4722 lines
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Entry
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- *616254 - CASEINOLYTIC PEPTIDASE B; CLPB
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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">*616254</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<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/616254">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<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=ENSG00000162129;t=ENST00000538039" 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=81570" 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=616254" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000162129;t=ENST00000538039" 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_001258392,NM_001258393,NM_001258394,NM_030813,XM_005274320,XM_011545289,XM_047427655,XM_047427656" 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_001258392" 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=616254" 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://www.proteinatlas.org/search/CLPB" 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/10435042,12053313,13540606,13623579,21740264,25009267,31417113,119595264,119595265,119595266,194378488,194378588,194378722,332367915,385719194,385719196,385719198,530397440,767968838,2217284870,2217284872,2462527867,2462527869,2462527871,2462527873" 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/Q9H078" 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=81570" 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=ENSG00000162129;t=ENST00000538039" 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=CLPB" 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=CLPB" 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+81570" 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/CLPB" 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:81570" 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/81570" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr11&hgg_gene=ENST00000538039.6&hgg_start=72285495&hgg_end=72434531&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:30664" 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/clpb" 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=616254[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=616254[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/CLPB/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000162129" 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=CLPB" 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=CLPB" 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=CLPB" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=CLPB&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/PA142672092" 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:30664" 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:1100517" 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/CLPB#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:1100517" 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/81570/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=81570" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-150227-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:81570" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=CLPB&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
|
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616254
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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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CASEINOLYTIC PEPTIDASE B; CLPB
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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">
|
|
ClpB, E. COLI, HOMOLOG OF<br />
|
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SUPPRESSOR OF POTASSIUM TRANSPORT DEFECT 3; SKD3
|
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</span>
|
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</h4>
|
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</div>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=CLPB" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CLPB</a></em></strong>
|
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/11/722?start=-3&limit=10&highlight=722">11q13.4</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr11:72285495-72434531&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">11:72,285,495-72,434,531</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
|
<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">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=619835,616271,619813" 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/11/722?start=-3&limit=10&highlight=722">
|
|
11q13.4
|
|
</a>
|
|
</span>
|
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</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
3-methylglutaconic aciduria, type VIIA, autosomal dominant
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/619835"> 619835 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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|
</span>
|
|
</td>
|
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<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>
|
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</td>
|
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
3-methylglutaconic aciduria, type VIIB, autosomal recessive
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/616271"> 616271 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<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>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Neutropenia, severe congenital, 9, autosomal dominant
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/619813"> 619813 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
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</tbody>
|
|
</table>
|
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</div>
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</div>
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<div>
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<p>Oligomeric AAA+ ATPases, such as CLPB, are key players in cellular quality control that either degrade or reactivate misfolded proteins. These enzymes use the energy of ATP hydrolysis to generate the mechanical force required to remodel bound substrates. In bacteria, oligomeric ClpB reactivates aggregated proteins via a conserved threading activity that refolds substrate proteins (summary by <a href="#4" class="mim-tip-reference" title="Haslberger, T., Zdanowicz, A., Brand, I., Kirstein, J., Turgay, K., Mogk, A., Bukau, B. <strong>Protein disaggregation by the AAA+ chaperone ClpB involves partial threading of looped polypeptide segments.</strong> Nature Struct. Molec. Biol. 15: 641-650, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18488042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18488042</a>] [<a href="https://doi.org/10.1038/nsmb.1425" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18488042">Haslberger et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18488042" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Perier, F., Radeke, C. M., Raab-Graham, K. F., Vandenberg, C. A. <strong>Expression of a putative ATPase suppresses the growth defect of a yeast potassium transport mutant: identification of a mammalian member of the Clp/HSP104 family.</strong> Gene 152: 157-163, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7835694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7835694</a>] [<a href="https://doi.org/10.1016/0378-1119(94)00697-q" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7835694">Perier et al. (1995)</a> cloned mouse ClpB, which they called Skd3. The deduced 677-amino acid protein has 4 N-terminal ankyrin (see <a href="/entry/612641">612641</a>)-like repeats predicted to mediate protein-protein interactions, followed by a 378-amino acid C-terminal domain with ATP-binding A and B consensus motifs. The C-terminal domain is similar to that found in the family of E. coli ATPases that includes ClpB. Northern blot analysis detected variable expression of a 2.3-kb transcript in all 8 mouse tissues examined, with highest expression in testis, followed by heart, skeletal muscle, and kidney. Little to no expression was detected in spleen. Skd3 expression was found in testis cell lines of both Leydig and Sertoli origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7835694" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Wortmann, S. B., Zietkiewicz, S., Kousi, M., Szklarczyk, R., Haack, T. B., Gersting, S. W., Muntau, A. C., Rakovic, A., Renkema, G. H., Rodenburg, R. J., Strom, T. M., Meitinger, T., and 23 others. <strong>CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.</strong> Am. J. Hum. Genet. 96: 245-257, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597510</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597510[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.2014.12.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25597510">Wortmann et al. (2015)</a> found expression of the CLPB gene in adult brain tissue; expression in fetal brain tissue was about 5 times lower than in adult brain. Low expression of the gene was also found in granulocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25597510" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Perier, F., Radeke, C. M., Raab-Graham, K. F., Vandenberg, C. A. <strong>Expression of a putative ATPase suppresses the growth defect of a yeast potassium transport mutant: identification of a mammalian member of the Clp/HSP104 family.</strong> Gene 152: 157-163, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7835694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7835694</a>] [<a href="https://doi.org/10.1016/0378-1119(94)00697-q" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7835694">Perier et al. (1995)</a> found that expression of mouse Skd3 countered the growth defect in yeast lacking the potassium transporters Trk1 and Trk2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7835694" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Cupo, R. R., Shorter, J. <strong>Skd3 (human ClpB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations.</strong> eLife 9: e55279, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32573439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32573439</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32573439[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/10.7554/eLife.55279" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32573439">Cupo and Shorter (2020)</a> demonstrated that SKD3 is an ATPase-dependent protein disaggregase and that the AAA+ elements within the SKD3 ankyrin-repeat domain had stand-alone disaggregase activity that did not require Hsp70 or Hsp40 for stimulation. SKD3 was found to be cleaved by the inner mitochondrial membrane rhomboid protease, PARL (<a href="/entry/607858">607858</a>), which enhanced SKD3 disaggregase activity. Furthermore, in SKD3-knockout HAP1 cells, mass spectrometry revealed a reduction in protein solubility in the mitochondria compared to wildtype cells. Among the insoluble proteins were proteins with a role in apoptosis and proteolysis, including HAX1 (<a href="/entry/605998">605998</a>), OPA1 (<a href="/entry/605290">605290</a>), PHB2 (<a href="/entry/610704">610704</a>), PARL, SMAC/DIABLO (<a href="/entry/605219">605219</a>) and HTRA2 (<a href="/entry/606441">606441</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32573439" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#3" class="mim-tip-reference" title="Hartz, P. A. <strong>Personal Communication.</strong> Baltimore, Md. 3/3/2015."None>Hartz (2015)</a> mapped the CLPB gene to chromosome 11q13.4 based on an alignment of the CLPB sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AK023214" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AK023214</a>) with the genomic sequence (GRCh38).</p>
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<p><strong><em>3-Methylglutaconic Aciduria, Type VIIB, Autosomal Recessive</em></strong></p><p>
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In 14 individuals from 9 unrelated families with autosomal recessive 3-methylglutaconic aciduria type VIIB (MGCA7B; <a href="/entry/616271">616271</a>), <a href="#10" class="mim-tip-reference" title="Wortmann, S. B., Zietkiewicz, S., Kousi, M., Szklarczyk, R., Haack, T. B., Gersting, S. W., Muntau, A. C., Rakovic, A., Renkema, G. H., Rodenburg, R. J., Strom, T. M., Meitinger, T., and 23 others. <strong>CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.</strong> Am. J. Hum. Genet. 96: 245-257, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597510</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597510[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.2014.12.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25597510">Wortmann et al. (2015)</a> identified 14 different homozygous or compound heterozygous mutations in the CLPB gene (see, e.g., <a href="#0001">616254.0001</a>-<a href="#0007">616254.0007</a>). Mutations in the first 2 unrelated patients were found by exome sequencing; mutations in subsequent patients were found by direct sequencing of the CLPB gene in 16 additional individuals with a similar phenotype. All patients had increased urinary 3-MGA, but the severity of other signs and symptoms was highly variable. Most patients had early onset of an encephalopathy involving the gray matter and moderate to severe neutropenia. There was no clear correlation between the severity of the disorder and the position and nature of the specific missense mutations, although patients with a more severe phenotype tended to carry mutations resulting in complete absence of the functional protein. Fibroblasts from affected individuals did not show defects in mitochondrial oxidative phosphorylation or phospholipid metabolism. In vitro functional expression studies performed on 1 of the mutations (R408G; <a href="#0006">616254.0006</a>) showed that the mutant protein had decreased ATPase activity at 26% of wildtype. Four missense variants were unable to rescue morpholino knockdown of the clpb ortholog in zebrafish, suggesting that these variants had little or no residual activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25597510" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 4 patients, including 2 sibs, of Greenlandic descent with MGCA7, <a href="#7" class="mim-tip-reference" title="Saunders, C., Smith, L., Wibrand, F., Ravn, K., Bross, P., Thiffault, I., Christensen, M., Atherton, A., Farrow, E., Miller, N., Kingsmore, S. F., Ostergaard, E. <strong>CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria.</strong> Am. J. Hum. Genet. 96: 258-265, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597511</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597511[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.2014.12.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25597511">Saunders et al. (2015)</a> identified a homozygous missense mutation in the CLPB gene (T268M; <a href="#0008">616254.0008</a>). The mutation was found by homozygosity mapping and candidate gene sequencing. Exome sequencing of an unrelated patient with a similar disorder identified compound heterozygous truncating mutations in the CLPB gene (<a href="#0007">616254.0007</a> and <a href="#0009">616254.0009</a>). Immunoblot analysis of patient fibroblasts showed absence of the CLPB protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25597511" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of the pathogenicity of mutations in the CLPB gene in patients with MGCA7, <a href="#2" class="mim-tip-reference" title="Cupo, R. R., Shorter, J. <strong>Skd3 (human ClpB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations.</strong> eLife 9: e55279, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32573439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32573439</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32573439[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/10.7554/eLife.55279" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32573439">Cupo and Shorter (2020)</a> found that residual disaggregase activity correlated with disease severity. CLPB with the T268M mutation (<a href="#0008">616254.0008</a>) was associated with moderate severity and had 27% disaggregase activity, whereas CLPB with the R475Q, A591V (<a href="#0003">616254.0003</a>), or R650P mutation was associated with severe disease and had 0 to 4% disaggregase activity. Residual CLPB ATPase activity did not correlate with disease severity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32573439" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 5-year-old girl with MGCA7B, <a href="#6" class="mim-tip-reference" title="Rivalta, B., Torraco, A., Martinelli, D., Luciani, M., Carrozzo, R., Finocchi, A. <strong>Biallelic CLPB mutation associated with isolated neutropenia and 3-MGA-uria.</strong> Pediat. Allergy Immun. 33: e13782, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35616898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35616898</a>] [<a href="https://doi.org/10.1111/pai.13782" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35616898">Rivalta et al. (2022)</a> identified compound heterozygous mutations in the CLPB gene (<a href="#0018">616254.0018</a>-<a href="#0019">616254.0019</a>). The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, were found in the carrier state in the parents. <a href="#6" class="mim-tip-reference" title="Rivalta, B., Torraco, A., Martinelli, D., Luciani, M., Carrozzo, R., Finocchi, A. <strong>Biallelic CLPB mutation associated with isolated neutropenia and 3-MGA-uria.</strong> Pediat. Allergy Immun. 33: e13782, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35616898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35616898</a>] [<a href="https://doi.org/10.1111/pai.13782" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35616898">Rivalta et al. (2022)</a> concluded that biallelic mutations in CLPB can cause a mild phenotype with isolated severe congenital neutropenia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35616898" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>3-Methylglutaconic Aciduria, Type VIIA, Autosomal Dominant</em></strong></p><p>
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In 6 unrelated patients with autosomal dominant 3-methylglutaconic aciduria type 7A (MGCA7A; <a href="/entry/619835">619835</a>) manifest as neutropenia and neurologic dysfunction, <a href="#9" class="mim-tip-reference" title="Wortmann, S. B., Zietkiewicz, S., Guerrero-Castillo, S., Feichtinger, R. G., Wagner, M., Russell, J., Ellaway, C., Mroz, D., Wyszkowski, H., Weis, D., Hannibal, I., von Stulpnagel, C., and 14 others. <strong>Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.</strong> Genet. Med. 23: 1705-1714, 2021. Note: Erratum: Genet. Med. 23: 1789 only, 2921.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34140661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34140661</a>] [<a href="https://doi.org/10.1038/s41436-021-01194-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34140661">Wortmann et al. (2021)</a> identified 4 different de novo heterozygous missense variants in the CLPB gene (see, e.g., <a href="#0011">616254.0011</a>-<a href="#0013">616254.0013</a>). The mutations, which were found by exome or genome sequencing, were not present in the gnomAD database. In vitro functional expression studies using a luciferase assay showed that the mutations caused a variable reduction in ATPase activity and impaired the renaturation and disaggregase activity of CLPB. When mixed with wildtype CLPB, the mutations demonstrated a dominant-negative effect. In control fibroblasts, HAX1 (<a href="/entry/605998">605998</a>) migrated predominantly as a monomer, whereas patient samples showed multiple HAX1 peaks comigrating at higher molecular masses with CLPB. These findings suggested a longer-lasting interaction between CLPB and HAX1; HAX1 is mutated in SCN3 (<a href="/entry/610738">610738</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34140661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Severe Congenital Neutropenia 9, Autosomal Dominant</em></strong></p><p>
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In 10 unrelated individuals with autosomal dominant severe congenital neutropenia-9 (SCN9; <a href="/entry/619813">619813</a>), <a href="#8" class="mim-tip-reference" title="Warren, J. T., Cupo, R. R., Wattanasirakul, P., Spencer, D. H., Locke, A. E., Makaryan, V., Bolyard, A. A., Kelley, M. L., Kingston, N. L., Shorter, J. Bellanne-Chantelot, C., Donadieu, J., Dale, D. C., Link, D. C. <strong>Heterozygous variants of CLPB are a cause of severe congenital neutropenia.</strong> Blood 139: 779-791, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34115842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34115842</a>] [<a href="https://doi.org/10.1182/blood.2021010762" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34115842">Warren et al. (2022)</a> identified 6 different heterozygous missense mutations in the CLPB gene (see, e.g., <a href="#0014">616254.0014</a>-<a href="#0016">616254.0016</a>). The mutations, which were found by exome sequencing, were not present in the gnomAD database. In 2 patients the mutations occurred de novo; family studies were not available for the other patients. All of the mutations occurred at conserved residues in the C-terminal ATP-binding pocket of CLPB. Knockdown of CLPB in CD34+ hematopoietic cells resulted in significantly fewer mature neutrophils and increased numbers of granulocyte precursors, indicating that CLPB is required for normal granulocyte differentiation. In vitro studies in transfected CD34+ cells showed that the CLPB variants tested impaired granulocytic differentiation and enhanced apoptosis without affecting the cell cycle or causing ER stress. Mixing studies indicated a dominant-negative effect of the mutations on CLPB ATPase activity and disaggregase activity. Additional studies showed that the tested ATP-binding pocket variants impaired mitochondrial respiration, suggesting a possible mechanistic link between mitochondrial dysfunction and defective granulopoiesis. In addition, 3 patients with cyclic neutropenia were found to carry a heterozygous R628C variant in the CLPB gene; functional studies of this variant were not performed. None of the 5 patients tested had 3-methylglutaconic aciduria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34115842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#10" class="mim-tip-reference" title="Wortmann, S. B., Zietkiewicz, S., Kousi, M., Szklarczyk, R., Haack, T. B., Gersting, S. W., Muntau, A. C., Rakovic, A., Renkema, G. H., Rodenburg, R. J., Strom, T. M., Meitinger, T., and 23 others. <strong>CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.</strong> Am. J. Hum. Genet. 96: 245-257, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597510</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597510[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.2014.12.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25597510">Wortmann et al. (2015)</a> found that morpholino knockdown of the clpb ortholog in zebrafish embryos resulted in dose-dependent cerebellar defects, microcephaly, and reduction of the size of the optic tectum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25597510" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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=616254[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<p>In an 18-year-old girl with a mild form of 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MGCA7B; <a href="/entry/616271">616271</a>), <a href="#10" class="mim-tip-reference" title="Wortmann, S. B., Zietkiewicz, S., Kousi, M., Szklarczyk, R., Haack, T. B., Gersting, S. W., Muntau, A. C., Rakovic, A., Renkema, G. H., Rodenburg, R. J., Strom, T. M., Meitinger, T., and 23 others. <strong>CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.</strong> Am. J. Hum. Genet. 96: 245-257, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597510</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597510[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.2014.12.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25597510">Wortmann et al. (2015)</a> identified compound heterozygous mutations in the CLPB gene: a c.1305_1307 inversion (c.1305_1307inv, NM_030813.4) in exon 12, resulting in a Glu435_Gly436delinsAspPro substitution in the AAA+ domain, and a c.1937G-T transversion (c.1937G-T, NM_030813.4) in exon 17, resulting in a gly646-to-val (G646V; <a href="#0002">616254.0002</a>) substitution at a highly conserved residue in the D2 domain. The mutations, which were found by exome sequencing, segregated with the disorder in the family and were filtered against public databases and an in-house database of 5,036 exomes. The c.1937G-T variant was found in 1 of 122,598 alleles in the Exome Aggregation Consortium. Expression of the G646V mutant allele was unable to rescue morpholino knockdown of the clpb ortholog in zebrafish, suggesting that this variant has little or no residual activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25597510" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>For discussion of the gly646-to-val (G646V) mutation (c.1937G-T, NM_030813.4) in the CLPB gene that was found in compound heterozygous state in a patient with 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MGCA7B; <a href="/entry/616271">616271</a>) by <a href="#10" class="mim-tip-reference" title="Wortmann, S. B., Zietkiewicz, S., Kousi, M., Szklarczyk, R., Haack, T. B., Gersting, S. W., Muntau, A. C., Rakovic, A., Renkema, G. H., Rodenburg, R. J., Strom, T. M., Meitinger, T., and 23 others. <strong>CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.</strong> Am. J. Hum. Genet. 96: 245-257, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597510</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597510[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.2014.12.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25597510">Wortmann et al. (2015)</a>, see <a href="#0001">616254.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25597510" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs748010262 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs748010262;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=rs748010262" 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=rs748010262" 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 girl with a severe form of 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MGCA7B; <a href="/entry/616271">616271</a>) resulting in death at age 3 years, 10 months, <a href="#10" class="mim-tip-reference" title="Wortmann, S. B., Zietkiewicz, S., Kousi, M., Szklarczyk, R., Haack, T. B., Gersting, S. W., Muntau, A. C., Rakovic, A., Renkema, G. H., Rodenburg, R. J., Strom, T. M., Meitinger, T., and 23 others. <strong>CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.</strong> Am. J. Hum. Genet. 96: 245-257, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597510</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597510[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.2014.12.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25597510">Wortmann et al. (2015)</a> identified a homozygous c.1772C-T transition (c.1772C-T, NM_030813.4) in exon 16 of the CLPB gene, resulting in an ala591-to-val (A591V) substitution at a highly conserved residue in the D2 domain. The mutation, which was found by exome sequencing, segregated with the disorder in the family and was filtered against public databases and an in-house database of 5,036 exomes; it was not present in the Exome Aggregation Consortium database. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25597510" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs786205137 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205137;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/rs786205137?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=rs786205137" 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=rs786205137" 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=RCV000167540 OR RCV001570412 OR RCV002515185" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000167540, RCV001570412, RCV002515185" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000167540...</a>
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<p>In 2 sibs with a mild form of 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MGCA7B; <a href="/entry/616271">616271</a>) and no neurologic impairment, <a href="#10" class="mim-tip-reference" title="Wortmann, S. B., Zietkiewicz, S., Kousi, M., Szklarczyk, R., Haack, T. B., Gersting, S. W., Muntau, A. C., Rakovic, A., Renkema, G. H., Rodenburg, R. J., Strom, T. M., Meitinger, T., and 23 others. <strong>CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.</strong> Am. J. Hum. Genet. 96: 245-257, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597510</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597510[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.2014.12.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25597510">Wortmann et al. (2015)</a> identified compound heterozygous mutations in the CLPB gene: a c.1233G-A transition (c.1233G-A, NM_030813.4) in exon 11, resulting in a met411-to-ile (M411I) substitution at a highly conserved residue in the AAA+ domain, and a c.1850A-G transition in exon 16, resulting in a tyr617-to-cys (Y617C; <a href="#0005">616254.0005</a>) substitution at a highly conserved residue in the D2 domain. Expression of the M411I or Y617C alleles could not rescue morpholino knockdown of the clpb ortholog in zebrafish, suggesting that these variants have little or no residual activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25597510" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIB</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> rs786205138 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205138;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/rs786205138?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=rs786205138" 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=rs786205138" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the tyr617-to-cys (Y617C) mutation (c.1850A-G, NM_030813.4) in the CLPB gene that was found in compound heterozygous state in a patient with 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MGCA7B; <a href="/entry/616271">616271</a>) by <a href="#10" class="mim-tip-reference" title="Wortmann, S. B., Zietkiewicz, S., Kousi, M., Szklarczyk, R., Haack, T. B., Gersting, S. W., Muntau, A. C., Rakovic, A., Renkema, G. H., Rodenburg, R. J., Strom, T. M., Meitinger, T., and 23 others. <strong>CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.</strong> Am. J. Hum. Genet. 96: 245-257, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597510</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597510[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.2014.12.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25597510">Wortmann et al. (2015)</a>, see <a href="#0004">616254.0004</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25597510" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIB</strong>
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CLPB, ARG408GLY
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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> rs144078282 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs144078282;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/rs144078282?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=rs144078282" 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=rs144078282" 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=RCV000167542 OR RCV000487136 OR RCV002492676 OR RCV002516522" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000167542, RCV000487136, RCV002492676, RCV002516522" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000167542...</a>
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<p>In 3 sibs with a moderately severe form of 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MGCA7B; <a href="/entry/616271">616271</a>), <a href="#10" class="mim-tip-reference" title="Wortmann, S. B., Zietkiewicz, S., Kousi, M., Szklarczyk, R., Haack, T. B., Gersting, S. W., Muntau, A. C., Rakovic, A., Renkema, G. H., Rodenburg, R. J., Strom, T. M., Meitinger, T., and 23 others. <strong>CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.</strong> Am. J. Hum. Genet. 96: 245-257, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597510</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597510[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.2014.12.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25597510">Wortmann et al. (2015)</a> identified compound heterozygous mutations in the CLPB gene: a c.1222A-G transition (c.1222A-G, NM_030813.4) in exon 11, resulting in an arg408-to-gly (R408G) substitution at a conserved residue in the AAA+ domain, and a c.1249C-T transition in exon 11, resulting in an arg417-to-ter (R417X; <a href="#0007">616254.0007</a>) substitution. The R408G mutation had a frequency of 0.011% (22 of 122,848 alleles) in the Exome Aggregation Consortium database, and the R417X mutation was found in 4 of 122,848 alleles in this database; all controls were heterozygous for the mutations. In vitro functional expression studies indicated that the R408G mutant protein had decreased ATPase activity at 26% of wildtype. Expression of the R408G mutant allele was unable to rescue morpholino knockdown of the clpb ortholog in zebrafish, suggesting that this variant has decreased residual activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25597510" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIB</strong>
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CLPB, ARG417TER
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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> rs200203460 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs200203460;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/rs200203460?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=rs200203460" 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=rs200203460" 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=RCV000167543 OR RCV002285272 OR RCV002326924 OR RCV002478519" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000167543, RCV002285272, RCV002326924, RCV002478519" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000167543...</a>
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<p>For discussion of the arg417-to-ter (R417X) mutation (c.1249C-T, NM_030813.4) in the CLPB gene that was found in compound heterozygous state in patients with 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MGCA7B; <a href="/entry/616271">616271</a>) by <a href="#10" class="mim-tip-reference" title="Wortmann, S. B., Zietkiewicz, S., Kousi, M., Szklarczyk, R., Haack, T. B., Gersting, S. W., Muntau, A. C., Rakovic, A., Renkema, G. H., Rodenburg, R. J., Strom, T. M., Meitinger, T., and 23 others. <strong>CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.</strong> Am. J. Hum. Genet. 96: 245-257, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597510</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597510[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.2014.12.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25597510">Wortmann et al. (2015)</a>, see <a href="#0006">616254.0006</a> and by <a href="#7" class="mim-tip-reference" title="Saunders, C., Smith, L., Wibrand, F., Ravn, K., Bross, P., Thiffault, I., Christensen, M., Atherton, A., Farrow, E., Miller, N., Kingsmore, S. F., Ostergaard, E. <strong>CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria.</strong> Am. J. Hum. Genet. 96: 258-265, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597511</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597511[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.2014.12.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25597511">Saunders et al. (2015)</a>, see <a href="#0009">616254.0009</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25597511+25597510" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIB</strong>
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CLPB, THR268MET (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs200032855;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs200032855</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> rs200032855 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs200032855;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/rs200032855?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=rs200032855" 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=rs200032855" 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=RCV000167544 OR RCV003965218 OR RCV004800307" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000167544, RCV003965218, RCV004800307" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000167544...</a>
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<p>In 4 patients, including a pair of sibs, from Greenland, with 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MGCA7B; <a href="/entry/616271">616271</a>), <a href="#7" class="mim-tip-reference" title="Saunders, C., Smith, L., Wibrand, F., Ravn, K., Bross, P., Thiffault, I., Christensen, M., Atherton, A., Farrow, E., Miller, N., Kingsmore, S. F., Ostergaard, E. <strong>CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria.</strong> Am. J. Hum. Genet. 96: 258-265, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597511</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597511[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.2014.12.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25597511">Saunders et al. (2015)</a> identified a homozygous c.803C-T transition (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs200032855;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs200032855</a>) in the CLPB gene, resulting in a thr268-to-met (T268M) substitution at a highly conserved residue in 1 of the ankyrin domains. The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in 1 of the families. The carrier frequency of the mutation in Greenlandic controls was found to be 3.3%. The variant was not found in 2,180 control samples in the U.S. or in the Exome Variant Server database, but was reported with a carrier frequency of 1 out of 662 in the ClinSeq database. Immunoblot analysis of patient fibroblasts showed absence of the CLPB protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25597511" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIB</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">rs786205139 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205139;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=rs786205139" 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=rs786205139" 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 girl with 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MGCA7B; <a href="/entry/616271">616271</a>), <a href="#7" class="mim-tip-reference" title="Saunders, C., Smith, L., Wibrand, F., Ravn, K., Bross, P., Thiffault, I., Christensen, M., Atherton, A., Farrow, E., Miller, N., Kingsmore, S. F., Ostergaard, E. <strong>CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria.</strong> Am. J. Hum. Genet. 96: 258-265, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597511</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597511[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.2014.12.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25597511">Saunders et al. (2015)</a> identified compound heterozygous mutations in the CLPB gene: a c.961A-T transversion (c.961A-T, NM_030813.4), resulting in a lys321-to-ter (K321X) substitution, and a c.1249C-T transition, resulting in an arg417-to-ter (R417X; <a href="#0007">616254.0007</a>) substitution. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and were not found in the Exome Sequencing Project database or in 2,180 in-house control samples. Immunoblot analysis of patient fibroblasts showed absence of the CLPB protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25597511" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIB</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">rs876657402 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs876657402;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=rs876657402" 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=rs876657402" 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=RCV000173020" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000173020" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000173020</a>
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<p>In 4 sibs, born of consanguineous Cambodian parents, with 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MGCA7B; <a href="/entry/616271">616271</a>), <a href="#1" class="mim-tip-reference" title="Capo-Chichi, J.-M., Boissel, S., Brustein, E., Pickles, S., Fallet-Bianco, C., Nassif, C., Patry, L., Dobrzeniecka, S., Liao, M., Labuda, D., Samuels, M. E., Hamdan, F. F., Vande Velde, C., Rouleau, G. A., Drapeau, P., Michaud, J. L. <strong>Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria.</strong> J. Med. Genet. 52: 303-311, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25650066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25650066</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102952" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25650066">Capo-Chichi et al. (2015)</a> identified a homozygous 1-bp deletion (c.1685delT, NM_030813.3) in the CLPB gene, resulting in a frameshift and premature termination (Ile562ThrfsTer23). The mutation was found by a combination of homozygosity mapping and exome sequencing and was confirmed by Sanger sequencing. It segregated with the disorder in the family and was not found in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases, or in 657 in-house control exomes. The patients had a severe phenotype: at birth they did not move or breathe spontaneously and showed sustained clonic movements induced by minimal tactile stimulation; all were ventilator-dependent and died in the first week of life after removal of respiratory support. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25650066" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0011 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIA</strong>
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CLPB, PRO427LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2135500838 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2135500838;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=rs2135500838" 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=rs2135500838" 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=RCV002221965" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002221965" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002221965</a>
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<p>In a girl (P2) who died at 19 months of age due to 3-methylglutaconic aciduria with neurologic involvement and neutropenia (MGCA7A; <a href="/entry/619835">619835</a>), <a href="#9" class="mim-tip-reference" title="Wortmann, S. B., Zietkiewicz, S., Guerrero-Castillo, S., Feichtinger, R. G., Wagner, M., Russell, J., Ellaway, C., Mroz, D., Wyszkowski, H., Weis, D., Hannibal, I., von Stulpnagel, C., and 14 others. <strong>Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.</strong> Genet. Med. 23: 1705-1714, 2021. Note: Erratum: Genet. Med. 23: 1789 only, 2921.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34140661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34140661</a>] [<a href="https://doi.org/10.1038/s41436-021-01194-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34140661">Wortmann et al. (2021)</a> identified a de novo heterozygous c.1280C-T transition in the CLPB gene, resulting in a pro427-to-leu (P427L) substitution in the pore area. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro functional expression studies using a luciferase assay showed that the mutation caused only a mild reduction in ATPase activity, but severely impaired the renaturation and disaggregase activity. When mixed with wildtype CLPB, the mutation demonstrated a dominant-negative effect. The patient presented in infancy with seizures and hypotonia and met almost no developmental milestones. Neutropenia and recurrent infections were also present. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34140661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIA</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">rs2135485868 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2135485868;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=rs2135485868" 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=rs2135485868" 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=RCV002221966 OR RCV002265063 OR RCV002468655" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002221966, RCV002265063, RCV002468655" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002221966...</a>
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<p>In 2 unrelated patients (P3 and P4) with 3-methylglutaconic aciduria with neurologic involvement and neutropenia (MGCA7A; <a href="/entry/619835">619835</a>), <a href="#9" class="mim-tip-reference" title="Wortmann, S. B., Zietkiewicz, S., Guerrero-Castillo, S., Feichtinger, R. G., Wagner, M., Russell, J., Ellaway, C., Mroz, D., Wyszkowski, H., Weis, D., Hannibal, I., von Stulpnagel, C., and 14 others. <strong>Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.</strong> Genet. Med. 23: 1705-1714, 2021. Note: Erratum: Genet. Med. 23: 1789 only, 2921.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34140661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34140661</a>] [<a href="https://doi.org/10.1038/s41436-021-01194-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34140661">Wortmann et al. (2021)</a> identified a de novo heterozygous c.1678G-A transition in the CLPB gene, resulting in a gly560-to-arg (G560R) substitution near the ATP binding site. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro functional expression studies using a luciferase assay showed that the mutation caused a reduction in ATPase activity and severely impaired the renaturation and disaggregase activity of CLPB. When mixed with wildtype CLPB, the mutation demonstrated a dominant-negative effect. The patients had global developmental delay with poor speech, microcephaly, and absence seizures. Both had neutropenia and recurrent infections; P4 underwent hematopoietic stem cell transplantation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34140661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0013 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIA</strong>
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CLPB, ARG561TRP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1949512456 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1949512456;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=rs1949512456" 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=rs1949512456" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 unrelated patients (P5 and P6) with 3-methylglutaconic aciduria with neurologic involvement and neutropenia (MGCA7A; <a href="/entry/619835">619835</a>), <a href="#9" class="mim-tip-reference" title="Wortmann, S. B., Zietkiewicz, S., Guerrero-Castillo, S., Feichtinger, R. G., Wagner, M., Russell, J., Ellaway, C., Mroz, D., Wyszkowski, H., Weis, D., Hannibal, I., von Stulpnagel, C., and 14 others. <strong>Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.</strong> Genet. Med. 23: 1705-1714, 2021. Note: Erratum: Genet. Med. 23: 1789 only, 2921.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34140661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34140661</a>] [<a href="https://doi.org/10.1038/s41436-021-01194-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34140661">Wortmann et al. (2021)</a> identified a de novo heterozygous c.1681C-T transition in the CLPB gene, resulting in an arg561-to-trp (R561W) substitution. The mutation, which was found by exome or genome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed, but molecular modeling predicted that it would be deleterious and likely have a dominant-negative effect on CLPB function. The patients had variable neurologic abnormalities: P5 had severe global developmental delay, poor speech, and atypical absence seizures, whereas P6 had only mild speech delay and did not have seizures. Both had neutropenia and recurrent infections; P6 underwent hematopoietic stem cell transplant. Neither patient had cataracts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34140661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs2135510485 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2135510485;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=rs2135510485" 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=rs2135510485" 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 French man (Fr-0019) with severe congenital neutropenia-9 (SCN9; <a href="/entry/619813">619813</a>), <a href="#8" class="mim-tip-reference" title="Warren, J. T., Cupo, R. R., Wattanasirakul, P., Spencer, D. H., Locke, A. E., Makaryan, V., Bolyard, A. A., Kelley, M. L., Kingston, N. L., Shorter, J. Bellanne-Chantelot, C., Donadieu, J., Dale, D. C., Link, D. C. <strong>Heterozygous variants of CLPB are a cause of severe congenital neutropenia.</strong> Blood 139: 779-791, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34115842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34115842</a>] [<a href="https://doi.org/10.1182/blood.2021010762" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34115842">Warren et al. (2022)</a> identified a de novo heterozygous c.1163C-A transversion in the CLPB gene, resulting in a thr388-to-lys (T388K) substitution at a conserved residue in the ATP-binding domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed. This patient was an adult, but had onset of neutropenia at 1.5 years of age. He had recurrent infections and cataracts but did not have neurologic involvement or 3-methylglutaconic aciduria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34115842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs1949512456 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1949512456;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=rs1949512456" 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=rs1949512456" 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 female patient (SCNIR-2) with severe congenital neutropenia-9 (SCN9; <a href="/entry/619813">619813</a>), <a href="#8" class="mim-tip-reference" title="Warren, J. T., Cupo, R. R., Wattanasirakul, P., Spencer, D. H., Locke, A. E., Makaryan, V., Bolyard, A. A., Kelley, M. L., Kingston, N. L., Shorter, J. Bellanne-Chantelot, C., Donadieu, J., Dale, D. C., Link, D. C. <strong>Heterozygous variants of CLPB are a cause of severe congenital neutropenia.</strong> Blood 139: 779-791, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34115842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34115842</a>] [<a href="https://doi.org/10.1182/blood.2021010762" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34115842">Warren et al. (2022)</a> identified a heterozygous c.1681C-G transversion in the CLPB gene, resulting in an arg561-to-gly (R561G) substitution at a conserved residue in the ATP-binding domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional studies showed that the R561G mutation impaired granulocyte differentiation and mitochondrial function in a dominant-negative manner. The variant resulted in decreased CLPB ATPase and disaggregase activity. The patient had recurrent infections but did not have neurologic involvement or 3-methylglutaconic aciduria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34115842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0016 NEUTROPENIA, SEVERE CONGENITAL, 9, AUTOSOMAL DOMINANT</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1590753221 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1590753221;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=rs1590753221" 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=rs1590753221" 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=RCV000796680 OR RCV001766643 OR RCV002221585" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000796680, RCV001766643, RCV002221585" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000796680...</a>
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<p>In 4 unrelated patients with severe congenital neutropenia-9 (SCN9; <a href="/entry/619813">619813</a>), <a href="#8" class="mim-tip-reference" title="Warren, J. T., Cupo, R. R., Wattanasirakul, P., Spencer, D. H., Locke, A. E., Makaryan, V., Bolyard, A. A., Kelley, M. L., Kingston, N. L., Shorter, J. Bellanne-Chantelot, C., Donadieu, J., Dale, D. C., Link, D. C. <strong>Heterozygous variants of CLPB are a cause of severe congenital neutropenia.</strong> Blood 139: 779-791, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34115842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34115842</a>] [<a href="https://doi.org/10.1182/blood.2021010762" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34115842">Warren et al. (2022)</a> identified a heterozygous c.1682G-A transition in the CLPB gene, resulting in an arg561-to-gln (R561Q) substitution at a conserved residue in the ATP-binding domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. The mutation was demonstrated to occur de novo in 1 patient. In vitro functional studies showed that the mutation impaired mitochondrial respiratory function. Three patients had infections, 1 had epilepsy and learning difficulties, and another had cataracts. The one patient tested did not have 3-methylglutaconic aciduria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34115842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs2135484821 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2135484821;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=rs2135484821" 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=rs2135484821" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 unrelated patients with severe congenital neutropenia-9 (SCN9; <a href="/entry/619813">619813</a>), <a href="#8" class="mim-tip-reference" title="Warren, J. T., Cupo, R. R., Wattanasirakul, P., Spencer, D. H., Locke, A. E., Makaryan, V., Bolyard, A. A., Kelley, M. L., Kingston, N. L., Shorter, J. Bellanne-Chantelot, C., Donadieu, J., Dale, D. C., Link, D. C. <strong>Heterozygous variants of CLPB are a cause of severe congenital neutropenia.</strong> Blood 139: 779-791, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34115842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34115842</a>] [<a href="https://doi.org/10.1182/blood.2021010762" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34115842">Warren et al. (2022)</a> identified a heterozygous c.1858C-T transition in the CLPB gene, resulting in an arg620-to-cys (R620C) substitution at a conserved residue in the ATP-binding domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional studies showed that the R620C mutation impaired granulocyte differentiation and mitochondrial function in a dominant-negative manner. The variant resulted in decreased CLPB ATPase and disaggregase activity. The patients had onset of neutropenia in infancy; 1 had recurrent infections. Neither had neurologic features or 3-methylglutaconic aciduria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34115842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs150343959 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs150343959;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/rs150343959?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=rs150343959" 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=rs150343959" 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=RCV000258954 OR RCV000316112 OR RCV003955419 OR RCV004586656 OR RCV004975380" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000258954, RCV000316112, RCV003955419, RCV004586656, RCV004975380" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000258954...</a>
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<p>In a 5-year-old girl with 3-methylglutaconic aciduria and neutropenia (MGCA7B; <a href="/entry/616271">616271</a>), <a href="#6" class="mim-tip-reference" title="Rivalta, B., Torraco, A., Martinelli, D., Luciani, M., Carrozzo, R., Finocchi, A. <strong>Biallelic CLPB mutation associated with isolated neutropenia and 3-MGA-uria.</strong> Pediat. Allergy Immun. 33: e13782, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35616898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35616898</a>] [<a href="https://doi.org/10.1111/pai.13782" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35616898">Rivalta et al. (2022)</a> identified compound heterozygosity for 2 mutations in the CLPB gene: a c.1882C-T transition resulting in an arg628-to-cys (R628C) substitution, and a 2-bp deletion and 2-bp insertion (c.1903_1904delinsAA) resulting in an ala635-to-lys (A635K; <a href="#0019">616254.0019</a>) substitution. Both mutations were located at highly conserved sites. The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, were found in the carrier state in the parents. Neither mutation was present in the ExAC, 1000 Genomes Project, and gnomAD databases. Complex V activity was reduced in fibroblasts from the patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35616898" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0019 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIB</strong>
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CLPB, ALA635LYS
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV002274866" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002274866" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002274866</a>
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<p>For discussion of the c.1903_1904delinsAA mutation in the CLPB gene, resulting in an ala635-to-lys (A635K) substitution, that was identified in compound heterozygous state in a patient with 3-methylglutaconic aciduria and neutropenia (MGCA7B; <a href="/entry/616271">616271</a>) by <a href="#6" class="mim-tip-reference" title="Rivalta, B., Torraco, A., Martinelli, D., Luciani, M., Carrozzo, R., Finocchi, A. <strong>Biallelic CLPB mutation associated with isolated neutropenia and 3-MGA-uria.</strong> Pediat. Allergy Immun. 33: e13782, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35616898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35616898</a>] [<a href="https://doi.org/10.1111/pai.13782" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35616898">Rivalta et al. (2022)</a>, see <a href="#0018">616254.0018</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35616898" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
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<a id="Capo-Chichi2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Capo-Chichi, J.-M., Boissel, S., Brustein, E., Pickles, S., Fallet-Bianco, C., Nassif, C., Patry, L., Dobrzeniecka, S., Liao, M., Labuda, D., Samuels, M. E., Hamdan, F. F., Vande Velde, C., Rouleau, G. A., Drapeau, P., Michaud, J. L.
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<strong>Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria.</strong>
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J. Med. Genet. 52: 303-311, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25650066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25650066</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25650066" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2014-102952" target="_blank">Full Text</a>]
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<a id="Cupo2020" class="mim-anchor"></a>
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Cupo, R. R., Shorter, J.
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<strong>Skd3 (human ClpB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations.</strong>
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eLife 9: e55279, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32573439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32573439</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32573439[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=32573439" 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/10.7554/eLife.55279" target="_blank">Full Text</a>]
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<a id="Hartz2015" class="mim-anchor"></a>
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Hartz, P. A.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 3/3/2015.
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<a id="Haslberger2008" class="mim-anchor"></a>
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Haslberger, T., Zdanowicz, A., Brand, I., Kirstein, J., Turgay, K., Mogk, A., Bukau, B.
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<strong>Protein disaggregation by the AAA+ chaperone ClpB involves partial threading of looped polypeptide segments.</strong>
|
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Nature Struct. Molec. Biol. 15: 641-650, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18488042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18488042</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18488042" 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/nsmb.1425" target="_blank">Full Text</a>]
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<a id="5" class="mim-anchor"></a>
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<a id="Perier1995" class="mim-anchor"></a>
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<p class="mim-text-font">
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Perier, F., Radeke, C. M., Raab-Graham, K. F., Vandenberg, C. A.
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<strong>Expression of a putative ATPase suppresses the growth defect of a yeast potassium transport mutant: identification of a mammalian member of the Clp/HSP104 family.</strong>
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Gene 152: 157-163, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7835694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7835694</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7835694" 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/10.1016/0378-1119(94)00697-q" target="_blank">Full Text</a>]
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<a id="Rivalta2022" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rivalta, B., Torraco, A., Martinelli, D., Luciani, M., Carrozzo, R., Finocchi, A.
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<strong>Biallelic CLPB mutation associated with isolated neutropenia and 3-MGA-uria.</strong>
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Pediat. Allergy Immun. 33: e13782, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35616898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35616898</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35616898" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/pai.13782" target="_blank">Full Text</a>]
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<a id="Saunders2015" class="mim-anchor"></a>
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Saunders, C., Smith, L., Wibrand, F., Ravn, K., Bross, P., Thiffault, I., Christensen, M., Atherton, A., Farrow, E., Miller, N., Kingsmore, S. F., Ostergaard, E.
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<strong>CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria.</strong>
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Am. J. Hum. Genet. 96: 258-265, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597511</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597511[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=25597511" 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.ajhg.2014.12.020" target="_blank">Full Text</a>]
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<a id="Warren2022" class="mim-anchor"></a>
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Warren, J. T., Cupo, R. R., Wattanasirakul, P., Spencer, D. H., Locke, A. E., Makaryan, V., Bolyard, A. A., Kelley, M. L., Kingston, N. L., Shorter, J. Bellanne-Chantelot, C., Donadieu, J., Dale, D. C., Link, D. C.
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<strong>Heterozygous variants of CLPB are a cause of severe congenital neutropenia.</strong>
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Blood 139: 779-791, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34115842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34115842</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34115842" 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/10.1182/blood.2021010762" target="_blank">Full Text</a>]
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Wortmann, S. B., Zietkiewicz, S., Guerrero-Castillo, S., Feichtinger, R. G., Wagner, M., Russell, J., Ellaway, C., Mroz, D., Wyszkowski, H., Weis, D., Hannibal, I., von Stulpnagel, C., and 14 others.
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<strong>Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.</strong>
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Genet. Med. 23: 1705-1714, 2021. Note: Erratum: Genet. Med. 23: 1789 only, 2921.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34140661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34140661</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34140661" 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/s41436-021-01194-x" target="_blank">Full Text</a>]
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<a id="Wortmann2015" class="mim-anchor"></a>
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Wortmann, S. B., Zietkiewicz, S., Kousi, M., Szklarczyk, R., Haack, T. B., Gersting, S. W., Muntau, A. C., Rakovic, A., Renkema, G. H., Rodenburg, R. J., Strom, T. M., Meitinger, T., and 23 others.
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<strong>CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.</strong>
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Am. J. Hum. Genet. 96: 245-257, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25597510/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25597510</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25597510[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=25597510" 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.ajhg.2014.12.013" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 08/11/2022
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Cassandra L. Kniffin - updated : 03/28/2022<br>Hilary J. Vernon - updated : 12/09/2021<br>Cassandra L. Kniffin - updated : 6/16/2015<br>Cassandra L. Kniffin - updated : 3/19/2015
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Creation Date:
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<span class="mim-text-font">
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Patricia A. Hartz : 3/3/2015
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carol : 09/08/2022
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carol : 08/12/2022<br>carol : 08/11/2022<br>carol : 04/14/2022<br>ckniffin : 04/13/2022<br>carol : 04/12/2022<br>carol : 04/11/2022<br>ckniffin : 03/28/2022<br>carol : 12/11/2021<br>carol : 12/10/2021<br>carol : 12/09/2021<br>carol : 12/17/2019<br>carol : 08/02/2017<br>carol : 06/18/2015<br>mcolton : 6/17/2015<br>ckniffin : 6/16/2015<br>carol : 4/7/2015<br>carol : 3/20/2015<br>mcolton : 3/20/2015<br>ckniffin : 3/19/2015<br>mgross : 3/12/2015<br>mcolton : 3/3/2015
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<span class="mim-font">
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<strong>*</strong> 616254
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<h3>
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<span class="mim-font">
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CASEINOLYTIC PEPTIDASE B; CLPB
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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ClpB, E. COLI, HOMOLOG OF<br />
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SUPPRESSOR OF POTASSIUM TRANSPORT DEFECT 3; SKD3
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: CLPB</em></strong>
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<strong>
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<em>
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Cytogenetic location: 11q13.4
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Genomic coordinates <span class="small">(GRCh38)</span> : 11:72,285,495-72,434,531 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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11q13.4
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<span class="mim-font">
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3-methylglutaconic aciduria, type VIIA, autosomal dominant
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<td>
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<span class="mim-font">
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619835
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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3-methylglutaconic aciduria, type VIIB, autosomal recessive
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<span class="mim-font">
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616271
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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<span class="mim-font">
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Neutropenia, severe congenital, 9, autosomal dominant
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<span class="mim-font">
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619813
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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<strong>TEXT</strong>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>Oligomeric AAA+ ATPases, such as CLPB, are key players in cellular quality control that either degrade or reactivate misfolded proteins. These enzymes use the energy of ATP hydrolysis to generate the mechanical force required to remodel bound substrates. In bacteria, oligomeric ClpB reactivates aggregated proteins via a conserved threading activity that refolds substrate proteins (summary by Haslberger et al., 2008). </p>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Perier et al. (1995) cloned mouse ClpB, which they called Skd3. The deduced 677-amino acid protein has 4 N-terminal ankyrin (see 612641)-like repeats predicted to mediate protein-protein interactions, followed by a 378-amino acid C-terminal domain with ATP-binding A and B consensus motifs. The C-terminal domain is similar to that found in the family of E. coli ATPases that includes ClpB. Northern blot analysis detected variable expression of a 2.3-kb transcript in all 8 mouse tissues examined, with highest expression in testis, followed by heart, skeletal muscle, and kidney. Little to no expression was detected in spleen. Skd3 expression was found in testis cell lines of both Leydig and Sertoli origin. </p><p>Wortmann et al. (2015) found expression of the CLPB gene in adult brain tissue; expression in fetal brain tissue was about 5 times lower than in adult brain. Low expression of the gene was also found in granulocytes. </p>
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<br />
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Perier et al. (1995) found that expression of mouse Skd3 countered the growth defect in yeast lacking the potassium transporters Trk1 and Trk2. </p><p>Cupo and Shorter (2020) demonstrated that SKD3 is an ATPase-dependent protein disaggregase and that the AAA+ elements within the SKD3 ankyrin-repeat domain had stand-alone disaggregase activity that did not require Hsp70 or Hsp40 for stimulation. SKD3 was found to be cleaved by the inner mitochondrial membrane rhomboid protease, PARL (607858), which enhanced SKD3 disaggregase activity. Furthermore, in SKD3-knockout HAP1 cells, mass spectrometry revealed a reduction in protein solubility in the mitochondria compared to wildtype cells. Among the insoluble proteins were proteins with a role in apoptosis and proteolysis, including HAX1 (605998), OPA1 (605290), PHB2 (610704), PARL, SMAC/DIABLO (605219) and HTRA2 (606441). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Hartz (2015) mapped the CLPB gene to chromosome 11q13.4 based on an alignment of the CLPB sequence (GenBank AK023214) with the genomic sequence (GRCh38).</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>3-Methylglutaconic Aciduria, Type VIIB, Autosomal Recessive</em></strong></p><p>
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In 14 individuals from 9 unrelated families with autosomal recessive 3-methylglutaconic aciduria type VIIB (MGCA7B; 616271), Wortmann et al. (2015) identified 14 different homozygous or compound heterozygous mutations in the CLPB gene (see, e.g., 616254.0001-616254.0007). Mutations in the first 2 unrelated patients were found by exome sequencing; mutations in subsequent patients were found by direct sequencing of the CLPB gene in 16 additional individuals with a similar phenotype. All patients had increased urinary 3-MGA, but the severity of other signs and symptoms was highly variable. Most patients had early onset of an encephalopathy involving the gray matter and moderate to severe neutropenia. There was no clear correlation between the severity of the disorder and the position and nature of the specific missense mutations, although patients with a more severe phenotype tended to carry mutations resulting in complete absence of the functional protein. Fibroblasts from affected individuals did not show defects in mitochondrial oxidative phosphorylation or phospholipid metabolism. In vitro functional expression studies performed on 1 of the mutations (R408G; 616254.0006) showed that the mutant protein had decreased ATPase activity at 26% of wildtype. Four missense variants were unable to rescue morpholino knockdown of the clpb ortholog in zebrafish, suggesting that these variants had little or no residual activity. </p><p>In 4 patients, including 2 sibs, of Greenlandic descent with MGCA7, Saunders et al. (2015) identified a homozygous missense mutation in the CLPB gene (T268M; 616254.0008). The mutation was found by homozygosity mapping and candidate gene sequencing. Exome sequencing of an unrelated patient with a similar disorder identified compound heterozygous truncating mutations in the CLPB gene (616254.0007 and 616254.0009). Immunoblot analysis of patient fibroblasts showed absence of the CLPB protein. </p><p>In a study of the pathogenicity of mutations in the CLPB gene in patients with MGCA7, Cupo and Shorter (2020) found that residual disaggregase activity correlated with disease severity. CLPB with the T268M mutation (616254.0008) was associated with moderate severity and had 27% disaggregase activity, whereas CLPB with the R475Q, A591V (616254.0003), or R650P mutation was associated with severe disease and had 0 to 4% disaggregase activity. Residual CLPB ATPase activity did not correlate with disease severity. </p><p>In a 5-year-old girl with MGCA7B, Rivalta et al. (2022) identified compound heterozygous mutations in the CLPB gene (616254.0018-616254.0019). The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, were found in the carrier state in the parents. Rivalta et al. (2022) concluded that biallelic mutations in CLPB can cause a mild phenotype with isolated severe congenital neutropenia. </p><p><strong><em>3-Methylglutaconic Aciduria, Type VIIA, Autosomal Dominant</em></strong></p><p>
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In 6 unrelated patients with autosomal dominant 3-methylglutaconic aciduria type 7A (MGCA7A; 619835) manifest as neutropenia and neurologic dysfunction, Wortmann et al. (2021) identified 4 different de novo heterozygous missense variants in the CLPB gene (see, e.g., 616254.0011-616254.0013). The mutations, which were found by exome or genome sequencing, were not present in the gnomAD database. In vitro functional expression studies using a luciferase assay showed that the mutations caused a variable reduction in ATPase activity and impaired the renaturation and disaggregase activity of CLPB. When mixed with wildtype CLPB, the mutations demonstrated a dominant-negative effect. In control fibroblasts, HAX1 (605998) migrated predominantly as a monomer, whereas patient samples showed multiple HAX1 peaks comigrating at higher molecular masses with CLPB. These findings suggested a longer-lasting interaction between CLPB and HAX1; HAX1 is mutated in SCN3 (610738). </p><p><strong><em>Severe Congenital Neutropenia 9, Autosomal Dominant</em></strong></p><p>
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In 10 unrelated individuals with autosomal dominant severe congenital neutropenia-9 (SCN9; 619813), Warren et al. (2022) identified 6 different heterozygous missense mutations in the CLPB gene (see, e.g., 616254.0014-616254.0016). The mutations, which were found by exome sequencing, were not present in the gnomAD database. In 2 patients the mutations occurred de novo; family studies were not available for the other patients. All of the mutations occurred at conserved residues in the C-terminal ATP-binding pocket of CLPB. Knockdown of CLPB in CD34+ hematopoietic cells resulted in significantly fewer mature neutrophils and increased numbers of granulocyte precursors, indicating that CLPB is required for normal granulocyte differentiation. In vitro studies in transfected CD34+ cells showed that the CLPB variants tested impaired granulocytic differentiation and enhanced apoptosis without affecting the cell cycle or causing ER stress. Mixing studies indicated a dominant-negative effect of the mutations on CLPB ATPase activity and disaggregase activity. Additional studies showed that the tested ATP-binding pocket variants impaired mitochondrial respiration, suggesting a possible mechanistic link between mitochondrial dysfunction and defective granulopoiesis. In addition, 3 patients with cyclic neutropenia were found to carry a heterozygous R628C variant in the CLPB gene; functional studies of this variant were not performed. None of the 5 patients tested had 3-methylglutaconic aciduria. </p>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Wortmann et al. (2015) found that morpholino knockdown of the clpb ortholog in zebrafish embryos resulted in dose-dependent cerebellar defects, microcephaly, and reduction of the size of the optic tectum. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>19 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIB</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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CLPB, 3-BP INV, NT1305
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<br />
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ClinVar: RCV000167537
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<div>
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<span class="mim-text-font">
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<p>In an 18-year-old girl with a mild form of 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MGCA7B; 616271), Wortmann et al. (2015) identified compound heterozygous mutations in the CLPB gene: a c.1305_1307 inversion (c.1305_1307inv, NM_030813.4) in exon 12, resulting in a Glu435_Gly436delinsAspPro substitution in the AAA+ domain, and a c.1937G-T transversion (c.1937G-T, NM_030813.4) in exon 17, resulting in a gly646-to-val (G646V; 616254.0002) substitution at a highly conserved residue in the D2 domain. The mutations, which were found by exome sequencing, segregated with the disorder in the family and were filtered against public databases and an in-house database of 5,036 exomes. The c.1937G-T variant was found in 1 of 122,598 alleles in the Exome Aggregation Consortium. Expression of the G646V mutant allele was unable to rescue morpholino knockdown of the clpb ortholog in zebrafish, suggesting that this variant has little or no residual activity. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIB</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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CLPB, GLY646VAL
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<br />
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SNP: rs759500860,
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gnomAD: rs759500860,
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ClinVar: RCV000167538
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the gly646-to-val (G646V) mutation (c.1937G-T, NM_030813.4) in the CLPB gene that was found in compound heterozygous state in a patient with 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MGCA7B; 616271) by Wortmann et al. (2015), see 616254.0001. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIB</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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CLPB, ALA591VAL
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<br />
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SNP: rs748010262,
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ClinVar: RCV000167539
|
|
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|
|
</span>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
<p>In a girl with a severe form of 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MGCA7B; 616271) resulting in death at age 3 years, 10 months, Wortmann et al. (2015) identified a homozygous c.1772C-T transition (c.1772C-T, NM_030813.4) in exon 16 of the CLPB gene, resulting in an ala591-to-val (A591V) substitution at a highly conserved residue in the D2 domain. The mutation, which was found by exome sequencing, segregated with the disorder in the family and was filtered against public databases and an in-house database of 5,036 exomes; it was not present in the Exome Aggregation Consortium database. Functional studies of the variant were not performed. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0004 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIB</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
CLPB, MET411ILE
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<br />
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SNP: rs786205137,
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gnomAD: rs786205137,
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|
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|
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ClinVar: RCV000167540, RCV001570412, RCV002515185
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs with a mild form of 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MGCA7B; 616271) and no neurologic impairment, Wortmann et al. (2015) identified compound heterozygous mutations in the CLPB gene: a c.1233G-A transition (c.1233G-A, NM_030813.4) in exon 11, resulting in a met411-to-ile (M411I) substitution at a highly conserved residue in the AAA+ domain, and a c.1850A-G transition in exon 16, resulting in a tyr617-to-cys (Y617C; 616254.0005) substitution at a highly conserved residue in the D2 domain. Expression of the M411I or Y617C alleles could not rescue morpholino knockdown of the clpb ortholog in zebrafish, suggesting that these variants have little or no residual activity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</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>.0005 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIB</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
CLPB, TYR617CYS
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|
<br />
|
|
|
|
SNP: rs786205138,
|
|
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|
|
gnomAD: rs786205138,
|
|
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|
|
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ClinVar: RCV000167541
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the tyr617-to-cys (Y617C) mutation (c.1850A-G, NM_030813.4) in the CLPB gene that was found in compound heterozygous state in a patient with 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MGCA7B; 616271) by Wortmann et al. (2015), see 616254.0004. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
|
|
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<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIB</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
CLPB, ARG408GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs144078282,
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|
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|
|
gnomAD: rs144078282,
|
|
|
|
|
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ClinVar: RCV000167542, RCV000487136, RCV002492676, RCV002516522
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 sibs with a moderately severe form of 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MGCA7B; 616271), Wortmann et al. (2015) identified compound heterozygous mutations in the CLPB gene: a c.1222A-G transition (c.1222A-G, NM_030813.4) in exon 11, resulting in an arg408-to-gly (R408G) substitution at a conserved residue in the AAA+ domain, and a c.1249C-T transition in exon 11, resulting in an arg417-to-ter (R417X; 616254.0007) substitution. The R408G mutation had a frequency of 0.011% (22 of 122,848 alleles) in the Exome Aggregation Consortium database, and the R417X mutation was found in 4 of 122,848 alleles in this database; all controls were heterozygous for the mutations. In vitro functional expression studies indicated that the R408G mutant protein had decreased ATPase activity at 26% of wildtype. Expression of the R408G mutant allele was unable to rescue morpholino knockdown of the clpb ortholog in zebrafish, suggesting that this variant has decreased residual activity. </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>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIB</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CLPB, ARG417TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs200203460,
|
|
|
|
|
|
gnomAD: rs200203460,
|
|
|
|
|
|
ClinVar: RCV000167543, RCV002285272, RCV002326924, RCV002478519
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the arg417-to-ter (R417X) mutation (c.1249C-T, NM_030813.4) in the CLPB gene that was found in compound heterozygous state in patients with 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MGCA7B; 616271) by Wortmann et al. (2015), see 616254.0006 and by Saunders et al. (2015), see 616254.0009. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIB</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CLPB, THR268MET ({dbSNP rs200032855})
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs200032855,
|
|
|
|
|
|
gnomAD: rs200032855,
|
|
|
|
|
|
ClinVar: RCV000167544, RCV003965218, RCV004800307
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 patients, including a pair of sibs, from Greenland, with 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MGCA7B; 616271), Saunders et al. (2015) identified a homozygous c.803C-T transition (rs200032855) in the CLPB gene, resulting in a thr268-to-met (T268M) substitution at a highly conserved residue in 1 of the ankyrin domains. The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in 1 of the families. The carrier frequency of the mutation in Greenlandic controls was found to be 3.3%. The variant was not found in 2,180 control samples in the U.S. or in the Exome Variant Server database, but was reported with a carrier frequency of 1 out of 662 in the ClinSeq database. Immunoblot analysis of patient fibroblasts showed absence of the CLPB protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIB</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CLPB, LYS321TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs786205139,
|
|
|
|
|
|
|
|
ClinVar: RCV000167545
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a girl with 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MGCA7B; 616271), Saunders et al. (2015) identified compound heterozygous mutations in the CLPB gene: a c.961A-T transversion (c.961A-T, NM_030813.4), resulting in a lys321-to-ter (K321X) substitution, and a c.1249C-T transition, resulting in an arg417-to-ter (R417X; 616254.0007) substitution. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and were not found in the Exome Sequencing Project database or in 2,180 in-house control samples. Immunoblot analysis of patient fibroblasts showed absence of the CLPB protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIB</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CLPB, 1-BP DEL, 1685T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs876657402,
|
|
|
|
|
|
|
|
ClinVar: RCV000173020
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 sibs, born of consanguineous Cambodian parents, with 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MGCA7B; 616271), Capo-Chichi et al. (2015) identified a homozygous 1-bp deletion (c.1685delT, NM_030813.3) in the CLPB gene, resulting in a frameshift and premature termination (Ile562ThrfsTer23). The mutation was found by a combination of homozygosity mapping and exome sequencing and was confirmed by Sanger sequencing. It segregated with the disorder in the family and was not found in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases, or in 657 in-house control exomes. The patients had a severe phenotype: at birth they did not move or breathe spontaneously and showed sustained clonic movements induced by minimal tactile stimulation; all were ventilator-dependent and died in the first week of life after removal of respiratory support. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CLPB, PRO427LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2135500838,
|
|
|
|
|
|
|
|
ClinVar: RCV002221965
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a girl (P2) who died at 19 months of age due to 3-methylglutaconic aciduria with neurologic involvement and neutropenia (MGCA7A; 619835), Wortmann et al. (2021) identified a de novo heterozygous c.1280C-T transition in the CLPB gene, resulting in a pro427-to-leu (P427L) substitution in the pore area. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro functional expression studies using a luciferase assay showed that the mutation caused only a mild reduction in ATPase activity, but severely impaired the renaturation and disaggregase activity. When mixed with wildtype CLPB, the mutation demonstrated a dominant-negative effect. The patient presented in infancy with seizures and hypotonia and met almost no developmental milestones. Neutropenia and recurrent infections were also present. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CLPB, GLY560ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2135485868,
|
|
|
|
|
|
|
|
ClinVar: RCV002221966, RCV002265063, RCV002468655
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated patients (P3 and P4) with 3-methylglutaconic aciduria with neurologic involvement and neutropenia (MGCA7A; 619835), Wortmann et al. (2021) identified a de novo heterozygous c.1678G-A transition in the CLPB gene, resulting in a gly560-to-arg (G560R) substitution near the ATP binding site. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro functional expression studies using a luciferase assay showed that the mutation caused a reduction in ATPase activity and severely impaired the renaturation and disaggregase activity of CLPB. When mixed with wildtype CLPB, the mutation demonstrated a dominant-negative effect. The patients had global developmental delay with poor speech, microcephaly, and absence seizures. Both had neutropenia and recurrent infections; P4 underwent hematopoietic stem cell transplantation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CLPB, ARG561TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1949512456,
|
|
|
|
|
|
|
|
ClinVar: RCV001089495, RCV002283523, RCV003145344
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated patients (P5 and P6) with 3-methylglutaconic aciduria with neurologic involvement and neutropenia (MGCA7A; 619835), Wortmann et al. (2021) identified a de novo heterozygous c.1681C-T transition in the CLPB gene, resulting in an arg561-to-trp (R561W) substitution. The mutation, which was found by exome or genome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed, but molecular modeling predicted that it would be deleterious and likely have a dominant-negative effect on CLPB function. The patients had variable neurologic abnormalities: P5 had severe global developmental delay, poor speech, and atypical absence seizures, whereas P6 had only mild speech delay and did not have seizures. Both had neutropenia and recurrent infections; P6 underwent hematopoietic stem cell transplant. Neither patient had cataracts. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 NEUTROPENIA, SEVERE CONGENITAL, 9, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CLPB, THR388LYS
|
|
|
|
|
|
<br />
|
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SNP: rs2135510485,
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ClinVar: RCV002221962
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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 French man (Fr-0019) with severe congenital neutropenia-9 (SCN9; 619813), Warren et al. (2022) identified a de novo heterozygous c.1163C-A transversion in the CLPB gene, resulting in a thr388-to-lys (T388K) substitution at a conserved residue in the ATP-binding domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed. This patient was an adult, but had onset of neutropenia at 1.5 years of age. He had recurrent infections and cataracts but did not have neurologic involvement or 3-methylglutaconic aciduria. </p>
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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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<h4>
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<span class="mim-font">
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<strong>.0015 NEUTROPENIA, SEVERE CONGENITAL, 9, AUTOSOMAL DOMINANT</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CLPB, ARG561GLY
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<br />
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SNP: rs1949512456,
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ClinVar: RCV002221963
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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 female patient (SCNIR-2) with severe congenital neutropenia-9 (SCN9; 619813), Warren et al. (2022) identified a heterozygous c.1681C-G transversion in the CLPB gene, resulting in an arg561-to-gly (R561G) substitution at a conserved residue in the ATP-binding domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional studies showed that the R561G mutation impaired granulocyte differentiation and mitochondrial function in a dominant-negative manner. The variant resulted in decreased CLPB ATPase and disaggregase activity. The patient had recurrent infections but did not have neurologic involvement or 3-methylglutaconic aciduria. </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 NEUTROPENIA, SEVERE CONGENITAL, 9, AUTOSOMAL DOMINANT</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CLPB, ARG561GLN
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<br />
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SNP: rs1590753221,
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ClinVar: RCV000796680, RCV001766643, RCV002221585
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 4 unrelated patients with severe congenital neutropenia-9 (SCN9; 619813), Warren et al. (2022) identified a heterozygous c.1682G-A transition in the CLPB gene, resulting in an arg561-to-gln (R561Q) substitution at a conserved residue in the ATP-binding domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. The mutation was demonstrated to occur de novo in 1 patient. In vitro functional studies showed that the mutation impaired mitochondrial respiratory function. Three patients had infections, 1 had epilepsy and learning difficulties, and another had cataracts. The one patient tested did not have 3-methylglutaconic aciduria. </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 NEUTROPENIA, SEVERE CONGENITAL, 9, AUTOSOMAL DOMINANT</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CLPB, ARG620CYS
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<br />
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SNP: rs2135484821,
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ClinVar: RCV002221964, RCV003588780
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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 unrelated patients with severe congenital neutropenia-9 (SCN9; 619813), Warren et al. (2022) identified a heterozygous c.1858C-T transition in the CLPB gene, resulting in an arg620-to-cys (R620C) substitution at a conserved residue in the ATP-binding domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional studies showed that the R620C mutation impaired granulocyte differentiation and mitochondrial function in a dominant-negative manner. The variant resulted in decreased CLPB ATPase and disaggregase activity. The patients had onset of neutropenia in infancy; 1 had recurrent infections. Neither had neurologic features or 3-methylglutaconic aciduria. </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 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIB</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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CLPB, ARG628CYS
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<br />
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SNP: rs150343959,
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gnomAD: rs150343959,
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ClinVar: RCV000258954, RCV000316112, RCV003955419, RCV004586656, RCV004975380
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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 5-year-old girl with 3-methylglutaconic aciduria and neutropenia (MGCA7B; 616271), Rivalta et al. (2022) identified compound heterozygosity for 2 mutations in the CLPB gene: a c.1882C-T transition resulting in an arg628-to-cys (R628C) substitution, and a 2-bp deletion and 2-bp insertion (c.1903_1904delinsAA) resulting in an ala635-to-lys (A635K; 616254.0019) substitution. Both mutations were located at highly conserved sites. The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, were found in the carrier state in the parents. Neither mutation was present in the ExAC, 1000 Genomes Project, and gnomAD databases. Complex V activity was reduced in fibroblasts from the patient. </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>.0019 3-@METHYLGLUTACONIC ACIDURIA, TYPE VIIB</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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CLPB, ALA635LYS
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<br />
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ClinVar: RCV002274866
|
|
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|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.1903_1904delinsAA mutation in the CLPB gene, resulting in an ala635-to-lys (A635K) substitution, that was identified in compound heterozygous state in a patient with 3-methylglutaconic aciduria and neutropenia (MGCA7B; 616271) by Rivalta et al. (2022), see 616254.0018. </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>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
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<div>
|
|
<ol>
|
|
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<li>
|
|
<p class="mim-text-font">
|
|
Capo-Chichi, J.-M., Boissel, S., Brustein, E., Pickles, S., Fallet-Bianco, C., Nassif, C., Patry, L., Dobrzeniecka, S., Liao, M., Labuda, D., Samuels, M. E., Hamdan, F. F., Vande Velde, C., Rouleau, G. A., Drapeau, P., Michaud, J. L.
|
|
<strong>Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria.</strong>
|
|
J. Med. Genet. 52: 303-311, 2015.
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[PubMed: 25650066]
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[Full Text: https://doi.org/10.1136/jmedgenet-2014-102952]
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</p>
|
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</li>
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|
<li>
|
|
<p class="mim-text-font">
|
|
Cupo, R. R., Shorter, J.
|
|
<strong>Skd3 (human ClpB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations.</strong>
|
|
eLife 9: e55279, 2020.
|
|
|
|
|
|
[PubMed: 32573439]
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[Full Text: https://doi.org/10.7554/eLife.55279]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Hartz, P. A.
|
|
<strong>Personal Communication.</strong>
|
|
Baltimore, Md. 3/3/2015.
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|
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</p>
|
|
</li>
|
|
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<li>
|
|
<p class="mim-text-font">
|
|
Haslberger, T., Zdanowicz, A., Brand, I., Kirstein, J., Turgay, K., Mogk, A., Bukau, B.
|
|
<strong>Protein disaggregation by the AAA+ chaperone ClpB involves partial threading of looped polypeptide segments.</strong>
|
|
Nature Struct. Molec. Biol. 15: 641-650, 2008.
|
|
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|
|
|
[PubMed: 18488042]
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[Full Text: https://doi.org/10.1038/nsmb.1425]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Perier, F., Radeke, C. M., Raab-Graham, K. F., Vandenberg, C. A.
|
|
<strong>Expression of a putative ATPase suppresses the growth defect of a yeast potassium transport mutant: identification of a mammalian member of the Clp/HSP104 family.</strong>
|
|
Gene 152: 157-163, 1995.
|
|
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|
|
[PubMed: 7835694]
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|
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[Full Text: https://doi.org/10.1016/0378-1119(94)00697-q]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Rivalta, B., Torraco, A., Martinelli, D., Luciani, M., Carrozzo, R., Finocchi, A.
|
|
<strong>Biallelic CLPB mutation associated with isolated neutropenia and 3-MGA-uria.</strong>
|
|
Pediat. Allergy Immun. 33: e13782, 2022.
|
|
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|
|
|
[PubMed: 35616898]
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|
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[Full Text: https://doi.org/10.1111/pai.13782]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Saunders, C., Smith, L., Wibrand, F., Ravn, K., Bross, P., Thiffault, I., Christensen, M., Atherton, A., Farrow, E., Miller, N., Kingsmore, S. F., Ostergaard, E.
|
|
<strong>CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria.</strong>
|
|
Am. J. Hum. Genet. 96: 258-265, 2015.
|
|
|
|
|
|
[PubMed: 25597511]
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|
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[Full Text: https://doi.org/10.1016/j.ajhg.2014.12.020]
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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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Warren, J. T., Cupo, R. R., Wattanasirakul, P., Spencer, D. H., Locke, A. E., Makaryan, V., Bolyard, A. A., Kelley, M. L., Kingston, N. L., Shorter, J. Bellanne-Chantelot, C., Donadieu, J., Dale, D. C., Link, D. C.
|
|
<strong>Heterozygous variants of CLPB are a cause of severe congenital neutropenia.</strong>
|
|
Blood 139: 779-791, 2022.
|
|
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|
|
|
[PubMed: 34115842]
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|
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[Full Text: https://doi.org/10.1182/blood.2021010762]
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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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Wortmann, S. B., Zietkiewicz, S., Guerrero-Castillo, S., Feichtinger, R. G., Wagner, M., Russell, J., Ellaway, C., Mroz, D., Wyszkowski, H., Weis, D., Hannibal, I., von Stulpnagel, C., and 14 others.
|
|
<strong>Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.</strong>
|
|
Genet. Med. 23: 1705-1714, 2021. Note: Erratum: Genet. Med. 23: 1789 only, 2921.
|
|
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|
|
|
[PubMed: 34140661]
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|
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[Full Text: https://doi.org/10.1038/s41436-021-01194-x]
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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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Wortmann, S. B., Zietkiewicz, S., Kousi, M., Szklarczyk, R., Haack, T. B., Gersting, S. W., Muntau, A. C., Rakovic, A., Renkema, G. H., Rodenburg, R. J., Strom, T. M., Meitinger, T., and 23 others.
|
|
<strong>CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.</strong>
|
|
Am. J. Hum. Genet. 96: 245-257, 2015.
|
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[PubMed: 25597510]
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[Full Text: https://doi.org/10.1016/j.ajhg.2014.12.013]
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</p>
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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 class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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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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Hilary J. Vernon - updated : 08/11/2022<br>Cassandra L. Kniffin - updated : 03/28/2022<br>Hilary J. Vernon - updated : 12/09/2021<br>Cassandra L. Kniffin - updated : 6/16/2015<br>Cassandra L. Kniffin - updated : 3/19/2015
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</span>
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<span class="text-nowrap mim-text-font">
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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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Patricia A. Hartz : 3/3/2015
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carol : 09/08/2022<br>carol : 08/12/2022<br>carol : 08/11/2022<br>carol : 04/14/2022<br>ckniffin : 04/13/2022<br>carol : 04/12/2022<br>carol : 04/11/2022<br>ckniffin : 03/28/2022<br>carol : 12/11/2021<br>carol : 12/10/2021<br>carol : 12/09/2021<br>carol : 12/17/2019<br>carol : 08/02/2017<br>carol : 06/18/2015<br>mcolton : 6/17/2015<br>ckniffin : 6/16/2015<br>carol : 4/7/2015<br>carol : 3/20/2015<br>mcolton : 3/20/2015<br>ckniffin : 3/19/2015<br>mgross : 3/12/2015<br>mcolton : 3/3/2015
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