16862115</a>] [<a href="https://doi.org/10.1038/nature05017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16862115">Cruts et al. (2006)</a> demonstrated a G-to-A transition in exon 1 of the GRN gene that destroyed the native Kozak sequence surrounding the met1 translation initiation codon (c.3G-A, NM_002087.2). Age of onset was 62 years; death occurred at 72 years. The patient's sister also suffered from dementia and died at age 64. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16862115" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs606231220 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231220;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=rs606231220" 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=rs606231220" 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=RCV000017383" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017383" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017383</a>
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<p>In a large Canadian family with 17 affected individuals segregating autosomal dominant frontotemporal dementia-2 (FTD2; T<a href="/entry/607485">607485</a>), originally reported by <a href="#34" class="mim-tip-reference" title="Mackenzie, I. R., Baker, M., West, G., Woulfe, J., Qadi, N., Gass, J., Cannon, A., Adamson, J., Feldman, H., Lindholm, C., Melquist, S., Pettman, R., Sadovnick, A. D., Dwosh, E., Whiteheart, S. W., Hutton, M., Pickering-Brown, S. M. <strong>A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17.</strong> Brain 129: 853-867, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16401619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16401619</a>] [<a href="https://doi.org/10.1093/brain/awh724" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16401619">Mackenzie et al. (2006)</a>, <a href="#4" class="mim-tip-reference" title="Baker, M., Mackenzie, I. R., Pickering-Brown, S. M., Gass, J., Rademakers, R., Lindholm, C., Snowden, J., Adamson, J., Sadovnick, A. D., Rollinson, S., Cannon, A., Dwosh, E., and 15 others. <strong>Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.</strong> Nature 442: 916-919, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16862116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16862116</a>] [<a href="https://doi.org/10.1038/nature05016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16862116">Baker et al. (2006)</a> identified a 4-bp insertion of CTGC between coding nucleotides 90 and 91 (c.90insCTGC) of the GRN gene, resulting in a frameshift and premature termination in progranulin (Cys31LeufsTer34). The mean age of onset of dementia in this family was 58 years of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16862116+16401619" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#46" class="mim-tip-reference" title="Rohrer, J. D., Warren, J. D., Omar, R., Mead, S., Beck, J., Revesz, T., Holton, J., Stevens, J. M., Al-Sarraj, S., Pickering-Brown, S. M., Hardy, J., Cox, N. C., Collinge, J., Warrington, E. K., Rossor, M. N. <strong>Parietal lobe deficits in frontotemporal lobar degeneration caused by a mutation in the progranulin gene.</strong> Arch. Neurol. 65: 506-513, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18413474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18413474</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18413474[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/10.1001/archneur.65.4.506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18413474">Rohrer et al. (2008)</a> reported a large British kindred with FTLDU associated with the 9c.0insCTGC mutation. The average age at disease onset was 57.8 years. All patients had clinical and radiographic features of frontotemporal lobar degeneration with behavioral changes and language deficits. Nonfluent aphasia was present in 2 patients, and 3 became mute several years into the illness. Most also had features suggestive of parietal lobe involvement, including dyscalculia, visuoperceptual/visuospatial dysfunction, and limb apraxia. Brain imaging showed extension of the atrophy to the parietal lobe. Haplotype analysis indicated common ancestry to the family reported by <a href="#34" class="mim-tip-reference" title="Mackenzie, I. R., Baker, M., West, G., Woulfe, J., Qadi, N., Gass, J., Cannon, A., Adamson, J., Feldman, H., Lindholm, C., Melquist, S., Pettman, R., Sadovnick, A. D., Dwosh, E., Whiteheart, S. W., Hutton, M., Pickering-Brown, S. M. <strong>A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17.</strong> Brain 129: 853-867, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16401619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16401619</a>] [<a href="https://doi.org/10.1093/brain/awh724" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16401619">Mackenzie et al. (2006)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16401619+18413474" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs63749801 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63749801;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=rs63749801" 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=rs63749801" 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=RCV000017384 OR RCV000084442 OR RCV000736253 OR RCV002513074 OR RCV003478976" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017384, RCV000084442, RCV000736253, RCV002513074, RCV003478976" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017384...</a>
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<p>In Canadian (UBC11) and British (F53) families segregating autosomal dominant ubiquitin-positive frontotemporal dementia-2 (FTD2; <a href="/entry/607485">607485</a>), <a href="#4" class="mim-tip-reference" title="Baker, M., Mackenzie, I. R., Pickering-Brown, S. M., Gass, J., Rademakers, R., Lindholm, C., Snowden, J., Adamson, J., Sadovnick, A. D., Rollinson, S., Cannon, A., Dwosh, E., and 15 others. <strong>Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.</strong> Nature 442: 916-919, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16862116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16862116</a>] [<a href="https://doi.org/10.1038/nature05016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16862116">Baker et al. (2006)</a> identified a c.388_391delCAGT deletion starting at nucleotide 388 of the GRN gene, resulting in frameshift (Gln130SerfsTer124). In the Canadian family with 6 affected individuals, the mean age of onset was 68, and in the U.K. family with 3 affected individuals, the mean age of onset was 60 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16862116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 FRONTOTEMPORAL DEMENTIA 2</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> rs606231221 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231221;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/rs606231221?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=rs606231221" 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=rs606231221" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a Canadian family (UBC19) with 9 affected individuals with autosomal dominant ubiquitin-positive frontotemporal dementia-2 (FTD2; <a href="/entry/607485">607485</a>), <a href="#4" class="mim-tip-reference" title="Baker, M., Mackenzie, I. R., Pickering-Brown, S. M., Gass, J., Rademakers, R., Lindholm, C., Snowden, J., Adamson, J., Sadovnick, A. D., Rollinson, S., Cannon, A., Dwosh, E., and 15 others. <strong>Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.</strong> Nature 442: 916-919, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16862116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16862116</a>] [<a href="https://doi.org/10.1038/nature05016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16862116">Baker et al. (2006)</a> identified a splice site mutation at the +1 position of intron 8 of the GRN gene (IVS8+1G-A). The mutation was predicted to lead to skipping of exon 8 from the progranulin mRNA resulting in frameshift (Val279GlyfsTer4); however, no RNA was available for study. Mean age of onset in this family was 61 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16862116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs63751243 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63751243;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/rs63751243?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=rs63751243" 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=rs63751243" 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=RCV000017386 OR RCV000084421 OR RCV001851887" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017386, RCV000084421, RCV001851887" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017386...</a>
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<p>In affected members of a large 4-generation kindred with autosomal dominant ubiquitin-positive frontotemporal dementia-2 (FTD2; <a href="/entry/607485">607485</a>), originally described as having 'hereditary dysphasic disinhibition dementia' (<a href="#32" class="mim-tip-reference" title="Lendon, C. L., Lynch, T., Norton, J., McKeel, D. W., Jr., Busfield, F., Craddock, N., Chakraverty, S., Gopalakrishnan, G., Shears, S. D., Grimmett, W., Wilhelmsen, K. C., Hansen, L., Morris, J. C., Goate, A. M. <strong>Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21-22.</strong> Neurology 50: 1546-1555, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9633693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9633693</a>] [<a href="https://doi.org/10.1212/wnl.50.6.1546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9633693">Lendon et al., 1998</a>), <a href="#38" class="mim-tip-reference" title="Mukherjee, O., Pastor, P., Cairns, N. J., Chakraverty, S., Kauwe, J. S. K., Shears, S., Behrens, M. I., Budde, J., Hinrichs, A. L., Norton, J., Levitch, D., Taylor-Reinwald, L., Gitcho, M., Tu, P.-H., Grinberg, L. T., Liscic, R. M., Armendariz, J., Morris, J. C., Goate, A. M. <strong>HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin.</strong> Ann. Neurol. 60: 314-322, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16983685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16983685</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16983685[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.20963" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16983685">Mukherjee et al. (2006)</a> identified a heterozygous C-A transversion (c.4068C-A) in exon 1 of the GRN gene, resulting in an ala9-to-asp (A9D) substitution. The A9D substitution is predicted to occur in or near the binding site of the signal recognition particle, which targets proteins to the endoplasmic reticulum membrane. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16983685+9633693" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Chen-Plotkin, A. S., Martinez-Lage, M., Sleiman, P. M. A., Hu, W., Greene, R., Wood, E. M., Bing, S., Grossman, M., Schellenberg, G. D., Hatanpaa, K. J., Weiner, M. F., White, C. L., III, and 43 others. <strong>Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration.</strong> Arch. Neurol. 68: 488-497, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21482928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21482928</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21482928[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/10.1001/archneurol.2011.53" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21482928">Chen-Plotkin et al. (2011)</a> found the A9D mutation (c.26C-A) in 6 (6.2%) of 97 unrelated probands with FTLD due to GRN mutations. Those with the A9D mutation appeared to have earlier disease onset and more parkinsonian features compared to patients with other GRN mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21482928" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Variant Function</em></strong></p><p>
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<a href="#39" class="mim-tip-reference" title="Mukherjee, O., Wang, J., Gitcho, M., Chakraverty, S., Taylor-Reinwald, L., Shears, S., Kauwe, J. S. K., Norton, J., Levitch, D., Bigio, E. H., Hatanpaa, K. J., White, C. L., Morris, J. C., Cairns, N. J., Goate, A. <strong>Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia.</strong> Hum. Mutat. 29: 512-521, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18183624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18183624</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18183624[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.20681" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18183624">Mukherjee et al. (2008)</a> reported that the A9D mutation resulted in normal levels of GRN mRNA, but about 50% decreased levels of secreted GRN protein in cell cultures from affected patients. Further in vitro studies showed that the A9D mutant protein was not glycosylated and was detected in the Golgi and cytosol, but not throughout the secretory pathway like the wildtype protein. The findings indicated that the mutation resulted in transcription of the protein with a defect in trafficking that likely resulted in functional haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18183624" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#49" class="mim-tip-reference" title="Shankaran, S. S., Capell, A., Hruscha, A. T., Fellerer, K., Neumann, M., Schmid, B., Haass, C. <strong>Missense mutations in the progranulin gene linked to frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions reduce progranulin production and secretion.</strong> J. Biol. Chem. 283: 1744-1753, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17984093/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17984093</a>] [<a href="https://doi.org/10.1074/jbc.M705115200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17984093">Shankaran et al. (2008)</a> found that expression of the A9D mutation in HeLa cells resulted in cytoplasmic missorting with extremely low protein expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17984093" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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CEROID LIPOFUSCINOSIS, NEURONAL, 11, INCLUDED
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GRN, ARG493TER (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63751294;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs63751294</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"><span class="text-primary">●</span> rs63751294 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63751294;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/rs63751294?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=rs63751294" 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=rs63751294" 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=RCV000017387 OR RCV000084491 OR RCV001039647 OR RCV004755740" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017387, RCV000084491, RCV001039647, RCV004755740" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017387...</a>
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<p><strong><em>Frontotemporal Dementia 2</em></strong></p><p>
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In 3 unrelated patients with ubiquitin-positive frontotemporal lobar degeneration-2 (FTD2; <a href="/entry/607485">607485</a>), <a href="#23" class="mim-tip-reference" title="Huey, E. D., Grafman, J., Wassermann, E. M., Pietrini, P., Tierney, M. C., Ghetti, B., Spina, S., Baker, M., Hutton, M., Elder, J. W., Berger, S. L., Heflin, K. A., Hardy, J., Momeni, P. <strong>Characteristics of frontotemporal dementia patients with a progranulin mutation.</strong> Ann. Neurol. 60: 374-380, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16983677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16983677</a>] [<a href="https://doi.org/10.1002/ana.20969" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16983677">Huey et al. (2006)</a> identified a heterozygous mutation in the GRN gene, resulting in an arg493-to-ter (R493X) substitution. Two patients had a clear family history of the disorder, and all presented with predominantly behavioral symptoms and had rapid disease progression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16983677" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#35" class="mim-tip-reference" title="Mesulam, M., Johnson, N., Krefft, T. A., Gass, J. M., Cannon, A. D., Adamson, J. L., Bigio, E. H., Weintraub, S., Dickson, D. W., Hutton, M. L., Graff-Radford, N. R. <strong>Progranulin mutations in primary progressive aphasia: the PPA1 and PPA3 families.</strong> Arch. Neurol. 64: 43-47, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17210807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17210807</a>] [<a href="https://doi.org/10.1001/archneur.64.1.43" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17210807">Mesulam et al. (2007)</a> identified heterozygosity for a c.1477C-T transition in exon 11 of the GRN gene, resulting in an R493X substitution, in 2 sisters with primary progressive aphasia, a manifestation of FTD2. The phenotype was an isolated aphasia beginning at ages 65 and 62 years, respectively, without other features. There was rapid progression of aphasia to complete mutism within 2 to 3 years. One sister developed a right-sided tremor, clumsiness, rigidity, and impaired motor function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17210807" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Davion, S., Johnson, N., Weintraub, S., Mesulam, M.-M., Engberg, A., Mishra, M., Baker, M., Adamson, J., Hutton, M., Rademakers, R., Bigio, E. H. <strong>Clinicopathologic correlation in PGRN mutations.</strong> Neurology 69: 1113-1121, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17522386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17522386</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17522386[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/10.1212/01.wnl.0000267701.58488.69" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17522386">Davion et al. (2007)</a> identified a heterozygous R493X mutation in 2 unrelated patients with pathologically confirmed FTLDU. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17522386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#43" class="mim-tip-reference" title="Rademakers, R., Baker, M., Gass, J., Adamson, J., Huey, E. D., Momeni, P., Spina, S., Coppola, G., Karydas, A. M., Stewart, H., Johnson, N., Hsiung, G.-Y., and 38 others. <strong>Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C-T (Arg493X) mutation: an international initiative.</strong> Lancet Neurol. 6: 857-868, 2007. Erratum: Lancet Neurol. 6: 1037 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17826340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17826340</a>] [<a href="https://doi.org/10.1016/S1474-4422(07)70221-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17826340">Rademakers et al. (2007)</a> identified the R493X mutation (c.1477C-T, NM_002087.2) in 16 (2%) of 731 patients with a clinical diagnosis of frontotemporal lobar dementia. Further investigation identified a total of 37 patients with R493X from 30 families with FTLD. Initial diagnoses included FTLD, primary progressive aphasia, and Alzheimer disease (<a href="/entry/104300">104300</a>). The majority of patients presented with executive dysfunction or personality changes, followed by memory deficits, and language impairment. In all 13 patients who came to autopsy, the pathological diagnosis was FTLD with neuronal inclusions that contained TDP43 (<a href="/entry/605078">605078</a>) or ubiquitin (UBB; <a href="/entry/191339">191339</a>), but not tau (MAPT; <a href="/entry/157140">157140</a>). Haplotype analyses suggested that R493X arose twice, with a single founder for 27 families. Linear regression analysis suggested that patients with the coding region SNP <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs9897526;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs9897526</a> on their wildtype GRN allele had delayed symptom onset. <a href="#47" class="mim-tip-reference" title="Seelaar, H., Kamphorst, W., Rosso, S. M., Azmani, A., Masdjedi, R., de Koning, I., Maat-Kievit, J. A., Anar, B., Kaat, L. D., Breedveld, G. J., Dooijes, D., Rosemuller, J. M., Bronner, I. F., Rizzu, P., van Swieten, J. C. <strong>Distinct genetic forms of frontotemporal dementia.</strong> Neurology 71: 1220-1226, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18703462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18703462</a>] [<a href="https://doi.org/10.1212/01.wnl.0000319702.37497.72" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18703462">Seelaar et al. (2008)</a> could not confirm the association between age at onset and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs9897526;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs9897526</a> in their cohort of 23 patients with FTLDU. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18703462+17826340" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Chen-Plotkin, A. S., Martinez-Lage, M., Sleiman, P. M. A., Hu, W., Greene, R., Wood, E. M., Bing, S., Grossman, M., Schellenberg, G. D., Hatanpaa, K. J., Weiner, M. F., White, C. L., III, and 43 others. <strong>Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration.</strong> Arch. Neurol. 68: 488-497, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21482928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21482928</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21482928[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/10.1001/archneurol.2011.53" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21482928">Chen-Plotkin et al. (2011)</a> found that R493X was the most common GRN mutation in an international cohort; it was found in 18 (18.6%) of 97 unrelated FTLD probands with GRN mutations. All patients with the R493X mutation shared a common haplotype, suggesting a founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21482928" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Neuronal Ceroid Lipofuscinosis 11</em></strong></p><p>
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In 3 patients from 2 unrelated families (consanguineous Pakistani family A and nonconsanguineous Caucasian family E) with neuronal ceroid lipofuscinosis-11 (CLN11; <a href="/entry/614706">614706</a>), <a href="#40" class="mim-tip-reference" title="Neuray, C., Sultan, T., Alvi, J. R., Franca, M. C., Jr., Assmann, B., Wagner, M., Canafoglia, L., Franceschetti, S., Rossi, G., Santana, I., Macario, M. C., Almeida, M. R., Kamate, M., Parikh, S., Elloumi, H. Z., Murphy, D., Efthymiou, S., Maroofian, R., Houlden, H. <strong>Early-onset phenotype of bi-allelic GRN mutations.</strong> Brain 144: e22, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33351065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33351065</a>] [<a href="https://doi.org/10.1093/brain/awaa414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33351065">Neuray et al. (2021)</a> identified a homozygous c.1477C-T transition in the GRN gene, resulting in an R493X substitution. Functional studies of the variant and studies of patient cells were not performed. All 3 patients had onset of symptoms, including seizures, late in the first decade. None of the carrier parents, who were in their late thirties and forties, had neurologic symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33351065" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs63750873 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63750873;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/rs63750873?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=rs63750873" 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=rs63750873" 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=RCV000084470 OR RCV002281921" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000084470, RCV002281921" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000084470...</a>
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<p>In 3 affected sibs with frontotemporal dementia-2 (FTD2; <a href="/entry/607485">607485</a>) presenting as primary progressive aphasia (PPA) reported by <a href="#29" class="mim-tip-reference" title="Krefft, T. A., Graff-Radford, N. R., Dickson, D. W., Baker, M., Castellani, R. J. <strong>Familial primary progressive aphasia.</strong> Alzheimer Dis. Assoc. Disord. 17: 106-112, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12794388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12794388</a>] [<a href="https://doi.org/10.1097/00002093-200304000-00009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12794388">Krefft et al. (2003)</a>, <a href="#35" class="mim-tip-reference" title="Mesulam, M., Johnson, N., Krefft, T. A., Gass, J. M., Cannon, A. D., Adamson, J. L., Bigio, E. H., Weintraub, S., Dickson, D. W., Hutton, M. L., Graff-Radford, N. R. <strong>Progranulin mutations in primary progressive aphasia: the PPA1 and PPA3 families.</strong> Arch. Neurol. 64: 43-47, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17210807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17210807</a>] [<a href="https://doi.org/10.1001/archneur.64.1.43" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17210807">Mesulam et al. (2007)</a> identified a heterozygous 1-bp deletion (c.998delG) in the GRN gene, resulting in a frameshift and premature termination of the protein. Onset of word-finding and naming difficulties occurred at ages 60, 65, and 61 years, respectively. All showed left frontotemporal atrophy. One patient had mild right motor impairment, including hemiparesis and mild tremor, whereas another had significant parkinsonism and cortical release signs. One patient developed behavioral changes and another dementia. Two patients died mute 12 and 4 years after onset, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17210807+12794388" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs63749905 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63749905;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=rs63749905" 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=rs63749905" 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=RCV000017389 OR RCV000084472 OR RCV001854478" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017389, RCV000084472, RCV001854478" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017389...</a>
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<p>In affected members of a large consanguineous Calabrian Italian family with FTD2 (<a href="/entry/607485">607485</a>), <a href="#11" class="mim-tip-reference" title="Bruni, A. C., Momeni, P., Bernardi, L., Tomaino, C., Frangipane, F., Elder, J., Kawarai, T., Sato, C., Pradella, S., Wakutani, Y., Anfossi, M., Gallo, M., and 12 others. <strong>Heterogeneity within a large kindred with frontotemporal dementia: a novel progranulin mutation.</strong> Neurology 69: 140-147, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17620546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17620546</a>] [<a href="https://doi.org/10.1212/01.wnl.0000265220.64396.b4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17620546">Bruni et al. (2007)</a> identified a heterozygous 1-bp insertion (c.1145insA, NM_002087.2) in exon 9 of the GRN gene, resulting in a frameshift and premature termination at residue 413. The mutation was present in 19 family members, but only 9 showed clinical symptoms. Some of the unaffected mutation carriers were younger than the mean age of onset in the affected members. Four individuals with a similar phenotype from a distant branch of the family did not carry the GRN mutation, suggesting a different genetic mechanism in these patients. The mean age at onset in those with and without the GRN mutation was 63.4 and 74.8 years, respectively, although the range in those with the GRN mutation was large (35 to 87 years). In contrast to the phenocopies, patients with the GRN mutation had more compromised language function, alteration of social behavior, somnolence, and primitive reflexes. Despite the large consanguineous unions in this extended family, there were no homozygous GRN mutation carriers, suggesting that homozygosity may be embryonic lethal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17620546" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs63750548 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63750548;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=rs63750548" 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=rs63750548" 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=RCV000084453 OR RCV000704513 OR RCV000995784 OR RCV001824019" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000084453, RCV000704513, RCV000995784, RCV001824019" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000084453...</a>
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<p>In a man (patient 3) with frontotemporal dementia-2 (FTD2; <a href="/entry/607485">607485</a>) presenting as primary progressive aphasia (PPA) beginning at age 53 years, <a href="#14" class="mim-tip-reference" title="Davion, S., Johnson, N., Weintraub, S., Mesulam, M.-M., Engberg, A., Mishra, M., Baker, M., Adamson, J., Hutton, M., Rademakers, R., Bigio, E. H. <strong>Clinicopathologic correlation in PGRN mutations.</strong> Neurology 69: 1113-1121, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17522386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17522386</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17522386[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/10.1212/01.wnl.0000267701.58488.69" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17522386">Davion et al. (2007)</a> identified a heterozygous A-to-G transition in intron 7 (c.709-2A-G) of the GRN gene, predicted to result in a frameshift and premature termination in exon 8 (Ala237TrpfsTer4). At first he had word finding difficulties, which progressed to problems in writing, reading, and speech comprehension. Language symptoms were predominant until 7 years after onset, when he showed rapid deterioration with behavioral changes. He died at age 61. His mother had been diagnosed with dementia in her fifties and died at age 64. Neuropathologic examination showed diffuse neuronal intranuclear and cytoplasmic inclusions in the frontal cortex and striatum, with significant involvement of the temporal cortex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17522386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs63751085 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63751085;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=rs63751085" 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=rs63751085" 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=RCV000017391 OR RCV000084584 OR RCV000995782 OR RCV001064002" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017391, RCV000084584, RCV000995782, RCV001064002" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017391...</a>
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<p>In a woman (patient 2) with frontotemporal dementia-2 (FTD2; <a href="/entry/607485">607485</a>) presenting as primary progressive aphasia (PPA) beginning at age 56 years, <a href="#14" class="mim-tip-reference" title="Davion, S., Johnson, N., Weintraub, S., Mesulam, M.-M., Engberg, A., Mishra, M., Baker, M., Adamson, J., Hutton, M., Rademakers, R., Bigio, E. H. <strong>Clinicopathologic correlation in PGRN mutations.</strong> Neurology 69: 1113-1121, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17522386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17522386</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17522386[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/10.1212/01.wnl.0000267701.58488.69" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17522386">Davion et al. (2007)</a> identified a heterozygous 2-bp deletion (c.675delCA) in exon 6 of the GRN gene, resulting in a frameshift and premature termination (Ser226TrpfsTer28). She had progressive word finding impairment leading to single word utterances within 2 years and complete mutism within 4 years. Neuropathologic examination showed diffuse neuronal intranuclear cytoplasmic inclusions in the frontal cortex, temporal cortex, and striatum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17522386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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=RCV000084453 OR RCV000704513 OR RCV000995784 OR RCV001824019" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000084453, RCV000704513, RCV000995784, RCV001824019" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000084453...</a>
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<p>In affected members of 2 unrelated families with FTD2 (<a href="/entry/607485">607485</a>), 1 of whom had been reported by <a href="#37" class="mim-tip-reference" title="Morris, J. C., Cole, M., Banker, B. Q., Wright, D. <strong>Hereditary dysphasic dementia and the Pick-Alzheimer spectrum.</strong> Ann. Neurol. 16: 455-466, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6497355/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6497355</a>] [<a href="https://doi.org/10.1002/ana.410160407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6497355">Morris et al. (1984)</a>, <a href="#39" class="mim-tip-reference" title="Mukherjee, O., Wang, J., Gitcho, M., Chakraverty, S., Taylor-Reinwald, L., Shears, S., Kauwe, J. S. K., Norton, J., Levitch, D., Bigio, E. H., Hatanpaa, K. J., White, C. L., Morris, J. C., Cairns, N. J., Goate, A. <strong>Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia.</strong> Hum. Mutat. 29: 512-521, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18183624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18183624</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18183624[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.20681" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18183624">Mukherjee et al. (2008)</a> identified a heterozygous A-to-G transition in intron 6 of the GRN gene, resulting in the skipping of exon 7 and premature protein termination. Haplotype analysis of the 2 families suggested a founder effect. Another affected patient unrelated to both families also carried the IVS6 mutation on a different haplotype, indicating that the mutation occurred independently on at least 2 occasions. Western blot analysis showed a 50% reduction in GRN protein compared to controls, suggesting haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18183624+6497355" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs63749877 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63749877;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=rs63749877" 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=rs63749877" 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=RCV000017393 OR RCV000017394 OR RCV000029169 OR RCV000084585 OR RCV001851888" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017393, RCV000017394, RCV000029169, RCV000084585, RCV001851888" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017393...</a>
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<p><strong><em>Frontotemporal Dementia 2</em></strong></p><p>
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In 4 (1.64%) of 243 unrelated Italian patients with frontotemporal dementia-2 (FTD2; <a href="/entry/607485">607485</a>), <a href="#9" class="mim-tip-reference" title="Borroni, B., Archetti, S., Alberici, A., Agosti, C., Gennarelli, M., Bigni, B., Bonvicini, C., Ferrari, M., Bellelli, G., Galimberti, D., Scarpini, E., Di Lorenzo, D., Caimi, L., Caltagirone, C., Di Luca, M., Padovani, A. <strong>Progranulin genetic variations in frontotemporal lobar degeneration: evidence for low mutation frequency in an Italian clinical series.</strong> Neurogenetics 9: 197-205, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18392865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18392865</a>] [<a href="https://doi.org/10.1007/s10048-008-0127-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18392865">Borroni et al. (2008)</a> identified the same heterozygous 4-bp deletion (c.813delCACT) in exon 8 of the GRN gene, resulting in a frameshift and premature termination. Two female patients were diagnosed with the behavioral variant of frontotemporal dementia, and 2 males with progressive nonfluent aphasia. The estimated age at onset ranged from 53 to 64 years, and all showed evidence of hypoperfusion of the frontotemporal brain regions. Three of the 4 had a family history of the disorder. Considering all patients in the study with a well-known family history for dementia, the frequency of this mutation was 6% (4 of 84). Haplotype analysis indicated a founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18392865" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Benussi, L., Ghidoni, R., Pegoiani, E., Moretti, D. V., Zanetti, O., Binetti, G. <strong>Progranulin Leu271LeufsX10 is one of the most common FTLD and CBS associated mutations worldwide.</strong> Neurobiol. Dis 33: 379-385, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19101631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19101631</a>] [<a href="https://doi.org/10.1016/j.nbd.2008.11.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19101631">Benussi et al. (2009)</a> found the heterozygous c.813delCACT mutation (c.813delCACT, NM_002087) in 27 (15%) of 151 Italian patients with a clinical diagnosis of neurodegenerative frontotemporal dementia-related disorders, indicating that it is one of the most common GRN mutations. Although the consequence of this mutation has been reported as Leu271LeufsTer10, <a href="#6" class="mim-tip-reference" title="Benussi, L., Ghidoni, R., Pegoiani, E., Moretti, D. V., Zanetti, O., Binetti, G. <strong>Progranulin Leu271LeufsX10 is one of the most common FTLD and CBS associated mutations worldwide.</strong> Neurobiol. Dis 33: 379-385, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19101631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19101631</a>] [<a href="https://doi.org/10.1016/j.nbd.2008.11.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19101631">Benussi et al. (2009)</a> noted that the Human Genome Variation Society recommended the frameshift nomenclature Thr272SerfsTer10. GRN mutation carriers had variable clinical diagnoses, including corticobasal degeneration syndrome, FTD with motorneuron disease, behavioral variant FTD, primary progressive aphasia, and Lewy body dementia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19101631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Neuronal Ceroid Lipofuscinosis 11</em></strong></p><p>
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<a href="#51" class="mim-tip-reference" title="Smith, K. R., Damiano, J., Franceschetti, S., Carpenter, S., Canafoglia, L., Morbin, M., Rossi, G., Pareyson, D., Mole, S. E., Staropoli, J. F., Sims, K. B., Lewis, J., Lin, W.-L., Dickson, D. W., Dahl, H.-H., Bahlo, M., Berkovic, S. F. <strong>Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage.</strong> Am. J. Hum. Genet. 90: 1102-1107, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22608501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22608501</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22608501[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.ajhg.2012.04.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22608501">Smith et al. (2012)</a> identified a homozygous c.813_816 deletion in the GRN gene (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63749877;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs63749877</a>) in 2 sibs, born of distantly related Italian parents, with young-adult onset of neuronal ceroid lipofuscinosis-11 (CLN11; <a href="/entry/614706">614706</a>). The patients developed rapidly progressive visual failure in their early twenties, followed by retinal dystrophy, seizures, cerebellar ataxia, and cerebellar hypoplasia. One had cognitive decline. Skin biopsy of 1 patient showed numerous fingerprint profiles in membrane-bound structures in eccrine secretory cells and endothelium. Plasma progranulin levels in the homozygous patients were undetectable and were about 50% decreased in the heterozygous parents. Family history revealed 3 cases of late-onset dementia in both sides of the family, but DNA was not available from these patients. The healthy parents were in their fifties; the molecular findings suggested that they may be at risk for later-onset dementia. <a href="#1" class="mim-tip-reference" title="Ahmed, Z., Sheng, H., Xu, Y., Lin, W.-L., Innes, A. E., Gass, J., Yu, X., Wuertzer, C. A., Hou, H., Chiba, S., Yamanouchi, K., Leissring, M., Petrucelli, L., Nishihara, M., Hutton, M. L., McGowan, E., Dickson, D. W., Lewis, J. <strong>Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging.</strong> Am. J. Path. 177: 311-324, 2010. Note: Erratum: Am. J. Path. 177: 2146 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20522652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20522652</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20522652[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/10.2353/ajpath.2010.090915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20522652">Ahmed et al. (2010)</a> found that Grn-null mice developed abnormal accumulation of abnormal intraneuronal ubiquitin-positive autofluorescent lipofuscin, detected by light microscopy. Electron microscopic examination of fixed brain tissue from Grn-null showed abundant rectilinear profiles diagnostic of CLN. <a href="#51" class="mim-tip-reference" title="Smith, K. R., Damiano, J., Franceschetti, S., Carpenter, S., Canafoglia, L., Morbin, M., Rossi, G., Pareyson, D., Mole, S. E., Staropoli, J. F., Sims, K. B., Lewis, J., Lin, W.-L., Dickson, D. W., Dahl, H.-H., Bahlo, M., Berkovic, S. F. <strong>Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage.</strong> Am. J. Hum. Genet. 90: 1102-1107, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22608501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22608501</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22608501[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.ajhg.2012.04.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22608501">Smith et al. (2012)</a> commented on the remarkable phenotypic differences between heterozygous and homozygous GRN mutations, and suggested that progranulin may have a lysosomal function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20522652+22608501" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 40-year-old man, born of distantly related Italian parents (family B), with CLN11, <a href="#40" class="mim-tip-reference" title="Neuray, C., Sultan, T., Alvi, J. R., Franca, M. C., Jr., Assmann, B., Wagner, M., Canafoglia, L., Franceschetti, S., Rossi, G., Santana, I., Macario, M. C., Almeida, M. R., Kamate, M., Parikh, S., Elloumi, H. Z., Murphy, D., Efthymiou, S., Maroofian, R., Houlden, H. <strong>Early-onset phenotype of bi-allelic GRN mutations.</strong> Brain 144: e22, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33351065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33351065</a>] [<a href="https://doi.org/10.1093/brain/awaa414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33351065">Neuray et al. (2021)</a> identified a homozygous c.813_816delCACT mutation in the GRN gene, predicted to result in a frameshift and premature termination (Thr272SerfsTer10). The carrier parents, who were in their early seventies, were unaffected. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33351065" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs63751073 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63751073;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/rs63751073?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=rs63751073" 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=rs63751073" 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=RCV000084427 OR RCV001241659 OR RCV002281919" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000084427, RCV001241659, RCV002281919" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000084427...</a>
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<p>In affected members of a large Swedish family with FTD2 (<a href="/entry/607485">607485</a>) mainly presenting as language and speech abnormalities, <a href="#50" class="mim-tip-reference" title="Skoglund, L., Brundin, R., Olofsson, T., Kalimo, H., Ingvast, S., Blom, E. S., Giedraitis, V., Ingelsson, M., Lannfelt, L., Basun, H., Glaser, A. <strong>Frontotemporal dementia in a large Swedish family is caused by a progranulin null mutation.</strong> Neurogenetics 10: 27-34, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18855025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18855025</a>] [<a href="https://doi.org/10.1007/s10048-008-0155-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18855025">Skoglund et al. (2009)</a> identified a 1-bp deletion (c.102delC) in exon 1 of the GRN gene, resulting in a frameshift and predicted truncated protein. In vitro functional expression studies showed that the mutant transcript was subject to nonsense-mediated mRNA decay, resulting in functional haploinsufficiency. Three mutation carriers were unaffected, suggesting incomplete penetrance or variation in age of onset. The family had previously been reported by <a href="#16" class="mim-tip-reference" title="Froelich, S., Basun, H., Forsell, C., Lilius, L., Axelman, K., Andreadis, A., Lannfelt, L. <strong>Mapping of a disease locus for familial rapidly progressive frontotemporal dementia to chromosome 17q12-21.</strong> Am. J. Med. Genet. 74: 380-385, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9259373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9259373</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19970725)74:4<380::aid-ajmg8>3.0.co;2-t" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9259373">Froelich et al. (1997)</a> and <a href="#5" class="mim-tip-reference" title="Basun, H., Almkvist, O., Axelman, K., Brun, A., Campbell, T. A., Collinge, J., Forsell, C., Froelich, S., Wahlund, L.-O., Wetterberg, L., Lannfelt, L. <strong>Clinical characteristics of a chromosome 17-linked rapidly progressive familial frontotemporal dementia.</strong> Arch. Neurol. 54: 539-544, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9152110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9152110</a>] [<a href="https://doi.org/10.1001/archneur.1997.00550170021010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9152110">Basun et al. (1997)</a>. The mutation was not identified in 165 control individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9259373+9152110+18855025" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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=RCV000084429 OR RCV002281920" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000084429, RCV002281920" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000084429...</a>
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<p>In 7 affected members of a family with autosomal dominant inheritance of FTD2 (<a href="/entry/607485">607485</a>), <a href="#27" class="mim-tip-reference" title="Kelley, B. J., Haidar, W., Boeve, B. F., Baker, M., Shiung, M., Knopman, D. S., Rademakers, R., Hutton, M., Adamson, J., Kuntz, K. M., Dickson, D. W., Parisi, J. E., Smith, G. E., Petersen, R. C. <strong>Alzheimer disease-like phenotype associated with the c.154delA mutation in progranulin.</strong> Arch. Neurol. 67: 171-177, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20142525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20142525</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20142525[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/10.1001/archneurol.2010.113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20142525">Kelley et al. (2010)</a> identified a heterozygous 1-bp deletion (c.154delA) in exon 2 of the GRN gene, resulting in a frameshift and premature termination (Thr52HisfsTer2). Of 10 affected individuals, 6 presented with early amnestic symptoms resulting in initial clinical diagnoses of Alzheimer disease (AD; <a href="/entry/104300">104300</a>) or amnestic mild cognitive impairment, and 3 with frontotemporal dementia; 1 had nonspecific dementia. Neuropathologic examination of 6 individuals showed FTLD with ubiquitin-positive neuronal cytoplasmic and intranuclear inclusions, even in those with an AD diagnosis. The mean age at onset was younger in the third generation (60.7 years) than in the second generation (75.8 years). <a href="#27" class="mim-tip-reference" title="Kelley, B. J., Haidar, W., Boeve, B. F., Baker, M., Shiung, M., Knopman, D. S., Rademakers, R., Hutton, M., Adamson, J., Kuntz, K. M., Dickson, D. W., Parisi, J. E., Smith, G. E., Petersen, R. C. <strong>Alzheimer disease-like phenotype associated with the c.154delA mutation in progranulin.</strong> Arch. Neurol. 67: 171-177, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20142525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20142525</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20142525[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/10.1001/archneurol.2010.113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20142525">Kelley et al. (2010)</a> noted that the presentation in some individuals with GRN-related FTLD may include Alzheimer disease-like clinical features, particularly anterograde amnesia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20142525" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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GRN, 78C-T, 3-PRIME UTR (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs5848;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs5848</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"><span class="text-primary">●</span> rs5848 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs5848;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/rs5848?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=rs5848" 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=rs5848" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#45" class="mim-tip-reference" title="Rademakers, R., Eriksen, J. L., Baker, M., Robinson, T., Ahmed, Z., Lincoln, S. J., Finch, N., Rutherford, N. J., Crook, R. J., Josephs, K. A., Boeve, B. F., Knopman, D. S., and 10 others. <strong>Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia.</strong> Hum. Molec. Genet. 17: 3631-3642, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18723524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18723524</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18723524[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/ddn257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18723524">Rademakers et al. (2008)</a> identified a C-to-T transition (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs5848;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs5848</a>) in the 3-prime untranslated region (UTR) of the GRN gene that appeared to confer increased risk for the development of GRN-related FTD2 (<a href="/entry/607485">607485</a>). The SNP was located 78 nucleotides downstream of the translation termination codon of the GRN gene within a predicted regulatory binding site for miRNA659 (MIR659; <a href="/entry/613556">613556</a>). The authors reanalyzed previously published data and found a significant increase in the T/T genotype among 339 FTLD patients, who were non-GRN mutation carriers, compared to 934 controls (16% versus 9%; p = 0.002). The findings were replicated in 59 patients with pathologically confirmed FTLDU and 433 controls (25.4% vs 9.9%; p = 0.003). Homozygosity for the minor T allele conferred an odds ratio of 3.18 for development of FTLDU, which increased to 3.76 when those with motor neuron disease were excluded. However, heterozygosity for the T allele was not associated with an increased disease risk. In silico analysis predicted that MIR659 would bind more efficiently to the T allele than the C allele. In vitro functional expression studies showed that low doses of MIR659 suppressed expression of GRN with the T allele, but not GRN with the wildtype C allele. Western blot, immunohistochemical and quantitative analysis showed a significant decrease (about 30%) of GRN expression in T/T carriers compared to C/C carriers, although mRNA levels did not differ, consistent with a mechanism affecting translation. The findings suggested that <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs5848;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs5848</a> in the GRN gene increases the risk of FTLDU by miRNA-mediated translational repression of GRN, thus resembling the clinical and pathologic phenotypes observed in patients with loss-of-function mutations in the GRN gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18723524" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs2143337085 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2143337085;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=rs2143337085" 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=rs2143337085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 23 patients from 13 families of Basque origin with frontotemporal dementia-2 (FTD2; <a href="/entry/607485">607485</a>), <a href="#36" class="mim-tip-reference" title="Moreno, F., Indakoetxea, B., Barandiaran, M., Alzualde, A., Gabilondo, A., Estanga, A., Ruiz, J., Ruibal, M., Bergareche, A., Marti-Masso, J. F., Lopez de Munain, A. <strong>'Frontotemporoparietal' dementia: clinical phenotype associated with the c.709-1G>A PGRN mutation.</strong> Neurology 73: 1367-1374, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19858458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19858458</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181bd82a7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19858458">Moreno et al. (2009)</a> identified a heterozygous G-to-A transition in intron 6 (c.709-1G-A) of the GRN gene, resulting in nonsense-mediated decay of the mRNA and haploinsufficiency. The mean age at onset was 59.2 years (range, 42 to 71 years), and 4 of 21 patients died after a mean duration of 4.75 years. Overall, 14 (66.7%) had a diagnosis of behavioral variant FTD, 10 (47.6%) had a diagnosis of corticobasal degeneration, and 7 (33.3%) had a diagnosis of progressive nonfluent aphasia. None developed signs of motor neuron disease/ALS, but 8 with corticobasal degeneration had motor signs, including limb rigidity or apraxia and myoclonus. The most prominent behavioral symptoms were apathy, impulsivity, disinhibition, and bulimia, suggesting involvement of the medial frontal and orbitofrontal cortex. Dysgraphia, dyscalculia, apraxia, and hemineglect suggested parietal dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19858458" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0020 CEROID LIPOFUSCINOSIS, NEURONAL, 11</strong>
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<p>In a 14-year-old Indian girl, born of consanguineous parents, with neuronal ceroid lipofuscinosis-11 (CLN11; <a href="/entry/614706">614706</a>), <a href="#26" class="mim-tip-reference" title="Kamate, M., Detroja, M., Hattiholi, V. <strong>Neuronal ceroid lipofuscinosis type-11 in an adolescent.</strong> Brain Dev. 41: 542-545, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30922528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30922528</a>] [<a href="https://doi.org/10.1016/j.braindev.2019.03.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30922528">Kamate et al. (2019)</a> identified a homozygous c.912G-A transversion (chr17:42428807G-A) in exon 9 of the GRN gene, predicted to result in a trp304-to-ter (W304X) substitution. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each unaffected parent and an unaffected sib. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a complete loss of GRN. Serum GRN levels were not assessed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30922528" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 sisters, born of possibly consanguineous Portuguese parents (family AAR-427), with neuronal ceroid lipofuscinosis-11 (CLN11; <a href="/entry/614706">614706</a>), <a href="#24" class="mim-tip-reference" title="Huin, V., Barbier, M., Bottani, A., Lobrinus, J. A., Clot, F., Lamari, F., Chat, L., Rucheton, B., Fluchere, F., Auvin, S., Myers, P., Gelot, A., and 9 others. <strong>Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms.</strong> Brain 143: 303-319, 2020. Note: Erratum: Brain 143: e24, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31855245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31855245</a>] [<a href="https://doi.org/10.1093/brain/awz377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31855245">Huin et al. (2020)</a> identified a homozygous 2-bp duplication (c.768_769dup, NM_002087.2) in exon 8 of the GRN gene, predicted to result in a frameshift and premature termination (Gln257ProfsTer27). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was inherited from the 2 unaffected heterozygous parents. Plasma GRN was undetectable in the sister who was tested. Plasma GRN was decreased in the unaffected parents (aged 57 and 61). Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31855245" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 25-year-old woman, born of consanguineous Brazilian parents (family D), with CLN11, <a href="#40" class="mim-tip-reference" title="Neuray, C., Sultan, T., Alvi, J. R., Franca, M. C., Jr., Assmann, B., Wagner, M., Canafoglia, L., Franceschetti, S., Rossi, G., Santana, I., Macario, M. C., Almeida, M. R., Kamate, M., Parikh, S., Elloumi, H. Z., Murphy, D., Efthymiou, S., Maroofian, R., Houlden, H. <strong>Early-onset phenotype of bi-allelic GRN mutations.</strong> Brain 144: e22, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33351065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33351065</a>] [<a href="https://doi.org/10.1093/brain/awaa414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33351065">Neuray et al. (2021)</a> identified a homozygous c.768dupCC mutation in the GRN gene. The patient's father was deceased; her 55-year-old healthy mother carried the mutation in the heterozygous state. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33351065" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 25-year-old woman, born of consanguineous Brazilian parents, with CLN11 and spastic paraplegia, <a href="#15" class="mim-tip-reference" title="Faber, I., Prota, J. R. M., Martinez, A. R. M., Lopes-Cendes, I., Franca, M. C., Jr. <strong>A new phenotype associated with homozygous GRN mutations: complicated spastic paraplegia.</strong> Europ. J. Neurol. 24: e3-e4, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28000352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28000352</a>] [<a href="https://doi.org/10.1111/ene.13194" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28000352">Faber et al. (2017)</a> identified a homozygous c.768dupCC mutation in the GRN gene, which they referred to as c.767_768insCC. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28000352" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 7-year-old girl, born of consanguineous Pakistani parents (family NCL-001), with neuronal ceroid lipofuscinosis-11 (CLN11; <a href="/entry/614706">614706</a>), <a href="#24" class="mim-tip-reference" title="Huin, V., Barbier, M., Bottani, A., Lobrinus, J. A., Clot, F., Lamari, F., Chat, L., Rucheton, B., Fluchere, F., Auvin, S., Myers, P., Gelot, A., and 9 others. <strong>Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms.</strong> Brain 143: 303-319, 2020. Note: Erratum: Brain 143: e24, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31855245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31855245</a>] [<a href="https://doi.org/10.1093/brain/awz377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31855245">Huin et al. (2020)</a> identified a homozygous c.1A-T transversion (c.1A-T, NM_002087.2) in exon 2 of the GRN gene, predicted to disrupt the initiation codon (Met1?). The mutation, which was found by sequencing of a CLN gene panel and confirmed by Sanger sequencing, segregated with the disorder in the family. Plasma GRN was undetectable in the patient. The carrier parents were asymptomatic at 46 and 47 years of age. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31855245" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0023 FRONTOTEMPORAL DEMENTIA 2, AUTOSOMAL RECESSIVE</strong>
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<p>In a French woman (family FTD-1042) with frontotemporal dementia-2 (FTD2; <a href="/entry/607485">607485</a>) who had onset of symptoms at age 56, <a href="#24" class="mim-tip-reference" title="Huin, V., Barbier, M., Bottani, A., Lobrinus, J. A., Clot, F., Lamari, F., Chat, L., Rucheton, B., Fluchere, F., Auvin, S., Myers, P., Gelot, A., and 9 others. <strong>Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms.</strong> Brain 143: 303-319, 2020. Note: Erratum: Brain 143: e24, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31855245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31855245</a>] [<a href="https://doi.org/10.1093/brain/awz377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31855245">Huin et al. (2020)</a> identified a homozygous C-to-G transversion in intron 7 of the GRN gene (c.709-3C-G, NM_002087.2), resulting in a splicing defect. The mutation was found by Sanger sequencing; parental DNA was not available for study. Lymphoblastoid cells from the patient showed 2 RNA fragments: one of the expected normal size and another abnormal larger fragment that included intron 7 and altered splicing, leading to a frameshift and premature termination (Ala237ValfsTer98). The aberrant transcript was degraded by nonsense-mediated mRNA decay. The proband had an 11.2-fold decrease of normal GRN transcripts and low levels of plasma progranulin. Her 2 children, who were each heterozygous for the mutation, were asymptomatic at 22 and 27 years of age and had low plasma progranulin levels that were slightly higher than those of their mother. <a href="#24" class="mim-tip-reference" title="Huin, V., Barbier, M., Bottani, A., Lobrinus, J. A., Clot, F., Lamari, F., Chat, L., Rucheton, B., Fluchere, F., Auvin, S., Myers, P., Gelot, A., and 9 others. <strong>Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms.</strong> Brain 143: 303-319, 2020. Note: Erratum: Brain 143: e24, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31855245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31855245</a>] [<a href="https://doi.org/10.1093/brain/awz377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31855245">Huin et al. (2020)</a> noted that the splice site mutation still allowed the synthesis of low levels of normally spliced GRN, suggesting it may be a hypomorphic mutation, leading to residual amounts of plasma progranulin and a milder phenotype. However, the authors also noted that another patient with FTD2 (patient FAM347 in <a href="#6" class="mim-tip-reference" title="Benussi, L., Ghidoni, R., Pegoiani, E., Moretti, D. V., Zanetti, O., Binetti, G. <strong>Progranulin Leu271LeufsX10 is one of the most common FTLD and CBS associated mutations worldwide.</strong> Neurobiol. Dis 33: 379-385, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19101631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19101631</a>] [<a href="https://doi.org/10.1016/j.nbd.2008.11.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19101631">Benussi et al., 2009</a>) with this same mutation in the heterozygous state developed symptoms at 49 years of age (earlier than their proband), suggesting that other unknown mechanisms are at play. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=31855245+19101631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0024 FRONTOTEMPORAL DEMENTIA 2, AUTOSOMAL RECESSIVE</strong>
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GRN, 2-BP DEL, NT443
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<p>In 2 French brothers (family FTDP-N12/1611) with autosomal recessive frontotemporal dementia-2 (FTD2; <a href="/entry/607485">607485</a>), <a href="#24" class="mim-tip-reference" title="Huin, V., Barbier, M., Bottani, A., Lobrinus, J. A., Clot, F., Lamari, F., Chat, L., Rucheton, B., Fluchere, F., Auvin, S., Myers, P., Gelot, A., and 9 others. <strong>Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms.</strong> Brain 143: 303-319, 2020. Note: Erratum: Brain 143: e24, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31855245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31855245</a>] [<a href="https://doi.org/10.1093/brain/awz377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31855245">Huin et al. (2020)</a> identified a homozygous 2-bp deletion (c.443_444del) in exon 5 of the GRN gene, predicted to result in a frameshift and premature termination (Gly148ValfsTer11). There was a family history of dementia and Parkinson disease, but genetic studies were not performed on the affected relatives. Plasma progranulin was undetectable. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31855245" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="Ahmed2010" class="mim-anchor"></a>
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Ahmed, Z., Sheng, H., Xu, Y., Lin, W.-L., Innes, A. E., Gass, J., Yu, X., Wuertzer, C. A., Hou, H., Chiba, S., Yamanouchi, K., Leissring, M., Petrucelli, L., Nishihara, M., Hutton, M. L., McGowan, E., Dickson, D. W., Lewis, J.
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<strong>Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging.</strong>
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Am. J. Path. 177: 311-324, 2010. Note: Erratum: Am. J. Path. 177: 2146 only, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20522652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20522652</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20522652[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=20522652" 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/10.2353/ajpath.2010.090915" target="_blank">Full Text</a>]
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<a id="Ashcroft2000" class="mim-anchor"></a>
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Ashcroft, G. S., Lei, K., Jin, W., Longenecker, G., Kulkarni, A. B., Greenwell-Wild, T., Hale-Donze, H., McGrady, G., Song, X.-Y., Wahl, S. M.
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<strong>Secretory leukocyte protease inhibitor mediates non-redundant functions necessary for normal wound healing.</strong>
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Nature Med. 6: 1147-1153, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017147</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11017147" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/80489" target="_blank">Full Text</a>]
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<a id="Baba1993" class="mim-anchor"></a>
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Baba, T., Hoff, H. B., III, Nemoto, H., Lee, H., Orth, J., Arai, Y., Gerton, G. L.
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<strong>Acrogranin, an acrosomal cysteine-rich glycoprotein, is the precursor of the growth-modulating peptides, granulins, and epithelins, and is expressed in somatic as well as male germ cells.</strong>
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Molec. Reprod. Dev. 34: 233-243, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8471244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8471244</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8471244" 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/mrd.1080340302" target="_blank">Full Text</a>]
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Baker, M., Mackenzie, I. R., Pickering-Brown, S. M., Gass, J., Rademakers, R., Lindholm, C., Snowden, J., Adamson, J., Sadovnick, A. D., Rollinson, S., Cannon, A., Dwosh, E., and 15 others.
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<strong>Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.</strong>
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Nature 442: 916-919, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16862116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16862116</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16862116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature05016" target="_blank">Full Text</a>]
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<a id="Basun1997" class="mim-anchor"></a>
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Basun, H., Almkvist, O., Axelman, K., Brun, A., Campbell, T. A., Collinge, J., Forsell, C., Froelich, S., Wahlund, L.-O., Wetterberg, L., Lannfelt, L.
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[<a href="https://doi.org/10.1001/archneur.1997.00550170021010" target="_blank">Full Text</a>]
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<a id="Benussi2009" class="mim-anchor"></a>
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Benussi, L., Ghidoni, R., Pegoiani, E., Moretti, D. V., Zanetti, O., Binetti, G.
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<strong>Progranulin Leu271LeufsX10 is one of the most common FTLD and CBS associated mutations worldwide.</strong>
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Neurobiol. Dis 33: 379-385, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19101631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19101631</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19101631" 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.nbd.2008.11.008" target="_blank">Full Text</a>]
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<a id="Bhandari1992" class="mim-anchor"></a>
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Bhandari, V., Bateman, A.
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<strong>Structure and chromosomal location of the human granulin gene.</strong>
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Biochem. Biophys. Res. Commun. 188: 57-63, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1417868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1417868</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1417868" 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/10.1016/0006-291x(92)92349-3" target="_blank">Full Text</a>]
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Bhandari, V., Palfree, R. G. E., Bateman, A.
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<strong>Isolation and sequence of the granulin precursor cDNA from human bone marrow reveals tandem cysteine-rich granulin domains.</strong>
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Proc. Nat. Acad. Sci. 89: 1715-1719, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1542665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1542665</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1542665" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.89.5.1715" target="_blank">Full Text</a>]
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Borroni, B., Archetti, S., Alberici, A., Agosti, C., Gennarelli, M., Bigni, B., Bonvicini, C., Ferrari, M., Bellelli, G., Galimberti, D., Scarpini, E., Di Lorenzo, D., Caimi, L., Caltagirone, C., Di Luca, M., Padovani, A.
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<strong>Progranulin genetic variations in frontotemporal lobar degeneration: evidence for low mutation frequency in an Italian clinical series.</strong>
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Neurogenetics 9: 197-205, 2008.
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[<a href="https://doi.org/10.1007/s10048-008-0127-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.64.10.1436" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000265220.64396.b4" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneurol.2011.53" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature05017" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000267701.58488.69" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/ene.13194" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(sici)1096-8628(19970725)74:4<380::aid-ajmg8>3.0.co;2-t" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.neuron.2010.09.034" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/brain/awaa414" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.immuni.2011.01.018" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.mp.4001198" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000319702.37497.72" target="_blank">Full Text</a>]
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<div class="">
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<p class="mim-text-font">
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Yu, C.-E., Bird, T. D., Bekris, L. M., Montine, T. J., Leverenz, J. B., Steinbart, E., Galloway, N. M., Feldman, H., Woltjer, R., Miller, C. A., Wood, E. M., Grossman, M., and 13 others.
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|
<strong>The spectrum of mutations in progranulin: a collaborative study screening 545 cases of neurodegeneration.</strong>
|
|
Arch. Neurol. 67: 161-170, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20142524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20142524</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20142524[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=20142524" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1001/archneurol.2009.328" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="57" class="mim-anchor"></a>
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<a id="Zhu2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhu, J., Nathan, C., Jin, W., Sim, D., Ashcroft, G. S., Wahl, S. M., Lacomis, L., Erdjument-Bromage, H., Tempst, P., Wright, C. D., Ding, A.
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<strong>Conversion of proepithelin to epithelins: roles of SLPI and elastase in host defense and wound repair.</strong>
|
|
Cell 111: 867-878, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12526812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12526812</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12526812" 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/s0092-8674(02)01141-8" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 08/21/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 02/12/2021<br>Bao Lige - updated : 09/24/2020<br>Patricia A. Hartz - updated : 02/12/2018<br>Paul J. Converse - updated : 12/21/2015<br>Cassandra L. Kniffin - updated : 7/9/2012<br>Cassandra L. Kniffin - updated : 11/28/2011<br>Cassandra L. Kniffin - updated : 10/17/2011<br>Paul J. Converse - updated : 9/8/2011<br>Ada Hamosh - updated : 7/8/2011<br>Cassandra L. Kniffin - updated : 3/8/2011<br>Cassandra L. Kniffin - updated : 9/15/2010<br>Patricia A. Hartz - updated : 9/10/2010<br>Cassandra L. Kniffin - updated : 5/6/2010<br>Cassandra L. Kniffin - updated : 3/27/2009<br>Cassandra L. Kniffin - updated : 2/18/2009<br>Matthew B. Gross - updated : 2/17/2009<br>Patricia A. Hartz - updated : 2/13/2009<br>Cassandra L. Kniffin - updated : 1/14/2009<br>Cassandra L. Kniffin - updated : 11/17/2008<br>Cassandra L. Kniffin - updated : 10/31/2008<br>Cassandra L. Kniffin - updated : 7/22/2008<br>Cassandra L. Kniffin - updated : 5/19/2008<br>Cassandra L. Kniffin - updated : 3/3/2008<br>Cassandra L. Kniffin - updated : 11/29/2007<br>Cassandra L. Kniffin - updated : 10/17/2007<br>Cassandra L. Kniffin - updated : 9/20/2007<br>Ada Hamosh - updated : 9/8/2006<br>Stylianos E. Antonarakis - updated : 1/16/2003<br>Victor A. McKusick - updated : 1/14/2003<br>Victor A. McKusick - updated : 5/1/2000<br>Victor A. McKusick - updated : 1/6/2000<br>Victor A. McKusick - updated : 9/15/1999
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 11/24/1992
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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|
alopez : 08/22/2024
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</span>
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</div>
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</div>
|
|
<div class="row collapse" id="mimCollapseEditHistory">
|
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
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ckniffin : 08/21/2024<br>carol : 02/12/2021<br>mgross : 09/24/2020<br>mgross : 02/12/2018<br>carol : 04/25/2017<br>carol : 08/12/2016<br>mgross : 12/22/2015<br>mgross : 12/21/2015<br>carol : 11/14/2014<br>tpirozzi : 10/1/2013<br>carol : 8/28/2013<br>terry : 7/27/2012<br>alopez : 7/13/2012<br>terry : 7/10/2012<br>ckniffin : 7/9/2012<br>carol : 11/29/2011<br>ckniffin : 11/28/2011<br>carol : 10/26/2011<br>carol : 10/26/2011<br>carol : 10/21/2011<br>terry : 10/21/2011<br>ckniffin : 10/17/2011<br>mgross : 9/19/2011<br>terry : 9/8/2011<br>alopez : 7/11/2011<br>alopez : 7/11/2011<br>terry : 7/8/2011<br>terry : 3/14/2011<br>wwang : 3/11/2011<br>ckniffin : 3/8/2011<br>wwang : 9/16/2010<br>ckniffin : 9/15/2010<br>mgross : 9/10/2010<br>wwang : 5/10/2010<br>ckniffin : 5/6/2010<br>terry : 12/16/2009<br>wwang : 4/10/2009<br>ckniffin : 3/27/2009<br>carol : 2/20/2009<br>ckniffin : 2/18/2009<br>mgross : 2/17/2009<br>mgross : 2/17/2009<br>terry : 2/13/2009<br>wwang : 1/22/2009<br>ckniffin : 1/14/2009<br>wwang : 12/1/2008<br>ckniffin : 11/17/2008<br>wwang : 11/10/2008<br>ckniffin : 10/31/2008<br>wwang : 7/29/2008<br>ckniffin : 7/22/2008<br>wwang : 5/27/2008<br>ckniffin : 5/19/2008<br>wwang : 3/19/2008<br>ckniffin : 3/3/2008<br>wwang : 12/5/2007<br>ckniffin : 11/29/2007<br>wwang : 10/25/2007<br>ckniffin : 10/17/2007<br>wwang : 10/2/2007<br>ckniffin : 9/20/2007<br>alopez : 9/20/2006<br>terry : 9/8/2006<br>terry : 5/16/2003<br>carol : 5/14/2003<br>alopez : 2/28/2003<br>tkritzer : 2/11/2003<br>mgross : 1/16/2003<br>alopez : 1/15/2003<br>terry : 1/14/2003<br>mcapotos : 5/26/2000<br>mcapotos : 5/23/2000<br>terry : 5/1/2000<br>mgross : 1/14/2000<br>terry : 1/6/2000<br>mgross : 9/21/1999<br>mgross : 9/16/1999<br>terry : 9/15/1999<br>carol : 2/11/1993<br>carol : 1/25/1993<br>carol : 11/24/1992
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
|
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<h3>
|
|
<span class="mim-font">
|
|
<strong>*</strong> 138945
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
GRANULIN PRECURSOR; GRN
|
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|
|
</span>
|
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</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
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</div>
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<div>
|
|
<div >
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
PROGRANULIN; PGRN<br />
|
|
EPITHELIN PRECURSOR<br />
|
|
PROEPITHELIN; PEPI<br />
|
|
GRANULIN-EPITHELIN PRECURSOR; GEP<br />
|
|
PC CELL-DERIVED GROWTH FACTOR; PCDGF<br />
|
|
ACROGRANIN<br />
|
|
GLYCOPROTEIN, 88-KD; GP88
|
|
</span>
|
|
</h4>
|
|
</div>
|
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</div>
|
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<div>
|
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<br />
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</div>
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<div>
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<div>
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<p>
|
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<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
GRANULINS, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
<div>
|
|
<span class="h4 mim-font">
|
|
|
|
EPITHELINS, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
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<div>
|
|
<br />
|
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</div>
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</div>
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|
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<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: GRN</em></strong>
|
|
</span>
|
|
</p>
|
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</div>
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<div>
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<p>
|
|
<span class="mim-text-font">
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|
|
<strong>SNOMEDCT:</strong> 230270009;
|
|
|
|
|
|
<strong>ICD10CM:</strong> G31.0, G31.01;
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|
<strong>ICD9CM:</strong> 331.1;
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</span>
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</p>
|
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 17q21.31
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 17:44,345,302-44,353,106 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
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|
|
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|
|
<div>
|
|
<br />
|
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</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
17q21.31
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Aphasia, primary progressive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
607485
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant; Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
|
|
|
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Ceroid lipofuscinosis, neuronal, 11
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
614706
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Frontotemporal dementia 2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
607485
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant; Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Progranulin is an 88-kD glycoprotein that functions as an autocrine growth factor. It can also be processed into several 6-kD growth-modulating peptides called granulins or epithelins, which are characterized by a highly conserved motif containing 12 cysteines (summary by Serrero, 2003). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
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|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>From a human bone marrow cDNA library, Bhandari et al. (1992) isolated GRN. The deduced 593-residue protein contains a 56-residue GrnA sequence, as well as 6 other cysteine-rich granulin-like domains, including GrnB, GrnC, and GrnD, which had previously been known only from N-terminal sequences. The results indicated that 4 known human granulin-like peptides are produced by the precursor protein, progranulin, which has a highly conserved 12-cysteine backbone defining a consensus sequence that is repeated 7 times. Northern blot analysis detected a 2.3-kb transcript with highest expression in epithelial cell lines, myelogenous leukemic cell lines, and kidney. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>He and Bateman (1999) demonstrated that overexpression of the progranulin gene in SW-13 adrenal carcinoma cells and MDCK nontransformed renal epithelia resulted in transfection-specific secretion of progranulin, acquired clonogenicity in semisolid agar, and increased mitosis in monolayer culture, whereas diminution of progranulin gene expression impaired growth of these cells. They proposed that the rate of growth of some epithelia is proportional to the level of intrinsic progranulin gene expression, and that elevated progranulin gene expression confers a transformed phenotype on epithelial cells including anchorage independence in vitro and growth as tumors in nude mice. </p><p>Liau et al. (2000) found that the 2.1-kb granulin mRNA is expressed predominantly in glial tumors of the brain, with lower levels in spleen, kidney, and testis, whereas expression was not detected in nontumor brain tissues. The differential expression pattern, tissue distribution, and implication of this glioma-associated molecule in growth regulation suggested a potentially important role for granulin in the pathogenesis and/or malignant progression of primary brain neoplasms. </p><p>He et al. (2003) reported that in murine transcutaneous puncture wounds, progranulin mRNA is expressed in the inflammatory infiltrate and is highly induced in dermal fibroblasts and endothelia following injury. When applied to a cutaneous wound, progranulin increased the accumulation of neutrophils, macrophages, blood vessels, and fibroblasts in the wound. It acted directly on isolated dermal fibroblasts and endothelial cells to promote division, migration, and the formation of capillary-like tubule structures. They concluded that progranulin is, therefore, probably a wound-related growth factor. </p><p>Increased leukocyte elastase (130130) activity in mice lacking secretory leukocyte protease inhibitor (SLPI; 107285) leads to impaired wound healing due to enhanced activity of transforming growth factor-beta (190180) and perhaps additional mechanisms (Ashcroft et al., 2000). Proepithelin (PEPI), also known as progranulin, an epithelial growth factor, can be converted to epithelins (EPIs) in vivo. Zhu et al. (2002) found that PEPI and EPIs exert opposing activities. EPIs inhibited the growth of epithelial cells but induced them to secrete the neutrophil attractant interleukin-8 (IL8; 146930), while PEPI blocked neutrophil activation by tumor necrosis factor (TNF; 191160), preventing release of oxidants and proteases. SLPI and PEPI formed complexes, preventing elastase from converting PEPI to EPIs. Supplying PEPI corrected the wound-healing defect in Slpi null mice. The authors concluded that SLPI/elastase act via PEPI/EPIs to operate a switch at the interface between innate immunity and wound healing. </p><p>Tangkeangsirisin and Serrero (2004) stated that progranulin stimulates growth in mesenchymal and epithelial cells via the MAP kinase (see MAPK1, 176948), PI3 kinase (see PIK3CA, 171834), and FAK (PTK2; 600758) pathways, and that its overexpression in breast cancer cells correlates positively with acquisition of estrogen-independent growth, tamoxifen resistance, and tumorigenicity. They showed that overexpression of progranulin in MCF-7 cells, an estrogen receptor (see ESR1; 133430)-positive human breast cancer cell line, stimulated anchorage-independent cell growth and accelerated cell migration in a 3-dimensional gel. Exogenous treatment of MCF-7 cells with progranulin gave similar results. Gelatin zymographs and Western blot analysis revealed that progranulin upregulated expression of matrix metalloprotease-9 (MMP9; 120361) expression. Progranulin also upregulated VEGF (192240) expression. Tangkeangsirisin and Serrero (2004) concluded that progranulin expression can promote angiogenesis and metastasis in human breast cancer cells, in addition to stimulating cell proliferation and survival. </p><p>Rademakers et al. (2008) identified a predicted binding site for microRNA-659 (MIR659; 613556) within the 3-prime UTR of GRN. They showed that transfected MIR659 inhibited expression of endogenous GRN in M17 human neuroblastoma cells. </p><p>Hu et al. (2010) showed in cellular studies that SORT1 (602458) is a cell surface binding site for PGRN. PGRN binds to SORT1 on cortical neurons via its C terminus, and the complex undergoes endocytosis, with delivery of PGRN to lysosomes. PGRN was induced in activated microglia cells surrounding motor neurons after murine spinal cord injury. Sort1-null mice had 5-fold increased levels of Pgrn in brain and serum, suggesting that SORT1 can control PGRN levels in vivo. Hu et al. (2010) suggested a role for the endosomal/autophagosomal/lysosomal pathway in the pathogenesis of GRN-related frontotemporal lobar dementia (607485). </p><p>Jiao et al. (2010) noted that expression of microRNA-29B (MIR29B; see 610783) overlaps with that of progranulin. They found that MIR29B suppressed production and secretion of human progranulin by binding directly to the 3-prime UTR of progranulin mRNA. </p><p>Tang et al. (2011) reported that PGRN bound directly to tumor necrosis factor receptors (TNFR1, 191190 and TNFR2, 191191) and disturbed the TNFA-TNFR interaction. Pgrn-deficient mice were susceptible to collagen-induced arthritis, and administration of PGRN reversed inflammatory arthritis. Atsttrin, an engineered protein composed of 3 PGRN fragments, exhibited selective TNFR binding. PGRN and Atsttrin prevented inflammation in multiple arthritis mouse models and inhibited TNFA-activated intracellular signaling. Tang et al. (2011) concluded that PGRN is a ligand of TNFR, an antagonist of TNFA signaling, and plays a critical role in the pathogenesis of inflammatory arthritis in mice. </p><p>Toll-like receptors, such as TLR9 (605474), recognize different components of microbial cells and play critical roles in innate and adaptive immunity. TLR9 belongs to a group of TLRs that detect nucleic acids and are found in endolysosomal compartments. By immunoprecipitation analysis of mouse macrophages, Park et al. (2011) found that granulin interacted with Tlr9. Exposure of mouse macrophages to TLR agonists and inhibitors of elastase, which is required for conversion of granulin from its precursor, blocked CpG-elicited Tnf production via Tlr9 signaling, but it did not interfere with signaling through other TLRs. Inhibitors of elastase had no effect on Tlr9 cleavage. Depletion of granulin in mouse cells impaired Tlr9 responses to CpG, whereas addition of granulin potentiated Tlr9 responses to CpG. In the absence of serum, macrophages from mice lacking granulin were also unable to generate Tlr9-mediated responses. Addition of exogenous granulin restored responses to CpG. Confocal microscopy demonstrated binding of CpG to Tlr9 from wildtype macrophages, but not from granulin -/- macrophages. Park et al. (2011) proposed that granulin contributes to innate immunity by functioning as a critical soluble cofactor for TLR9 signaling. </p><p>Using immunohistochemical analysis, Huang et al. (2015) demonstrated marked expression of PGRN in epidermal keratinocytes of psoriasis (see 177900) patients, but no expression in nearly all controls. RT-PCR detected significantly higher PGRN levels in psoriatic lesions compared with normal skin. Serum PGRN levels were significantly higher in patients compared with controls, but they were at the same level as healthy controls after treatment. Serum levels of TNF were also significantly higher in untreated patients compared with controls. Psoriasis severity was negatively correlated with PGRN/TNF ratio. </p><p><strong><em>Reviews</em></strong></p><p>
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Serrero (2003) reviewed the role of progranulin in breast cancer tumorigenesis. </p>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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<span class="mim-text-font">
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<p>Bhandari and Bateman (1992) showed that the protein-coding region of the GRN gene comprises 12 exons covering about 3,700 bp. Each tandem granulin repeat is encoded by 2 nonequivalent exons, a configuration unique to the granulins that would permit the formation of hybrid granulin-like proteins by alternate splicing. Cruts et al. (2006) stated that the GRN gene comprises a total of 13 exons, including a noncoding exon 0. </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p>Using DNA from human-hamster somatic cell hybrids, Bhandari and Bateman (1992) assigned the granulin precursor gene to chromosome 17. </p><p>In the course of studying the relationship between the ITGA2B (607759) and ITGB3 (173470) genes, which are both located on 17q21.32, Thornton et al. (1999) found that the GRN gene is located approximately 18 kb downstream to ITGA2B. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<p><strong><em>Autosomal Dominant Frontotemporal Dementia</em></strong></p><p>
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Baker et al. (2006) and Cruts et al. (2006) demonstrated that mutations in progranulin that create null alleles cause tau-negative frontotemporal lobar degeneration with ubiquitin (UBB; 191339)-positive inclusions (607485). Patients with frontotemporal dementia caused by mutations in progranulin exhibit ubiquitin-immunoreactive nuclear cytoplasmic inclusions and characteristic lentiform ubiquitin-immunoreactive neuronal intranuclear inclusions. </p><p>In affected members of a large 4-generation kindred with autosomal dominant ubiquitin-positive frontotemporal dementia, originally described as having 'hereditary dysphasic disinhibition dementia' (Lendon et al., 1998), Mukherjee et al. (2006) identified a heterozygous mutation in the GRN gene (138945.0008). </p><p>Le Ber et al. (2007) identified 9 novel null mutations in the GRN gene in 10 (4.8%) of 210 unrelated patients with frontotemporal dementia. The frequency was 12.8% (5 of 39) in familial cases and 3.2% (5 of 158) in sporadic cases. The phenotype was heterogeneous with age at onset ranging from 45 to 74 years and frequent occurrence of early apraxia (50%), visual hallucinations (30%), and parkinsonism (30%). No GRN mutations were identified in 43 patients with a dementia and motor neuron disease. Le Ber et al. (2007) stated that 31 GRN mutations had been identified in patients worldwide. </p><p>Bruni et al. (2007) identified a mutation in the GRN gene (138945.0011) in 1 of 78 unrelated families with frontotemporal dementia. They noted that incidence of 1.3% was lower than in a previously published series (about 10%). </p><p>By quantitative analysis of PGRN in a series of 103 Belgian patients with frontotemporal dementia, Gijselinck et al. (2008) identified 1 (1%) patient with a heterozygous 54 to 69-kb genomic deletion encompassing the PGRN gene and 2 centromeric neighboring genes: RUNDC3A (605448) and SLC25A39 (610820). The patient developed classic frontotemporal dementia at age 71 years without additional symptoms and died 3 years later. The findings confirmed that PGRN haploinsufficiency results in the disease phenotype. </p><p>Most progranulin mutations are nonsense mutations, resulting in nonsense-mediated mRNA decay and reduced protein levels. Shankaran et al. (2008) demonstrated that missense mutations in the PGRN gene (see, e.g., A9D; 138945.0008) resulted in decreased protein expression or secretion, consistent with haploinsufficiency. Downregulation of PGRN in human cells did not result in a major redistribution of TDP43 (TARDBP; 605078). </p><p>Gijselinck et al. (2008) provided a detailed review of granulin mutations associated with frontotemporal lobar degeneration (FTLD). They noted that 63 heterozygous loss-of-function mutations had been identified in 163 families worldwide, representing about 5 to 10% of FTLD. </p><p>In a population-based study of 59 patients with pathologically confirmed FTLDU and 433 controls, Rademakers et al. (2008) identified a C-to-T SNP in the 3-prime untranslated region of the GRN gene (rs5848; 138945.0018) that conferred increased risk for the development of FTLDU when present in the homozygous state. Functional studies showed that the T allele of rs5848 increased binding of MIR659, a translation suppressor, this providing a novel mechanism for loss of GRN function. </p><p>Yu et al. (2010) reported the results of a large collaborative study of GRN mutations involving 8 academic centers. Twenty-four pathogenic GRN mutations, including 8 novel mutations, were found among 434 patients with various forms of cognitive neurodegenerative diseases. Approximately 55% of the patients with FTD for whom information was available had a family history of the disorder. Overall, the frequency of GRN mutations was 6.9% (30 of 434) of all FTD-spectrum cases. The frequency was 21.4% (9 of 42) in those with a pathologically confirmed diagnosis of FTLD-U; 16.0% (28 of 175) of FTD-spectrum cases with a family history; and 56.2% (9 of 16) of FTLD-U with a family history. The authors noted that GRN mutations were found only in FTD-spectrum cases and not in other related neurodegenerative diseases, such as Pick disease (172700) or progressive supranuclear palsy (PSNP1; 601104). In addition, GRN mutations were not found in patients with ALS (105400) or multiple system atrophy (MSA; 146500) in whom TDP43 deposits were a neuropathologic feature. Yu et al. (2010) concluded that haploinsufficiency of GRN is the predominant mechanism leading to FTD. </p><p>Kuang et al. (2020) evaluated whether aminoglycosides could facilitate the readthrough of nonsense mutations in the GRN gene by transfecting N2A cells with plasmids with wildtype GRN, one of 3 mutations associated with FTD (R493X, 138945.0009; Q125X, 138945.0002; or Y229X), or a mutation associated with juvenile-onset amyotrophic lateral sclerosis (R495X), and testing the readthrough effects of 11 aminoglycosides and a clinically approved readthrough small molecule, PTC124. Both G418 and gentamicin induced the readthrough of GRN with the R493X mutation, but not the other GRN mutants, in a time- and dose-dependent manner. G418 had a stronger effect on readthrough than gentamicin. The readthrough product of the R493X GRN mutant had similar subcellular localization as wildtype GRN, and partially colocalized with the lysosomal marker Lamp1 (153330) and the Golgi marker GM130 (602580). G418 also led to increased mRNA expression of the R493X mutant, which suggested that G418 also stabilized the mutant mRNA. </p><p><strong><em>Autosomal Recessive Frontotemporal Dementia 2</em></strong></p><p>
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In 3 patients from 2 unrelated French families with autosomal recessive FTD2, Huin et al. (2020) identified homozygous mutations in the GRN gene: a splice site mutation (138945.0024) and a frameshift (138945.0025). Aside from the 2 sibs in 1 family, additional family segregation studies could not be performed. Huin et al. (2020) noted that both mutations have been detected in the heterozygous state in patients with autosomal dominant FTD2, suggesting the presence of additional modifying factors. </p><p><strong><em>Autosomal Recessive Neuronal Ceroid Lipofuscinosis-11</em></strong></p><p>
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Smith et al. (2012) identified a homozygous c.813_816 deletion in the GRN gene (138945.0015) in 2 Italian sibs with young-adult onset of neuronal ceroid lipofuscinosis-11 (CLN11; 614706). The patients developed rapidly progressive visual failure in their early twenties, followed by retinal dystrophy, seizures, cerebellar ataxia, and cerebellar hypoplasia. One had cognitive decline. Skin biopsy of 1 patient showed numerous fingerprint profiles in membrane-bound structures in eccrine secretory cells and endothelium. Plasma progranulin levels in the homozygous patients were undetectable and were about 50% decreased in the heterozygous parents. Family history revealed 3 cases of late-onset dementia in both sides of the family, but DNA was not available from these patients. The healthy parents were in their fifties; the molecular findings suggested that they may be at risk for later-onset dementia. Smith et al. (2012) commented on the remarkable phenotypic differences between heterozygous and homozygous GRN mutations, and suggested that progranulin may have a lysosomal function. </p><p>In a 14-year-old Indian girl, born of consanguineous parents, with CLN11, Kamate et al. (2019) identified a homozygous nonsense mutation in the GRN gene (W304X; 138945.0020). The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each unaffected parent and an unaffected sib. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a complete loss of GRN. Serum GRN levels were not assessed. </p><p>In 3 patients from 2 unrelated families with CLN11, Huin et al. (2020) identified homozygous putative loss-of-function mutations in the GRN gene: a frameshift (138945.0021) and a mutation affecting the initiation codon (Met1?; 138945.0022). The mutations, which were found by exome sequencing or molecular screening of a CLN panel and confirmed by Sanger sequencing, segregated with the disorder in both families. Functional studies of the mutations were not performed, but plasma progranulin was undetectable in the patients, suggesting a complete loss of function. </p><p>In 6 patients from 5 unrelated families with CLN11, Neuray et al. (2021) identified homozygous putative loss-of-function mutations in the GRN gene (R493X, 138945.0009; c.813delCACT, 138945.0015; and c.768dupCC, 138945.0021). One of the mutations was a deletion of the entire GRN coding sequence. Functional studies of the variants were not performed. Of note, some of these mutations caused FTD2 in the heterozygous state. However, all of the carrier parents, who ranged from 36 to 72 years of age, were healthy and unaffected, although the authors noted that some may have been too young to manifest dementia. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Nomenclature</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Plowman et al. (1992) referred to progranulin as epithelin precursor. Baba et al. (1993) referred to it as acrogranin. </p><p>Serrero (2003) noted that progranulin has also been called PC cell-derived growth factor (PCDGF). She suggested that the names progranulin and granulin/epithelin precursor do not reflect the true biologic function of the 88-kD glycoprotein and proposed renaming the protein GP88 to recognize its unique role as a cell growth promoter. </p>
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</span>
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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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</h4>
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<span class="mim-text-font">
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<p>Shankaran et al. (2008) demonstrated that downregulation of Pgrn in zebrafish did not affect the subcellular localization of Tdp43 homologs. </p><p>Ahmed et al. (2010) found that Grn-null mice were viable, although produced at lower than predicted frequency. Heterozygous Grn (+/-) mice were neuropathologically indistinguishable from controls. In contrast, Grn-null mice developed age-associated, abnormal accumulation of intraneuronal ubiquitin-positive autofluorescent lipofuscin. Lipofuscin was noted in aged wildtype mice at levels comparable with those of young Grn-null mice. Grn-null mice developed microgliosis, astrogliosis, and tissue vacuolation, with focal neuronal loss and severe gliosis becoming apparent with age. Ahmed et al. (2010) suggested that Grn may play a role in maintaining neuronal function during aging, consistent with it being a trophic factor essential for long-term neuronal survival. Using electron microscopy in fixed brain tissue of Grn-null mice, Smith et al. (2012) found abundant rectilinear profiles diagnostic of neuronal ceroid lipofuscinosis. </p><p>By repeated topical application of the TPA mitogen to mouse ears, Huang et al. (2015) induced psoriasis-like inflammation in mouse skin and observed increased expression of Pgrn in epidermis and infiltrating inflammatory cells. RT-PCR also detected increased Pgrn expression. Unexpectedly, Pgrn -/- mice had an enhanced inflammatory response to the TPA mitogen in skin compared with wildtype mice. The exacerbated response was associated with lower percentages of regulatory T cells, but not helper T cells, in skin and cervical lymph node. </p><p>Using gene ontology analysis, Klein et al. (2017) found that lysosomal enzymes and markers were upregulated in maturing Grn -/- mouse brain. Elevated lysosomal enzyme activities followed elevated protein content, suggesting that lysosomal enzymes were properly folded and functional in Grn -/- brain. In contrast, Tmem106b (613413) -/- mice showed downregulation of multiple lysosomal enzymes upregulated in Grn -/- brain. Deletion of Tmem1206b in Grn -/- mice corrected lysosomal enzyme protein levels and activities, with concomitant correction of FLD-related behaviors and retinal degeneration, but did not improve lipofuscin, C1q (see 120550), and microglial accumulation. </p>
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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>24 Selected Examples):</strong>
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</h4>
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<p />
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<h4>
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<span class="mim-font">
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<strong>.0001 FRONTOTEMPORAL DEMENTIA 2</strong>
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</span>
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</h4>
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GRN, IVS0DS, G-C, +5
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SNP: rs63750313,
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ClinVar: RCV000084418, RCV001089936
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<p>In 8 families with autosomal dominant ubiquitin-positive frontotemporal dementia-2 (FTD2; 607485) all segregating the same haplotype, presumably from the same Belgian founder (van der Zee et al., 2006), Cruts et al. (2006) identified a heterozygous G-to-C transversion at the +5 position of the intron following the first noncoding exon of the GRN gene (IVS0+5G-C). In silico analysis predicted a marked drop in binding efficiency of the U1 snRNP complex (see 180680). Furthermore, analysis of full-length progranulin cDNA in lymphoblasts and brain of 2 probands did not identify aberrant transcripts. However, these 2 probands, who were heterozygous for a C/T single-nucleotide polymorphism (SNP) in the 3-prime untranslated sequence, with the C allele segregating on the disease haplotype, showed only the T allele when their lymphoblast and/or brain progranulin cDNAs were sequenced. These data suggested that the mutation results in absent granulin mRNA and protein. This mutation was not identified in 436 control individuals. </p><p>Brouwers et al. (2007) identified the IVS0+5G-C mutation in 2 of 666 Belgian patients with a clinical diagnosis of Alzheimer disease (see 104300). Clinical features of 1 of the cases included memory loss, disorientation, and loss of spontaneous speech. The other patient was shown to be a member of 1 of the families reported by Cruts et al. (2006), reported as having FTLDU. Thus, the phenotype in both patients was also consistent with FTLDU. Brouwers et al. (2007) also identified the IVS0+5G-C mutation in 1 of 255 Belgian patients with a clinical diagnosis of Parkinson disease (see 168600). Although the man presented with parkinsonism, he later developed progressive memory problems, apathy, hypophonia, and frontotemporal dementia. All 3 patients had the same haplotype reported by Cruts et al. (2006). </p>
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<h4>
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<span class="mim-font">
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<strong>.0002 FRONTOTEMPORAL DEMENTIA 2</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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GRN, GLN125TER
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<br />
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SNP: rs63750077,
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ClinVar: RCV000017380, RCV000084439
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<span class="mim-text-font">
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<p>In the large Dutch family with 19 individuals segregating autosomal dominant ubiquitin-positive frontotemporal dementia-2 (FTD2; 607485) originally reported by Rademakers et al. (2002), Baker et al. (2006) and Cruts et al. (2006) found a C-to-T transition at nucleotide 373 (c.373C-T, NM_002087.2) of the GRN gene, resulting in a substitution of a termination codon for glutamine-125 (Q125X). Baker et al. (2006) found the mean age of onset in this family to be 65 years. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 FRONTOTEMPORAL DEMENTIA 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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GRN, MET1THR
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<br />
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SNP: rs63751006,
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gnomAD: rs63751006,
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ClinVar: RCV000017381, RCV000084419, RCV002513073
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<span class="mim-text-font">
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<p>In an American proband with autosomal dominant ubiquitin-positive frontotemporal dementia-2 (FTD2; 607485), Baker et al. (2006) found a T-to-C transition of the second nucleotide in exon 1 of the GRN gene, which altered the initiating methionine codon (c.2T-C). RT-PCR analysis showed a substantial reduction of mutant mRNA in brain. Another alteration at this codon was found by Cruts et al. (2006) (138945.0004). </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 FRONTOTEMPORAL DEMENTIA 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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GRN, MET1ILE
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<br />
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SNP: rs63750331,
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gnomAD: rs63750331,
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ClinVar: RCV000017382, RCV000084420
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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 Belgian patient with ubiquitin-positive frontotemporal dementia-2 (FTD2; 607485), Cruts et al. (2006) demonstrated a G-to-A transition in exon 1 of the GRN gene that destroyed the native Kozak sequence surrounding the met1 translation initiation codon (c.3G-A, NM_002087.2). Age of onset was 62 years; death occurred at 72 years. The patient's sister also suffered from dementia and died at age 64. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 FRONTOTEMPORAL DEMENTIA 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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GRN, 4-BP INS, NT90
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<br />
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SNP: rs606231220,
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ClinVar: RCV000017383
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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 large Canadian family with 17 affected individuals segregating autosomal dominant frontotemporal dementia-2 (FTD2; T607485), originally reported by Mackenzie et al. (2006), Baker et al. (2006) identified a 4-bp insertion of CTGC between coding nucleotides 90 and 91 (c.90insCTGC) of the GRN gene, resulting in a frameshift and premature termination in progranulin (Cys31LeufsTer34). The mean age of onset of dementia in this family was 58 years of age. </p><p>Rohrer et al. (2008) reported a large British kindred with FTLDU associated with the 9c.0insCTGC mutation. The average age at disease onset was 57.8 years. All patients had clinical and radiographic features of frontotemporal lobar degeneration with behavioral changes and language deficits. Nonfluent aphasia was present in 2 patients, and 3 became mute several years into the illness. Most also had features suggestive of parietal lobe involvement, including dyscalculia, visuoperceptual/visuospatial dysfunction, and limb apraxia. Brain imaging showed extension of the atrophy to the parietal lobe. Haplotype analysis indicated common ancestry to the family reported by Mackenzie et al. (2006). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0006 FRONTOTEMPORAL DEMENTIA 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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GRN, 4-BP DEL, NT388
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<br />
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SNP: rs63749801,
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ClinVar: RCV000017384, RCV000084442, RCV000736253, RCV002513074, RCV003478976
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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 Canadian (UBC11) and British (F53) families segregating autosomal dominant ubiquitin-positive frontotemporal dementia-2 (FTD2; 607485), Baker et al. (2006) identified a c.388_391delCAGT deletion starting at nucleotide 388 of the GRN gene, resulting in frameshift (Gln130SerfsTer124). In the Canadian family with 6 affected individuals, the mean age of onset was 68, and in the U.K. family with 3 affected individuals, the mean age of onset was 60 years. </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>.0007 FRONTOTEMPORAL DEMENTIA 2</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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GRN, IVS8AS, G-A, +1
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<br />
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SNP: rs606231221,
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gnomAD: rs606231221,
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ClinVar: RCV000017385, RCV002513075
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|
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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 Canadian family (UBC19) with 9 affected individuals with autosomal dominant ubiquitin-positive frontotemporal dementia-2 (FTD2; 607485), Baker et al. (2006) identified a splice site mutation at the +1 position of intron 8 of the GRN gene (IVS8+1G-A). The mutation was predicted to lead to skipping of exon 8 from the progranulin mRNA resulting in frameshift (Val279GlyfsTer4); however, no RNA was available for study. Mean age of onset in this family was 61 years. </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>.0008 FRONTOTEMPORAL DEMENTIA 2</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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GRN, ALA9ASP
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<br />
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SNP: rs63751243,
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gnomAD: rs63751243,
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ClinVar: RCV000017386, RCV000084421, RCV001851887
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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 affected members of a large 4-generation kindred with autosomal dominant ubiquitin-positive frontotemporal dementia-2 (FTD2; 607485), originally described as having 'hereditary dysphasic disinhibition dementia' (Lendon et al., 1998), Mukherjee et al. (2006) identified a heterozygous C-A transversion (c.4068C-A) in exon 1 of the GRN gene, resulting in an ala9-to-asp (A9D) substitution. The A9D substitution is predicted to occur in or near the binding site of the signal recognition particle, which targets proteins to the endoplasmic reticulum membrane. </p><p>Chen-Plotkin et al. (2011) found the A9D mutation (c.26C-A) in 6 (6.2%) of 97 unrelated probands with FTLD due to GRN mutations. Those with the A9D mutation appeared to have earlier disease onset and more parkinsonian features compared to patients with other GRN mutations. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
Mukherjee et al. (2008) reported that the A9D mutation resulted in normal levels of GRN mRNA, but about 50% decreased levels of secreted GRN protein in cell cultures from affected patients. Further in vitro studies showed that the A9D mutant protein was not glycosylated and was detected in the Golgi and cytosol, but not throughout the secretory pathway like the wildtype protein. The findings indicated that the mutation resulted in transcription of the protein with a defect in trafficking that likely resulted in functional haploinsufficiency. </p><p>Shankaran et al. (2008) found that expression of the A9D mutation in HeLa cells resulted in cytoplasmic missorting with extremely low protein expression. </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>.0009 FRONTOTEMPORAL DEMENTIA 2</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
CEROID LIPOFUSCINOSIS, NEURONAL, 11, INCLUDED
|
|
</span>
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</div>
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<div>
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<span class="mim-text-font">
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GRN, ARG493TER ({dbSNP rs63751294})
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<br />
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SNP: rs63751294,
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gnomAD: rs63751294,
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|
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ClinVar: RCV000017387, RCV000084491, RCV001039647, RCV004755740
|
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|
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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 />
|
|
<p><strong><em>Frontotemporal Dementia 2</em></strong></p><p>
|
|
In 3 unrelated patients with ubiquitin-positive frontotemporal lobar degeneration-2 (FTD2; 607485), Huey et al. (2006) identified a heterozygous mutation in the GRN gene, resulting in an arg493-to-ter (R493X) substitution. Two patients had a clear family history of the disorder, and all presented with predominantly behavioral symptoms and had rapid disease progression. </p><p>Mesulam et al. (2007) identified heterozygosity for a c.1477C-T transition in exon 11 of the GRN gene, resulting in an R493X substitution, in 2 sisters with primary progressive aphasia, a manifestation of FTD2. The phenotype was an isolated aphasia beginning at ages 65 and 62 years, respectively, without other features. There was rapid progression of aphasia to complete mutism within 2 to 3 years. One sister developed a right-sided tremor, clumsiness, rigidity, and impaired motor function. </p><p>Davion et al. (2007) identified a heterozygous R493X mutation in 2 unrelated patients with pathologically confirmed FTLDU. </p><p>Rademakers et al. (2007) identified the R493X mutation (c.1477C-T, NM_002087.2) in 16 (2%) of 731 patients with a clinical diagnosis of frontotemporal lobar dementia. Further investigation identified a total of 37 patients with R493X from 30 families with FTLD. Initial diagnoses included FTLD, primary progressive aphasia, and Alzheimer disease (104300). The majority of patients presented with executive dysfunction or personality changes, followed by memory deficits, and language impairment. In all 13 patients who came to autopsy, the pathological diagnosis was FTLD with neuronal inclusions that contained TDP43 (605078) or ubiquitin (UBB; 191339), but not tau (MAPT; 157140). Haplotype analyses suggested that R493X arose twice, with a single founder for 27 families. Linear regression analysis suggested that patients with the coding region SNP rs9897526 on their wildtype GRN allele had delayed symptom onset. Seelaar et al. (2008) could not confirm the association between age at onset and rs9897526 in their cohort of 23 patients with FTLDU. </p><p>Chen-Plotkin et al. (2011) found that R493X was the most common GRN mutation in an international cohort; it was found in 18 (18.6%) of 97 unrelated FTLD probands with GRN mutations. All patients with the R493X mutation shared a common haplotype, suggesting a founder effect. </p><p><strong><em>Neuronal Ceroid Lipofuscinosis 11</em></strong></p><p>
|
|
In 3 patients from 2 unrelated families (consanguineous Pakistani family A and nonconsanguineous Caucasian family E) with neuronal ceroid lipofuscinosis-11 (CLN11; 614706), Neuray et al. (2021) identified a homozygous c.1477C-T transition in the GRN gene, resulting in an R493X substitution. Functional studies of the variant and studies of patient cells were not performed. All 3 patients had onset of symptoms, including seizures, late in the first decade. None of the carrier parents, who were in their late thirties and forties, had neurologic symptoms. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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|
|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 FRONTOTEMPORAL DEMENTIA 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
GRN, 1-BP DEL, 998G
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|
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|
|
<br />
|
|
|
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SNP: rs63750873,
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|
|
|
|
|
gnomAD: rs63750873,
|
|
|
|
|
|
ClinVar: RCV000084470, RCV002281921
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 affected sibs with frontotemporal dementia-2 (FTD2; 607485) presenting as primary progressive aphasia (PPA) reported by Krefft et al. (2003), Mesulam et al. (2007) identified a heterozygous 1-bp deletion (c.998delG) in the GRN gene, resulting in a frameshift and premature termination of the protein. Onset of word-finding and naming difficulties occurred at ages 60, 65, and 61 years, respectively. All showed left frontotemporal atrophy. One patient had mild right motor impairment, including hemiparesis and mild tremor, whereas another had significant parkinsonism and cortical release signs. One patient developed behavioral changes and another dementia. Two patients died mute 12 and 4 years after onset, respectively. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 FRONTOTEMPORAL DEMENTIA 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GRN, 1-BP INS, 1145A
|
|
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<br />
|
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|
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SNP: rs63749905,
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|
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|
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ClinVar: RCV000017389, RCV000084472, RCV001854478
|
|
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|
|
|
</span>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a large consanguineous Calabrian Italian family with FTD2 (607485), Bruni et al. (2007) identified a heterozygous 1-bp insertion (c.1145insA, NM_002087.2) in exon 9 of the GRN gene, resulting in a frameshift and premature termination at residue 413. The mutation was present in 19 family members, but only 9 showed clinical symptoms. Some of the unaffected mutation carriers were younger than the mean age of onset in the affected members. Four individuals with a similar phenotype from a distant branch of the family did not carry the GRN mutation, suggesting a different genetic mechanism in these patients. The mean age at onset in those with and without the GRN mutation was 63.4 and 74.8 years, respectively, although the range in those with the GRN mutation was large (35 to 87 years). In contrast to the phenocopies, patients with the GRN mutation had more compromised language function, alteration of social behavior, somnolence, and primitive reflexes. Despite the large consanguineous unions in this extended family, there were no homozygous GRN mutation carriers, suggesting that homozygosity may be embryonic lethal. </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>.0012 FRONTOTEMPORAL DEMENTIA 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GRN, IVS7AS, A-G, -2
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs63750548,
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|
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|
|
|
|
|
ClinVar: RCV000084453, RCV000704513, RCV000995784, RCV001824019
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a man (patient 3) with frontotemporal dementia-2 (FTD2; 607485) presenting as primary progressive aphasia (PPA) beginning at age 53 years, Davion et al. (2007) identified a heterozygous A-to-G transition in intron 7 (c.709-2A-G) of the GRN gene, predicted to result in a frameshift and premature termination in exon 8 (Ala237TrpfsTer4). At first he had word finding difficulties, which progressed to problems in writing, reading, and speech comprehension. Language symptoms were predominant until 7 years after onset, when he showed rapid deterioration with behavioral changes. He died at age 61. His mother had been diagnosed with dementia in her fifties and died at age 64. Neuropathologic examination showed diffuse neuronal intranuclear and cytoplasmic inclusions in the frontal cortex and striatum, with significant involvement of the temporal cortex. </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>.0013 FRONTOTEMPORAL DEMENTIA 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
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|
GRN, 2-BP DEL, 675CA
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<br />
|
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|
|
SNP: rs63751085,
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|
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|
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ClinVar: RCV000017391, RCV000084584, RCV000995782, RCV001064002
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a woman (patient 2) with frontotemporal dementia-2 (FTD2; 607485) presenting as primary progressive aphasia (PPA) beginning at age 56 years, Davion et al. (2007) identified a heterozygous 2-bp deletion (c.675delCA) in exon 6 of the GRN gene, resulting in a frameshift and premature termination (Ser226TrpfsTer28). She had progressive word finding impairment leading to single word utterances within 2 years and complete mutism within 4 years. Neuropathologic examination showed diffuse neuronal intranuclear cytoplasmic inclusions in the frontal cortex, temporal cortex, and striatum. </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>.0014 FRONTOTEMPORAL DEMENTIA 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
GRN, IVS6AS, A-G, -2
|
|
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|
|
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<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000084453, RCV000704513, RCV000995784, RCV001824019
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 2 unrelated families with FTD2 (607485), 1 of whom had been reported by Morris et al. (1984), Mukherjee et al. (2008) identified a heterozygous A-to-G transition in intron 6 of the GRN gene, resulting in the skipping of exon 7 and premature protein termination. Haplotype analysis of the 2 families suggested a founder effect. Another affected patient unrelated to both families also carried the IVS6 mutation on a different haplotype, indicating that the mutation occurred independently on at least 2 occasions. Western blot analysis showed a 50% reduction in GRN protein compared to controls, suggesting haploinsufficiency. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<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>.0015 FRONTOTEMPORAL DEMENTIA 2</strong>
|
|
</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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CEROID LIPOFUSCINOSIS, NEURONAL, 11, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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GRN, 4-BP DEL, 813CACT ({dbSNP rs63749877})
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<br />
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SNP: rs63749877,
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ClinVar: RCV000017393, RCV000017394, RCV000029169, RCV000084585, RCV001851888
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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 />
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<p><strong><em>Frontotemporal Dementia 2</em></strong></p><p>
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|
In 4 (1.64%) of 243 unrelated Italian patients with frontotemporal dementia-2 (FTD2; 607485), Borroni et al. (2008) identified the same heterozygous 4-bp deletion (c.813delCACT) in exon 8 of the GRN gene, resulting in a frameshift and premature termination. Two female patients were diagnosed with the behavioral variant of frontotemporal dementia, and 2 males with progressive nonfluent aphasia. The estimated age at onset ranged from 53 to 64 years, and all showed evidence of hypoperfusion of the frontotemporal brain regions. Three of the 4 had a family history of the disorder. Considering all patients in the study with a well-known family history for dementia, the frequency of this mutation was 6% (4 of 84). Haplotype analysis indicated a founder effect. </p><p>Benussi et al. (2009) found the heterozygous c.813delCACT mutation (c.813delCACT, NM_002087) in 27 (15%) of 151 Italian patients with a clinical diagnosis of neurodegenerative frontotemporal dementia-related disorders, indicating that it is one of the most common GRN mutations. Although the consequence of this mutation has been reported as Leu271LeufsTer10, Benussi et al. (2009) noted that the Human Genome Variation Society recommended the frameshift nomenclature Thr272SerfsTer10. GRN mutation carriers had variable clinical diagnoses, including corticobasal degeneration syndrome, FTD with motorneuron disease, behavioral variant FTD, primary progressive aphasia, and Lewy body dementia. </p><p><strong><em>Neuronal Ceroid Lipofuscinosis 11</em></strong></p><p>
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Smith et al. (2012) identified a homozygous c.813_816 deletion in the GRN gene (rs63749877) in 2 sibs, born of distantly related Italian parents, with young-adult onset of neuronal ceroid lipofuscinosis-11 (CLN11; 614706). The patients developed rapidly progressive visual failure in their early twenties, followed by retinal dystrophy, seizures, cerebellar ataxia, and cerebellar hypoplasia. One had cognitive decline. Skin biopsy of 1 patient showed numerous fingerprint profiles in membrane-bound structures in eccrine secretory cells and endothelium. Plasma progranulin levels in the homozygous patients were undetectable and were about 50% decreased in the heterozygous parents. Family history revealed 3 cases of late-onset dementia in both sides of the family, but DNA was not available from these patients. The healthy parents were in their fifties; the molecular findings suggested that they may be at risk for later-onset dementia. Ahmed et al. (2010) found that Grn-null mice developed abnormal accumulation of abnormal intraneuronal ubiquitin-positive autofluorescent lipofuscin, detected by light microscopy. Electron microscopic examination of fixed brain tissue from Grn-null showed abundant rectilinear profiles diagnostic of CLN. Smith et al. (2012) commented on the remarkable phenotypic differences between heterozygous and homozygous GRN mutations, and suggested that progranulin may have a lysosomal function. </p><p>In a 40-year-old man, born of distantly related Italian parents (family B), with CLN11, Neuray et al. (2021) identified a homozygous c.813_816delCACT mutation in the GRN gene, predicted to result in a frameshift and premature termination (Thr272SerfsTer10). The carrier parents, who were in their early seventies, were unaffected. Functional studies of the variant were not performed. </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>.0016 FRONTOTEMPORAL DEMENTIA 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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GRN, 1-BP DEL, 102C
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<br />
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SNP: rs63751073,
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gnomAD: rs63751073,
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ClinVar: RCV000084427, RCV001241659, RCV002281919
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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 affected members of a large Swedish family with FTD2 (607485) mainly presenting as language and speech abnormalities, Skoglund et al. (2009) identified a 1-bp deletion (c.102delC) in exon 1 of the GRN gene, resulting in a frameshift and predicted truncated protein. In vitro functional expression studies showed that the mutant transcript was subject to nonsense-mediated mRNA decay, resulting in functional haploinsufficiency. Three mutation carriers were unaffected, suggesting incomplete penetrance or variation in age of onset. The family had previously been reported by Froelich et al. (1997) and Basun et al. (1997). The mutation was not identified in 165 control individuals. </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>.0017 FRONTOTEMPORAL DEMENTIA 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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GRN, 1-BP DEL, 154A
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<br />
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SNP: rs63751092,
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gnomAD: rs63751092,
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ClinVar: RCV000084429, RCV002281920
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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 7 affected members of a family with autosomal dominant inheritance of FTD2 (607485), Kelley et al. (2010) identified a heterozygous 1-bp deletion (c.154delA) in exon 2 of the GRN gene, resulting in a frameshift and premature termination (Thr52HisfsTer2). Of 10 affected individuals, 6 presented with early amnestic symptoms resulting in initial clinical diagnoses of Alzheimer disease (AD; 104300) or amnestic mild cognitive impairment, and 3 with frontotemporal dementia; 1 had nonspecific dementia. Neuropathologic examination of 6 individuals showed FTLD with ubiquitin-positive neuronal cytoplasmic and intranuclear inclusions, even in those with an AD diagnosis. The mean age at onset was younger in the third generation (60.7 years) than in the second generation (75.8 years). Kelley et al. (2010) noted that the presentation in some individuals with GRN-related FTLD may include Alzheimer disease-like clinical features, particularly anterograde amnesia. </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>.0018 FRONTOTEMPORAL DEMENTIA 2, SUSCEPTIBILITY TO</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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GRN, 78C-T, 3-PRIME UTR ({dbSNP rs5848})
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<br />
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SNP: rs5848,
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gnomAD: rs5848,
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ClinVar: RCV000022594, RCV000353944, RCV000650262, RCV000791344, RCV001636606
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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>Rademakers et al. (2008) identified a C-to-T transition (rs5848) in the 3-prime untranslated region (UTR) of the GRN gene that appeared to confer increased risk for the development of GRN-related FTD2 (607485). The SNP was located 78 nucleotides downstream of the translation termination codon of the GRN gene within a predicted regulatory binding site for miRNA659 (MIR659; 613556). The authors reanalyzed previously published data and found a significant increase in the T/T genotype among 339 FTLD patients, who were non-GRN mutation carriers, compared to 934 controls (16% versus 9%; p = 0.002). The findings were replicated in 59 patients with pathologically confirmed FTLDU and 433 controls (25.4% vs 9.9%; p = 0.003). Homozygosity for the minor T allele conferred an odds ratio of 3.18 for development of FTLDU, which increased to 3.76 when those with motor neuron disease were excluded. However, heterozygosity for the T allele was not associated with an increased disease risk. In silico analysis predicted that MIR659 would bind more efficiently to the T allele than the C allele. In vitro functional expression studies showed that low doses of MIR659 suppressed expression of GRN with the T allele, but not GRN with the wildtype C allele. Western blot, immunohistochemical and quantitative analysis showed a significant decrease (about 30%) of GRN expression in T/T carriers compared to C/C carriers, although mRNA levels did not differ, consistent with a mechanism affecting translation. The findings suggested that rs5848 in the GRN gene increases the risk of FTLDU by miRNA-mediated translational repression of GRN, thus resembling the clinical and pathologic phenotypes observed in patients with loss-of-function mutations in the GRN gene. </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>.0019 FRONTOTEMPORAL DEMENTIA 2</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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GRN, IVS6AS, G-A, -1
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<br />
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SNP: rs2143337085,
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ClinVar: RCV000022595, RCV004783729
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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 23 patients from 13 families of Basque origin with frontotemporal dementia-2 (FTD2; 607485), Moreno et al. (2009) identified a heterozygous G-to-A transition in intron 6 (c.709-1G-A) of the GRN gene, resulting in nonsense-mediated decay of the mRNA and haploinsufficiency. The mean age at onset was 59.2 years (range, 42 to 71 years), and 4 of 21 patients died after a mean duration of 4.75 years. Overall, 14 (66.7%) had a diagnosis of behavioral variant FTD, 10 (47.6%) had a diagnosis of corticobasal degeneration, and 7 (33.3%) had a diagnosis of progressive nonfluent aphasia. None developed signs of motor neuron disease/ALS, but 8 with corticobasal degeneration had motor signs, including limb rigidity or apraxia and myoclonus. The most prominent behavioral symptoms were apathy, impulsivity, disinhibition, and bulimia, suggesting involvement of the medial frontal and orbitofrontal cortex. Dysgraphia, dyscalculia, apraxia, and hemineglect suggested parietal dysfunction. </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>.0020 CEROID LIPOFUSCINOSIS, NEURONAL, 11</strong>
|
|
</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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GRN, TRP304TER
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a 14-year-old Indian girl, born of consanguineous parents, with neuronal ceroid lipofuscinosis-11 (CLN11; 614706), Kamate et al. (2019) identified a homozygous c.912G-A transversion (chr17:42428807G-A) in exon 9 of the GRN gene, predicted to result in a trp304-to-ter (W304X) substitution. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each unaffected parent and an unaffected sib. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a complete loss of GRN. Serum GRN levels were not assessed. </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>.0021 CEROID LIPOFUSCINOSIS, NEURONAL, 11</strong>
|
|
</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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GRN, 2-BP DUP, 768CC
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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 sisters, born of possibly consanguineous Portuguese parents (family AAR-427), with neuronal ceroid lipofuscinosis-11 (CLN11; 614706), Huin et al. (2020) identified a homozygous 2-bp duplication (c.768_769dup, NM_002087.2) in exon 8 of the GRN gene, predicted to result in a frameshift and premature termination (Gln257ProfsTer27). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was inherited from the 2 unaffected heterozygous parents. Plasma GRN was undetectable in the sister who was tested. Plasma GRN was decreased in the unaffected parents (aged 57 and 61). Functional studies of the variant were not performed. </p><p>In a 25-year-old woman, born of consanguineous Brazilian parents (family D), with CLN11, Neuray et al. (2021) identified a homozygous c.768dupCC mutation in the GRN gene. The patient's father was deceased; her 55-year-old healthy mother carried the mutation in the heterozygous state. Functional studies of the variant were not performed. </p><p>In a 25-year-old woman, born of consanguineous Brazilian parents, with CLN11 and spastic paraplegia, Faber et al. (2017) identified a homozygous c.768dupCC mutation in the GRN gene, which they referred to as c.767_768insCC. Functional studies of the variant were not performed. </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>.0022 CEROID LIPOFUSCINOSIS, NEURONAL, 11</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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GRN, MET1?
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a 7-year-old girl, born of consanguineous Pakistani parents (family NCL-001), with neuronal ceroid lipofuscinosis-11 (CLN11; 614706), Huin et al. (2020) identified a homozygous c.1A-T transversion (c.1A-T, NM_002087.2) in exon 2 of the GRN gene, predicted to disrupt the initiation codon (Met1?). The mutation, which was found by sequencing of a CLN gene panel and confirmed by Sanger sequencing, segregated with the disorder in the family. Plasma GRN was undetectable in the patient. The carrier parents were asymptomatic at 46 and 47 years of age. Functional studies of the variant were not performed. </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>.0023 FRONTOTEMPORAL DEMENTIA 2, AUTOSOMAL RECESSIVE</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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GRN, IVS7AS, C-G, -3
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a French woman (family FTD-1042) with frontotemporal dementia-2 (FTD2; 607485) who had onset of symptoms at age 56, Huin et al. (2020) identified a homozygous C-to-G transversion in intron 7 of the GRN gene (c.709-3C-G, NM_002087.2), resulting in a splicing defect. The mutation was found by Sanger sequencing; parental DNA was not available for study. Lymphoblastoid cells from the patient showed 2 RNA fragments: one of the expected normal size and another abnormal larger fragment that included intron 7 and altered splicing, leading to a frameshift and premature termination (Ala237ValfsTer98). The aberrant transcript was degraded by nonsense-mediated mRNA decay. The proband had an 11.2-fold decrease of normal GRN transcripts and low levels of plasma progranulin. Her 2 children, who were each heterozygous for the mutation, were asymptomatic at 22 and 27 years of age and had low plasma progranulin levels that were slightly higher than those of their mother. Huin et al. (2020) noted that the splice site mutation still allowed the synthesis of low levels of normally spliced GRN, suggesting it may be a hypomorphic mutation, leading to residual amounts of plasma progranulin and a milder phenotype. However, the authors also noted that another patient with FTD2 (patient FAM347 in Benussi et al., 2009) with this same mutation in the heterozygous state developed symptoms at 49 years of age (earlier than their proband), suggesting that other unknown mechanisms are at play. </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>.0024 FRONTOTEMPORAL DEMENTIA 2, AUTOSOMAL RECESSIVE</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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GRN, 2-BP DEL, NT443
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 French brothers (family FTDP-N12/1611) with autosomal recessive frontotemporal dementia-2 (FTD2; 607485), Huin et al. (2020) identified a homozygous 2-bp deletion (c.443_444del) in exon 5 of the GRN gene, predicted to result in a frameshift and premature termination (Gly148ValfsTer11). There was a family history of dementia and Parkinson disease, but genetic studies were not performed on the affected relatives. Plasma progranulin was undetectable. Functional studies of the variant were not performed. </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>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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Ahmed, Z., Sheng, H., Xu, Y., Lin, W.-L., Innes, A. E., Gass, J., Yu, X., Wuertzer, C. A., Hou, H., Chiba, S., Yamanouchi, K., Leissring, M., Petrucelli, L., Nishihara, M., Hutton, M. L., McGowan, E., Dickson, D. W., Lewis, J.
|
|
<strong>Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging.</strong>
|
|
Am. J. Path. 177: 311-324, 2010. Note: Erratum: Am. J. Path. 177: 2146 only, 2010.
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[PubMed: 20522652]
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[Full Text: https://doi.org/10.2353/ajpath.2010.090915]
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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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Ashcroft, G. S., Lei, K., Jin, W., Longenecker, G., Kulkarni, A. B., Greenwell-Wild, T., Hale-Donze, H., McGrady, G., Song, X.-Y., Wahl, S. M.
|
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<strong>Secretory leukocyte protease inhibitor mediates non-redundant functions necessary for normal wound healing.</strong>
|
|
Nature Med. 6: 1147-1153, 2000.
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[PubMed: 11017147]
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[Full Text: https://doi.org/10.1038/80489]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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Cassandra L. Kniffin - updated : 08/21/2024<br>Hilary J. Vernon - updated : 02/12/2021<br>Bao Lige - updated : 09/24/2020<br>Patricia A. Hartz - updated : 02/12/2018<br>Paul J. Converse - updated : 12/21/2015<br>Cassandra L. Kniffin - updated : 7/9/2012<br>Cassandra L. Kniffin - updated : 11/28/2011<br>Cassandra L. Kniffin - updated : 10/17/2011<br>Paul J. Converse - updated : 9/8/2011<br>Ada Hamosh - updated : 7/8/2011<br>Cassandra L. Kniffin - updated : 3/8/2011<br>Cassandra L. Kniffin - updated : 9/15/2010<br>Patricia A. Hartz - updated : 9/10/2010<br>Cassandra L. Kniffin - updated : 5/6/2010<br>Cassandra L. Kniffin - updated : 3/27/2009<br>Cassandra L. Kniffin - updated : 2/18/2009<br>Matthew B. Gross - updated : 2/17/2009<br>Patricia A. Hartz - updated : 2/13/2009<br>Cassandra L. Kniffin - updated : 1/14/2009<br>Cassandra L. Kniffin - updated : 11/17/2008<br>Cassandra L. Kniffin - updated : 10/31/2008<br>Cassandra L. Kniffin - updated : 7/22/2008<br>Cassandra L. Kniffin - updated : 5/19/2008<br>Cassandra L. Kniffin - updated : 3/3/2008<br>Cassandra L. Kniffin - updated : 11/29/2007<br>Cassandra L. Kniffin - updated : 10/17/2007<br>Cassandra L. Kniffin - updated : 9/20/2007<br>Ada Hamosh - updated : 9/8/2006<br>Stylianos E. Antonarakis - updated : 1/16/2003<br>Victor A. McKusick - updated : 1/14/2003<br>Victor A. McKusick - updated : 5/1/2000<br>Victor A. McKusick - updated : 1/6/2000<br>Victor A. McKusick - updated : 9/15/1999
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Victor A. McKusick : 11/24/1992
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alopez : 08/22/2024<br>ckniffin : 08/21/2024<br>carol : 02/12/2021<br>mgross : 09/24/2020<br>mgross : 02/12/2018<br>carol : 04/25/2017<br>carol : 08/12/2016<br>mgross : 12/22/2015<br>mgross : 12/21/2015<br>carol : 11/14/2014<br>tpirozzi : 10/1/2013<br>carol : 8/28/2013<br>terry : 7/27/2012<br>alopez : 7/13/2012<br>terry : 7/10/2012<br>ckniffin : 7/9/2012<br>carol : 11/29/2011<br>ckniffin : 11/28/2011<br>carol : 10/26/2011<br>carol : 10/26/2011<br>carol : 10/21/2011<br>terry : 10/21/2011<br>ckniffin : 10/17/2011<br>mgross : 9/19/2011<br>terry : 9/8/2011<br>alopez : 7/11/2011<br>alopez : 7/11/2011<br>terry : 7/8/2011<br>terry : 3/14/2011<br>wwang : 3/11/2011<br>ckniffin : 3/8/2011<br>wwang : 9/16/2010<br>ckniffin : 9/15/2010<br>mgross : 9/10/2010<br>wwang : 5/10/2010<br>ckniffin : 5/6/2010<br>terry : 12/16/2009<br>wwang : 4/10/2009<br>ckniffin : 3/27/2009<br>carol : 2/20/2009<br>ckniffin : 2/18/2009<br>mgross : 2/17/2009<br>mgross : 2/17/2009<br>terry : 2/13/2009<br>wwang : 1/22/2009<br>ckniffin : 1/14/2009<br>wwang : 12/1/2008<br>ckniffin : 11/17/2008<br>wwang : 11/10/2008<br>ckniffin : 10/31/2008<br>wwang : 7/29/2008<br>ckniffin : 7/22/2008<br>wwang : 5/27/2008<br>ckniffin : 5/19/2008<br>wwang : 3/19/2008<br>ckniffin : 3/3/2008<br>wwang : 12/5/2007<br>ckniffin : 11/29/2007<br>wwang : 10/25/2007<br>ckniffin : 10/17/2007<br>wwang : 10/2/2007<br>ckniffin : 9/20/2007<br>alopez : 9/20/2006<br>terry : 9/8/2006<br>terry : 5/16/2003<br>carol : 5/14/2003<br>alopez : 2/28/2003<br>tkritzer : 2/11/2003<br>mgross : 1/16/2003<br>alopez : 1/15/2003<br>terry : 1/14/2003<br>mcapotos : 5/26/2000<br>mcapotos : 5/23/2000<br>terry : 5/1/2000<br>mgross : 1/14/2000<br>terry : 1/6/2000<br>mgross : 9/21/1999<br>mgross : 9/16/1999<br>terry : 9/15/1999<br>carol : 2/11/1993<br>carol : 1/25/1993<br>carol : 11/24/1992
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